Development of (6R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): A New Lead for Visceral LeishmaniasisClick to copy article linkArticle link copied!
- Andrew M. Thompson*Andrew M. Thompson*E-mail: [email protected]. Phone: (+649) 923-6145. Fax: (+649) 373-7502.Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New ZealandMore by Andrew M. Thompson
- Patrick D. O’ConnorPatrick D. O’ConnorAuckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New ZealandMore by Patrick D. O’Connor
- Andrew J. MarshallAndrew J. MarshallAuckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New ZealandMore by Andrew J. Marshall
- Adrian BlaserAdrian BlaserAuckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New ZealandMore by Adrian Blaser
- Vanessa YardleyVanessa YardleyFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, United KingdomMore by Vanessa Yardley
- Louis MaesLouis MaesLaboratory for Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumMore by Louis Maes
- Suman GuptaSuman GuptaDivision of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226031, IndiaMore by Suman Gupta
- Delphine LaunayDelphine LaunayDrugs for Neglected Diseases initiative, 15 Chemin Louis Dunant, 1202 Geneva, SwitzerlandMore by Delphine Launay
- Stephanie BraillardStephanie BraillardDrugs for Neglected Diseases initiative, 15 Chemin Louis Dunant, 1202 Geneva, SwitzerlandMore by Stephanie Braillard
- Eric ChatelainEric ChatelainDrugs for Neglected Diseases initiative, 15 Chemin Louis Dunant, 1202 Geneva, SwitzerlandMore by Eric Chatelain
- Baojie WanBaojie WanInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesMore by Baojie Wan
- Scott G. FranzblauScott G. FranzblauInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesMore by Scott G. Franzblau
- Zhenkun MaZhenkun MaGlobal Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United StatesMore by Zhenkun Ma
- Christopher B. CooperChristopher B. CooperGlobal Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United StatesMore by Christopher B. Cooper
- William A. DennyWilliam A. DennyAuckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New ZealandMore by William A. Denny
Abstract
Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads (R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure–activity relationship investigation pinpointed two compounds (R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
Introduction
Figure 1
Figure 1. Structures of antitubercular or antileishmanial agents.
Chemistry
Scheme 1
Scheme 1. a
aReagents and conditions: (i) 70–75 or 95 °C, 18–23 h; (ii) 3,4-dihydro-2H-pyran, PPTS, CH2Cl2, 20 °C, 3.5–24 h; (iii) TBAF, THF, 20 °C, 1–4.5 h, or 0–20 °C, 14 h (for 47); (iv) MsOH, MeOH, 20 °C, 1–2 h; (v) 4-OCF3BnBr or 4-BnOBnCl or 4-BnOBnI, NaH, DMF, 20 °C for 3–20 h or 0–20 °C for 0.7–2.2 h; (vi) TBSOTf, Et3N, CH2Cl2, 20 °C, 3 h; (vii) m-CPBA, CH2Cl2, 20 °C, 18 h; (viii) NaH, DMF, 20 °C for 18 h or 0–20 °C for 3.5 h; (ix) 3.3 M HCl, MeOH, 20 °C, 5 h; (x) DIPEA, toluene, 89–105 °C, 67 h.
Scheme 2
Scheme 2. a
aReagents and conditions: (i) NaH, DMF, 0–20 °C, 2.3–3.5 h; (ii) ArB(OH)2, DMF, (toluene, EtOH), 2 M Na2CO3 or 2 M KHCO3, Pd(dppf)Cl2 under N2, 70–88 °C, 2.2–4 h; (iii) NBS, PPh3, CH2Cl2, 20 °C, 3.5 h.
Scheme 3
Scheme 3. a
aReagents and conditions: (i) NaH, DMF, 0–20 °C (or 0–8 °C), 2–2.7 h; (ii) ArB(OH)2, DMF, (toluene, EtOH), 2 M Na2CO3 or 2 M KHCO3, Pd(dppf)Cl2 under N2, 80–89 °C for 2–4 h or 70 °C for 16 h; (iii) m-CPBA, Na2HPO4, CH2Cl2, 20 °C, 16 h.
Scheme 4
Scheme 4. a
aReagents and conditions: (i) NaH, DMF, 0–20 °C, 0.25–5.5 h; (ii) TBAF, THF, 20 °C, 0.5–18 h; (iii) ArI or ArBr, Et3N, DMF, CuI, Pd(PPh3)2Cl2 under N2, 70 °C for 0.25–1 h or 20 °C for 16 h; (iv) 4-OCF3PhOH, DEAD, PPh3, THF, 0–20 °C, 60 h; (v) DDQ, CH2Cl2, 20 °C, 10–28 h (then TsOH, MeOH, 20 °C, 12 h for 135); (vi) I2, PPh3, imidazole, CH2Cl2, 20 °C, 12–35 h; (vii) 128 or 133, K2CO3, DMF, 85–92 °C, 64–111 h; (viii) CuCl, DMF, 20 °C, 33–43 h; (ix) triphosgene, Et3N, THF, 0–20 °C, 1.7 h, then 142, THF, 20 °C, 3.5 h.
Scheme 5
Scheme 5. a
aReagents and conditions: (i) TsCl, pyridine, 49 °C, 17 h; (ii) NaN3, DMSO, 64 °C, 3.5 days; (iii) HS(CH2)3SH, Et3N, MeOH, 20 °C, 0.5 h, then HCl, dioxane; (iv) NaBH3CN, AcOH, DMF, 0–20 °C, 7–20 h; (v) DIPEA, DMF, 20 °C, 10–25 h; (vi) NMM or DIPEA, Bu2Sn(OAc)2, DMF, 20 °C, 4–18 h; (vii) NaH, DMF, 0–20 °C, 2.7–3.4 h; (viii) ArB(OH)2, DMF, toluene, EtOH, 2 M Na2CO3, Pd(dppf)Cl2 under N2, 84–89 °C, 1.3–3.5 h; (ix) 6-bromopyridin-3-ol, DEAD, PPh3, THF, 0–20 °C, 89 h; (x) TBAF, THF, 20 °C, 13 h; (xi) I2, PPh3, imidazole, CH2Cl2, 20 °C, 41 h; (xii) 164, K2CO3, DMF, 88 °C, 122 h; (xiii) DDQ, CH2Cl2, 20 °C, 98 h, then TsOH, MeOH, CH2Cl2, 20 °C, 10 h.
Results and Discussion

IC50a,b (μM) | MICb,c (μM) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
compd | form | R | CLogP | L. don | L. inf | T. cruzi | T. brucei | MRC-5 | MABA | LORA |
6d | Aa | OCF3 | 2.48 | 0.39 | 0.95 | 0.39 | >64 | >64 | 2.9 | 9.6 |
1e | Ab | OCF3 | 2.70 | 0.39 | 4.0 | 1.2 | >64 | >64 | 1.1 | 4.4 |
7e | Ab | OBn | 3.32 | 1.1 | 5.9 | 0.38 | >64 | >64 | 0.11 | 2.7 |
14 | Bb | OCF3 | 3.24 | 78 | >64 | 50 | >64 | >64 | 7.4 | 55 |
22 | Cb | OCF3 | 3.74 | 5.5 | 2.2 | 0.53 | 34 | >64 | 1.2 | 9.6 |
23 | Cb | OBn | 4.36 | 0.77 | 2.5 | 0.27 | 29 | >64 | 2.2 | 8.3 |
24f | Da | OCF3 | 2.78 | 0.46 | 4.0 | <0.13 | >64 | >64 | 0.63 | 16 |
25f | Db | OCF3 | 2.77 | 2.6 | 1.7 | <0.13 | >64 | >64 | 2.4 | 7.9 |
26f | Db | OBn | 3.39 | 2.0 | 2.6 | <0.13 | >64 | >64 | 3.1 | 35 |
32 | Eb | OCF3 | 2.74 | >2 | >64 | 51 | >64 | >64 | >128 | >128 |
33 | Eb | OBn | 3.36 | >2 | 16 | 2.3 | 23 | >64 | >128 | >128 |
39 | Fb | OCF3 | 2.74 | 0.63 | >64 | 4.2 | >64 | 58 | 52 | 35 |
40 | Fb | OBn | 3.36 | 0.26 | >64 | 2.3 | 3.2 | >64 | >128 | 86 |
41g | Gb | OCF3 | 2.88 | 0.03 | 0.12 | 1.2 | >64 | >64 | 1.0 | 7.5 |
42g | Gb | OBn | 3.50 | 0.05 | 0.46 | 3.0 | ||||
47 | Ha | OCF3 | 2.51 | >64 | 1.3 | >64 | >64 | |||
48e | Hb | OCF3 | 2.74 | >64 | 0.73 | 38 | >64 | >128 | >128 | |
49e | Hb | OBn | 3.36 | >64 | 0.25 | >64 | >64 | >128 | >128 | |
50e | Ib | OCF3 | 3.26 | >64 | 8.2 | 46 | >64 | >128 | >128 |
IC50 values for inhibition of the growth of L. don and L. inf (in mouse macrophages), T. cruzi (on MRC-5 cells), and T. brucei, or for cytotoxicity toward human lung fibroblasts (MRC-5 cells).
Each value (except the single-test L. don data) is the mean of at least two independent determinations. For complete results (mean ± SD), see the Supporting Information.
Minimum inhibitory concentration against M. tb, determined under aerobic (MABA) (59) or hypoxic (LORA) (60) conditions.
TB data from ref (42).
TB data from ref (40).
TB data from ref (30).
Data from ref (24).

IC50a,b (μM) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
compd | form | link | aza | R | CLogP | L. don | L. inf | T. cruzi | T. brucei | MRC-5 |
S-51c | 3.97 | 0.25 | 2.3 | 4.2 | >64 | >64 | ||||
S-52c | 2.60 | 0.40 | 5.2 | 4.9 | >64 | >64 | ||||
S-58d | A | 2′ | 4-OCF3 | 4.36 | 0.18 | 30 | 0.88 | >64 | >64 | |
R-58 | B | 2′ | 4-OCF3 | 4.36 | 0.17 | 1.1 | 0.64 | >64 | >64 | |
R-60 | B | 3′ | 4-OCF3 | 4.36 | 0.31 | 2.3 | 0.43 | 22 | 62 | |
R-62 | B | 4′ | 4-OCF3 | 4.36 | 1.2 | >64 | 0.12 | >64 | >64 | |
S-64e | A | 4′ | 2 | 4-CF3, 6-Cl | 4.46 | 0.13 | 1.5 | 3.3 | 54 | >64 |
R-64 | B | 4′ | 2 | 4-CF3, 6-Cl | 4.46 | 0.21 | 0.87 | 0.65 | 43 | 57 |
S-69 | A | 2′ | 3′ | 4-OCF3 | 3.01 | 28 | >64 | 6.7 | >64 | >64 |
R-69 | B | 2′ | 3′ | 4-OCF3 | 3.01 | 0.78 | 2.0 | 1.9 | >64 | >64 |
S-74 | A | 2′ | 6′ | 4-OCF3 | 3.04 | 4.8 | 9.1 | 6.3 | >64 | >64 |
R-74 | B | 2′ | 6′ | 4-OCF3 | 3.04 | 0.86 | 2.0 | 1.3 | 18 | >64 |
S-77e | A | 3′ | 2′ | 4-OCF3 | 3.01 | 0.12 | 1.9 | 2.0 | >64 | 47 |
R-77 | B | 3′ | 2′ | 4-OCF3 | 3.01 | 0.06 | 0.63 | 0.25 | 46 | 61 |
S-79 | A | 3′ | 2′ | 2-F, 4-OCF3 | 3.57 | 2.4 | 3.8 | >64 | >64 | |
R-79 | B | 3′ | 2′ | 2-F, 4-OCF3 | 3.57 | 0.45 | 0.56 | >64 | >64 | |
R-80 | B | 3′ | 2′ | 4-OCF2H | 2.16 | 0.51 | 0.26 | >64 | >64 | |
S-81e | A | 3′ | 2′ | 4-F | 2.10 | 0.24 | 32 | 3.9 | >64 | >64 |
R-81 | B | 3′ | 2′ | 4-F | 2.10 | 0.12 | 0.73 | 0.36 | >64 | >64 |
S-84e | A | 4′ | 2′ | 4-OCF3 | 3.04 | 0.83 | 10 | 1.4 | 43 | >64 |
R-84 | B | 4′ | 2′ | 4-OCF3 | 3.04 | (0.24)f | 0.71 | 0.043 | >64 | >64 |
S-85g | A | 4′ | 2′-Oh | 4-OCF3 | 0.94 | 9.1 | 5.4 | 11 | >64 | |
R-85 | B | 4′ | 2′-Oh | 4-OCF3 | 0.94 | 1.6 | 3.3 | >64 | >64 | |
88i | 3.08 | 41 | 0.52 | 3.5 | 14 | |||||
S-89e | A | 4′ | 2′ | 2-F, 4-OCF3 | 3.60 | 0.18 | 14 | 1.8 | >64 | >64 |
R-89 | B | 4′ | 2′ | 2-F, 4-OCF3 | 3.60 | (0.27)f | 0.62 | 0.078 | >64 | >64 |
R-90 | B | 4′ | 2′ | 3-F, 4-OCF3 | 3.02 | 3.5 | 0.025 | >64 | >64 | |
S-91e | A | 4′ | 2′ | 2-Cl, 4-OCF3 | 3.75 | 0.16 | 2.4 | 2.5 | 35 | 20 |
R-91 | B | 4′ | 2′ | 2-Cl, 4-OCF3 | 3.75 | (0.31)f | 0.57 | 0.12 | 35 | 41 |
S-92e | A | 4′ | 2′ | 4-OCF2H | 2.19 | 0.08 | 3.4 | 1.2 | 46 | >64 |
R-92 | B | 4′ | 2′ | 4-OCF2H | 2.19 | 0.86 | 0.63 | 0.078 | >64 | >64 |
R-93 | B | 4′ | 2′ | 4-CF3 | 3.17 | 6.1 | 0.072 | >64 | >64 | |
R-94 | B | 4′ | 2′ | 4-F | 2.13 | 0.18 | 2.3 | 0.16 | >64 | >64 |
S-96 | A | 4′ | 2′ | 2,4-diF | 2.67 | 1.4 | 7.8 | >64 | >64 | |
R-96 | B | 4′ | 2′ | 2,4-diF | 2.67 | (0.39)f | 1.2 | 0.23 | 55 | >64 |
R-2 | B | 4′ | 3′ | 4-OCF3 | 3.01 | 1.4 | 4.1 | 0.27 | >64 | >64 |
S-99e | A | 4′ | 3′ | 2-F, 4-OCF3 | 3.57 | 0.33 | >64 | 1.4 | >64 | >64 |
R-99 | B | 4′ | 3′ | 2-F, 4-OCF3 | 3.57 | (0.48)f | 1.1 | 0.19 | >64 | >64 |
R-100 | B | 4′ | 3′ | 3-F, 4-OCF3 | 2.99 | 12 | 0.24 | >64 | >64 | |
S-101e | A | 4′ | 3′ | 2-Cl, 4-OCF3 | 3.72 | 0.34 | 5.2 | 2.4 | 23 | 20 |
R-101 | B | 4′ | 3′ | 2-Cl, 4-OCF3 | 3.72 | 0.61 | 0.15 | 34 | 17 | |
R-102 | B | 4′ | 3′ | 4-OCF2H | 2.16 | 1.9 | 0.56 | >64 | >64 | |
R-103 | B | 4′ | 3′ | 4-CF3 | 3.14 | 11 | 0.64 | >64 | >64 | |
R-104 | B | 4′ | 3′ | 4-F | 2.10 | 1.9 | 1.7 | >64 | >64 | |
S-106 | A | 4′ | 3′ | 2,4-diF | 2.64 | 5.3 | 51 | >64 | >64 | |
R-106 | B | 4′ | 3′ | 2,4-diF | 2.64 | (0.64)f | 0.85 | 1.3 | >64 | >64 |
R-109 | B | 4′ | 2′,3′ | 4-OCF3 | 1.52 | 2.3 | 0.55 | >64 | >64 | |
R-112 | B | 4′ | 2′,5′ | 4-OCF3 | 2.19 | 2.8 | 0.27 | >64 | >64 | |
R-115 | B | 4′ | 2′,6′ | 4-OCF3 | 2.63 | 1.4 | 0.28 | >64 | >64 | |
116g | C | 4′ | 3′ | 4-OCF3 | 3.38 | 0.05 | 6.1 | <0.13 | 0.63 | >64 |
117g | C | 4′ | 3′ | 4-F | 2.46 | 0.02 | 6.3 | <0.13 | 17 | >64 |
IC50 values for inhibition of the growth of L. don and L. inf (in mouse macrophages), T. cruzi (on MRC-5 cells), and T. brucei, or for cytotoxicity toward human lung fibroblasts (MRC-5 cells).
Each value (except the single-test L. don data) is the mean of at least two independent determinations. For complete results (mean ± SD), see the Supporting Information.
From ref (49).
From ref (47).
From ref (39).
LMPH data (mean of three or four values).
From ref (30).
N-Oxide.
Racemic nitrotriazolooxazine analogue of R-84.

IC50a,b (μM) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
compd | form | X | aza | R | CLogP | L. don | L. inf | T. cruzi | T. brucei | MRC-5 |
S-1c | A | OCH2 | 4-OCF3 | 2.70 | 3.9 | 59 | 10 | >64 | >64 | |
R-1d | B | OCH2 | 4-OCF3 | 2.70 | 0.54 | 4.7 | 0.40 | >64 | >64 | |
R-118 | B | OCH2 | 3-OCF3 | 2.70 | 2.5 | 0.31 | >64 | >64 | ||
R-119 | B | OCH2 | 2-OCF3 | 2.70 | 1.4 | 0.20 | >64 | >64 | ||
S-48e | C | OCH2 | 4-OCF3 | 2.74 | >64 | 0.74 | >64 | >64 | ||
R-48e | D | OCH2 | 4-OCF3 | 2.74 | >64 | 0.54 | >64 | >64 | ||
S-7c | A | OCH2 | 4-OBn | 3.32 | 1.7 | >64 | 51 | >64 | >64 | |
R-7c | B | OCH2 | 4-OBn | 3.32 | 0.14 | 0.87 | 0.39 | >64 | >64 | |
R-122 | B | OCH2C≡C | 4-OCF3 | 3.94 | 0.33 | 0.11 | >64 | >64 | ||
R-123 | B | OCH2C≡C | 2 | 4-CF3 | 2.47 | 0.44 | 1.4 | 21 | 28 | |
R-124 | B | OCH2C≡C | 3 | 4-CF3 | 2.47 | 0.53 | 1.2 | >64 | >64 | |
S-6 | A | O | 4-OCF3 | 2.48 | 8.2 | 7.3 | >64 | >64 | ||
R-6 | B | O | 4-OCF3 | 2.48 | (0.19)f | 0.53 | 0.15 | >64 | >64 | |
R-136 | B | O | 2 | 4-CF3 | 2.33 | (0.15)f | 1.1 | 0.34 | 25 | >64 |
R-137 | B | O | 2 | 3-CF3 | 2.13 | 1.2 | 0.35 | >64 | >64 | |
R-138 | B | O | 2 | 5-CF3 | 1.73 | 0.85 | 2.4 | 23 | >64 | |
139g | 2.37 | >64 | 23 | >64 | >64 | |||||
R-24h | A | CH2O | 4-OCF3 | 2.78 | 0.13 | 0.86 | 0.33 | 57 | >64 | |
S-24h | B | CH2O | 4-OCF3 | 2.78 | 0.11 | 2.2 | <0.13 | >64 | >64 | |
S-140c | A | OCONH | 4-OCF3 | 2.11 | 3.3 | 7.3 | 6.8 | >64 | >64 | |
R-140 | B | OCONH | 4-OCF3 | 2.11 | 2.1 | 3.5 | 48 | >64 | ||
R-141 | B | OCONH | 2-OCF3 | 2.51 | 6.4 | 1.5 | >64 | >64 | ||
S-143i | A | OCOpipj | 4-OCF3 | 1.56 | 0.88 | 14 | 2.1 | >64 | >64 | |
R-143 | B | OCOpipj | 4-OCF3 | 1.56 | 17 | 0.27 | >64 | >64 | ||
S-147i | A | NHCH2 | 4-OCF3 | 2.26 | 6.1 | >64 | 11 | 3.6 | >64 | |
R-147 | B | NHCH2 | 4-OCF3 | 2.26 | 12 | 1.8 | 3.3 | >64 | ||
R-148 | B | NHCH2 | 3-OCF3 | 2.26 | 6.9 | <0.13 | 2.0 | >64 | ||
R-149 | B | NHCH2 | 2-OCF3 | 2.26 | 8.6 | 0.15 | 2.1 | >64 | ||
S-150c | A | NHCO | 4-OCF3 | 1.75 | 6.0 | 19 | >64 | >64 | ||
R-150 | B | NHCO | 4-OCF3 | 1.75 | 57 | 2.5 | >64 | >64 | ||
S-151i | A | NHCO | 3-OCF3 | 1.22 | 0.25 | 5.6 | 25 | >64 | >64 | |
R-151 | B | NHCO | 3-OCF3 | 1.22 | 12 | 0.87 | >64 | >64 | ||
S-152i | A | NHCO | 2-OCF3 | 1.40 | 5.8 | 53 | >64 | >64 | ||
R-152 | B | NHCO | 2-OCF3 | 1.40 | 18 | 0.96 | >64 | >64 | ||
S-154c | A | NHCONH | 4-OCF3 | 1.47 | 10 | 7.5 | 22 | >64 | ||
R-154 | B | NHCONH | 4-OCF3 | 1.47 | >64 | 2.3 | 19 | >64 | ||
S-155 | A | NHCONH | 2-OCF3 | 1.73 | 0.23 | 6.8 | 3.1 | 4.9 | 16 | |
R-155 | B | NHCONH | 2-OCF3 | 1.73 | 55 | 1.3 | >64 | 48 |
IC50 values for inhibition of the growth of L. don and L. inf (in mouse macrophages), T. cruzi (on MRC-5 cells), and T. brucei, or for cytotoxicity toward human lung fibroblasts (MRC-5 cells).
Each value (except the single-test L. don data) is the mean of at least two independent determinations. For complete results (mean ± SD), see the Supporting Information.
From ref (32).
From ref (38).
From ref (40).
LMPH data (mean of three values).
Racemic nitrotriazolooxazine analogue of R-136.
From ref (30).
From ref (48).
N-Piperazine.

IC50a,b (μM) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
compd | form | link | aza | R | CLogP | L. don | L. inf | T. cruzi | T. brucei | MRC-5 |
R-157 | B | 3′ | 2′ | 4-OCF3 | 3.27 | 0.31 | <0.13 | 7.5 | >64 | |
R-158 | B | 3′ | 2′ | 4-F | 2.35 | 0.41 | 0.30 | >64 | >64 | |
R-160 | B | 4′ | 2′ | 4-OCF3 | 3.35 | 0.64 | 0.11 | 9.3 | 42 | |
R-161 | B | 4′ | 2′ | 4-F | 2.43 | 0.43 | <0.13 | 10 | >64 | |
R-168 | B | 4′ | 3′ | 4-OCF3 | 3.07 | 0.13 | 0.15 | >64 | >64 | |
R-169 | B | 4′ | 3′ | 4-F | 2.15 | 0.20 | 0.40 | >64 | >64 | |
S-171c | A | 3′ | 4′,6′ | 4-OCF3 | 2.79 | 0.10 | 23 | 2.0 | >64 | 47 |
R-171 | B | 3′ | 4′,6′ | 4-OCF3 | 2.79 | 21 | <0.13 | >64 | >64 | |
R-172 | B | 3′ | 4′,6′ | 4-F | 1.87 | 49 | 0.68 | >64 | >64 | |
R-174 | B | 4′ | 2′,6′ | 4-OCF3 | 2.71 | 0.65 | 0.48 | >64 | >64 | |
R-175 | B | 4′ | 2′,6′ | 4-F | 1.80 | 0.83 | 0.64 | >64 | >64 |
IC50 values for inhibition of the growth of L. don and L. inf (in mouse macrophages), T. cruzi (on MRC-5 cells), and T. brucei, or for cytotoxicity toward human lung fibroblasts (MRC-5 cells).
Each value (except the single-test L. don data) is the mean of at least two independent determinations. For complete results (mean ± SD), see the Supporting Information.
From ref (42).
Figure 2
Figure 2. Schematic diagram of the two lead optimization approaches (A and B) employed.
Scaffold Modification: Initial Hits
aqueous solubilitya (μg/mL) | microsomal stabilityb [% remaining at 1 (0.5) h] | in vivo efficacy against L. don (% inhibition at dose in mg/kg)c | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
compd | pH 7 | pH 1 | H | M | Ham | 50 | 25 | 12.5 | 6.25 | ED50d |
S-1 | 19 | 82 | 94 | |||||||
R-1 | 18 | 92 | 86 | 31 | 50 | |||||
R-6 | 12 | 81 | 79 | 19 | >99 | >99 | 81 | 42 | 7.5 | |
22 | 6.0 | 92 | 72 | |||||||
24 | 3.9 | (78) | (88) | (70) | 31 | |||||
S-51 | 1.6 | (78) | (75) | (43) | ||||||
S-52 | 2.7 | 87 | 67 | |||||||
R-69 | 0.51 | 263 | 35 | 44 | 3.0 | 20 | ||||
R-74 | 78 | 7350 | 8.0 | 0.2 | 0.1 | |||||
S-77 | 3.0 | 211 | (75) | (78) | (31) | 44 | ||||
R-77 | 1.5 | 167 | (68) | (68) | (31) | 52 | ||||
S-81 | 15 | 439 | (96) | (74) | (15) | 35 | ||||
R-81 | 6.0 | 691 | (79) | (68) | (0) | |||||
R-84 | 3.0 | 1040 | 27 (66) | 36 (70) | 10 (61) | >99 | 76 | 42 | 36 | 12 |
S-89 | 1.4 | 479 | (88) | (84) | (69) | 45 | ||||
R-89 | 3.4 | 503 | 27 (75) | 40 (79) | 10 (69) | >99 | 72 | 48 | 17 | 14 |
S-91 | 1.4 | 384 | (73) | (100) | (75) | 69 | ||||
R-91 | 2.9 | 12 | 16 (65) | 27 (81) | 5.8 (57) | >99 | 38 | 6 | 28 | |
S-92 | 4.0 | 1780 | (92) | (88) | (59) | 37 | ||||
R-92 | 5.7 | 2050 | 49 (71) | 56 (86) | 11 (45) | 94 | 54 | 20 | 20 | |
R-94 | 11 | 4600 | 58 (85) | 66 (77) | 10 (37) | 83 | ||||
R-96 | 40 | 7140 | 59 | 57 | 5.2 | 97 | 48 | 29 | 17 | 28 |
R-99 | 2.9 | 364 | 37 | 41 | 9.2 | 97 | 64 | 31 | 8 | 19 |
R-102 | 2.1 | 857 | 58 | 56 | 7.9 | |||||
R-106 | 3.9 | 925 | 58 | 67 | 10 | 91 | ||||
116 | 0.13 | 32 | (88) | (96) | (88) | 49 | ||||
117 | 0.27 | 132 | (85) | (66) | (64) | 23 | ||||
R-136 | 110 | 90 | 92 | 48 | >99 | 30 | ||||
R-147 | 84 | 38100 | 84 | 61 | 7.5 | 12 | ||||
S-151 | 132 | (100) | (83) | (81) | 72 | |||||
R-151 | 85 | 87 | 86 | 59 | 5 | |||||
S-155 | 22 | (74) | (43) | (64) | ||||||
R-168 | 0.36 | 36 | 40 | 35 | >99 | >99 | <3.1 | |||
R-169 | 1.2 | 325 | 73 | 59 | >99 | 72 |
Kinetic solubility in water (pH 7) or 0.1 M HCl (pH 1) at 20 °C, determined by HPLC (see Method A in Experimental Section).
Pooled human (H), CD-1 mouse (M), or hamster (Ham) liver microsomes; data in parentheses are the percentage parent compound remaining following a 30 min incubation.
Dosing was done orally, once daily for 5 days consecutively; data are the mean percentage reduction of parasite burden in the liver.
Dose in milligrams per kilogram required to achieve a mean 50% reduction in parasite burden.
intravenous (1–2 mg/kg)a | oral (25–50 mg/kg)a | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
compd | C0 (μg/mL) | CL (mL/min/kg) | Vdss (L/kg) | t1/2 (h) | AUClastb (μg·h/mL) | Cmax (μg/mL) | Tmax (h) | t1/2 (h) | AUClastb (μg·h/mL) | Fc (%) |
Mice | ||||||||||
R-6 | 21 | 5.3 | 7.8 | 272 | ||||||
24 | 0.34 | 13 | 2.5 | 2.0 | 1.25 | 1.5 | 1.0 | 15.7 | 50 | |
R-84 | 16 | 4.7 | 9.4 | 211 | ||||||
R-89 | 32 | 3.3 | 6.1 | 265 | ||||||
116 | 0.75 | 1.2 | 1.9 | 20 | 11.7 | 0.87 | 10 | 32.2 | 11 | |
117 | 0.44 | 5.2 | 1.8 | 2.7 | 3.18 | 0.84 | 8.0 | 12.0 | 15 | |
R-136 | 96 | 3.1 | 30 | 1777 | ||||||
Rats | ||||||||||
R-6 | 0.54 | 11 | 2.7 | 3.0 | 1.51 | 5.2 | 6.7 | -d | 80.6 | 100 |
R-136 | 0.84 | 6.1 | 1.5 | 2.7 | 2.47 | 18 | 2.7 | 3.5 | 164 | 100 |
Hamsters | ||||||||||
R-6 | 0.66 | 81 | 6.5 | 1.4 | 0.42 | 2.1 | 3.3 | 2.2 | 11.2 | 100 |
R-84 | 0.65 | 23 | 8.2 | 6.3 | 1.30 | 5.7 | 3.0 | 5.8 | 62.7 | 100 |
R-89 | 0.94 | 18 | 4.2 | 3.9 | 1.89 | 4.2 | 2.0 | 3.9 | 26.7 | 74 |
R-96 | 0.93 | 63 | 4.0 | 0.83 | 0.48 | 1.9 | 0.75 | 0.83 | 3.95 | 37 |
R-99 | 1.1 | 8.8 | 3.2 | 5.3 | 3.69 | 4.7 | 3.3 | 5.8 | 46.5 | 64 |
R-106 | 0.52 | 59 | 5.4 | 1.4 | 0.71 | 1.1 | 1.7 | 17 | 3.40 | 21 |
R-136 | 12 | 3.3 | 3.1 | 71.0 |
The intravenous dose was 1 mg/kg for mice and rats and 2 mg/kg for hamsters. The oral dose was 25 mg/kg for 24, 116, and 117, 50 mg/kg for R-106 and R-136, and 40 mg/kg for the other compounds.
Area under the curve calculated to the last time point (24 or 48 h).
Oral bioavailability, determined using dose-normalized AUClast values.
Not calculable.
Library Screening and Hit to Lead Assessments for VL
Figure 3
Figure 3. Potencies of 17 selected phenotypic screening hits (30,39,42,46−49) against L. don (percent inhibition data from IPK, IC50s from CDRI).
SAR of 6-Substituted 2-Nitroimidazooxazines for VL
Additional Assessments To Determine the Best VL Lead
Figure 4
Figure 4. Comparative in vivo efficacy in the L. don mouse model: (a) 25 mg/kg and (b) 6.25 mg/kg. All compounds except racemates 24, 116, and 117 are the 6R form.
% inhibition in target organsb | ||||
---|---|---|---|---|
compd | dosea (mg/kg) | liver | spleen | bone marrow |
MIL | 40 | 99.0 | 99.5 | 96.8 |
R-6 | 50 | 100 | 100 | 99.8 |
25 | 98.4 | 99.2 | 97.0 | |
12.5 | 53.5 | 47.6 | 37.3 | |
R-84 | 50 | 100 | 99.9 | 99.9 |
25 | 98.1 | 98.4 | 88.3 | |
12.5 | 69.6 | 55.7 | 33.6 | |
R-89 | 50 | 99.9 | 99.9 | 98.9 |
25 | 99.1 | 93.7 | 81.3 | |
12.5 | 83.5 | 70.6 | 50.4 | |
R-96 | 50 | 73.0 | 55.1 | 55.7 |
R-99 | 50 | 97.7 | 97.5 | 86.0 |
R-106 | 50 | 55.7 | 17.6 | 45.0 |
R-136 | 50 | 100 | 100 | 99.9 |
25 | 99.5 | 97.3 | 97.7 | |
12.5 | 44.4 | 43.0 | 53.0 |
All test compounds were dosed orally, twice daily for 5 days consecutively; miltefosine (MIL) was dosed once daily for the same period.
Data are the mean percentage reductions in parasite burden in target organs.
Figure 5
Figure 5. Comparative in vivo efficacy in the L. inf hamster model. All compounds are the 6R form.
Further Appraisal of VL lead R-6
property | 4a | R-6 |
---|---|---|
molecular weight (Da) | 359.3 | 345.2 |
LogD (measured) | 3.10 | 2.59 |
thermodynamic solubility (μM) at pH 7.4 | 2.8 | 23 |
permeability, Papp (×10–6 cm/s) A to B/B to A | 22.6/24.7b | 32.4/18.9c |
plasma protein binding (%) | ||
mouse | 96.2 | 86.7 |
rat | 93.2 | 82.1 |
hamster | 92.4 | 87.2 |
human | 93.9 | 85.2 |
mutagenic effect (Ames test) | no | nod |
hERG IC50 (μM) | 10.5 | >30 |
CYP3A4 IC50 (μM) | >25 | >40 |
MABA MIC (μM) | 0.046 | 31e |
LORA MIC (μM) | 5.9 | >128 |
IC50 (μM)a | |||||
---|---|---|---|---|---|
strain (origin) | R-6 | SSGb | Amp Bc | MILd | PMe |
VL Strains | |||||
L. don MHOM/IN/80/DD8 (India) | 0.22 | 54.3 | 0.02 | 2.50 | >30 |
L. don MHOM/ET/67/HU3 (Ethiopia) | 0.33 | NT | 0.05 | 2.05 | NT |
L. inf MHOM/MA/67/ITMAP263 (Morocco) | 0.51 | NT | NT | 2.30 | 136 |
L. don MHOM/SD/62/1SCL2D (Sudan) | 2.16 | NT | NT | NT | NT |
L. inf MHOM/FR/96/LEM3323 C14 MIL4 (France)f | 0.59 | NT | NT | >20 | 78.5 |
VL Clinical Isolates | |||||
L. don BHU1 (India)g | 1.34 | >150 | 0.20 | 3.80 | >30 |
L. don SUKA001 (Sudan) | 0.57 | 29.9 | 0.05 | 2.13 | >30 |
L. don GR265 (Ethiopia) | 0.19 | 14.5 | 0.05 | 4.60 | >30 |
L. inf LEM5695 (Algeria; dog) | 1.77 | NT | NT | 1.86 | 165 |
L. inf MCAN/BR/2002/BH400 (Brazil; dog) | 1.23 | NT | NT | 1.11 | 64.1 |
L. inf L3034 (Paraguay; HIV patient) | 0.75 | NT | NT | 1.25 | 87.7 |
L. inf LEM5159 (France; HIV patient)f,h | 5.41 | NT | NT | >20 | 64.9 |
L. inf LEM3323 (France; HIV patient)h | 2.22 | NT | NT | 0.74 | 142 |
CL Strains | |||||
Leishmania aethiopica MHOM/ET/84/KH (Ethiopia) | 3.17 | NT | 0.11 | 36.1 | NT |
Leishmania amazonensis MPRO/BR/72/M1841 (Brazil)i | 4.68 | NT | 0.13 | 15.0 | NT |
Leishmania major MHOM/SA/85/JISH118 (Saudi Arabia) | 2.34 | NT | 0.05 | 22.3 | NT |
Leishmania mexicana MNYC/BZ/62/M379 (Belize) | 1.17 | NT | 0.08 | 6.55 | NT |
Leishmania panamensis MHOM/PA/67/Boynton (Panama) | 0.34 | NT | 0.07 | 21.3 | NT |
Leishmania tropica Anwari (Syrian clinical isolate) | 1.57 | >100 | 0.11 | 8.22 | NT |
Sodium stibogluconate (IC50 in micrograms per milliliter).
Amphotericin B.
Miltefosine.
Paromomycin.
Resistant to miltefosine.
Resistant to sodium stibogluconate.
Failed amphotericin B treatment.
DsRed2 transgenic strain.
SAR of 6-Substituted 2-Nitroimidazo(or 2-Nitrotriazolo)oxazines for Chagas Disease
Conclusions
Experimental Section
Compounds of Table 1
Synthesis of 14 (Scheme 1A)
Procedure A: 1-[(tert-Butyldimethylsilyl)oxy]-3-(2,4-dinitro-1H-imidazol-1-yl)-2-methylpropan-2-ol (10)
Procedure B: 1-{3-[(tert-Butyldimethylsilyl)oxy]-2-methyl-2-[(tetrahydro-2H-pyran-2-yl)oxy]propyl}-2,4-dinitro-1H-imidazole (11)
Procedure C: 6-Methyl-2-nitro-6-[(tetrahydro-2H-pyran-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (12)
Procedure D: 6-Methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol (13)
Procedure E: 6-Methyl-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (14)
Synthesis of 39 and 41 (Scheme 1D)
2-Bromo-4-nitro-1-{3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[(triisopropylsilyl)oxy]butyl}-1H-imidazole (35)
4-(2-Bromo-4-nitro-1H-imidazol-1-yl)-2-[(tetrahydro-2H-pyran-2-yl)oxy]butan-1-ol (36)
Procedure F: 2-Nitro-7-[(tetrahydro-2H-pyran-2-yl)oxy]-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepine (37)
2-Nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepin-7-ol (38)
Procedure G: 2-Nitro-7-{[4-(trifluoromethoxy)benzyl]oxy}-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepine (39) and 2-Nitro-7-({[4-(trifluoromethoxy)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (41)
Compounds of Table 2
Synthesis of R-58 (Scheme 2A)
(6R)-6-[(2-Iodobenzyl)oxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (57)
Procedure H: (6R)-2-Nitro-6-{[4′-(trifluoromethoxy)(1,1′-biphenyl)-2-yl]methoxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (R-58)
Synthesis of R-69 (Scheme 2B)
(6R)-6-[(2-Bromopyridin-3-yl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (68)
Procedure I: (6R)-2-Nitro-6-({2-[4-(trifluoromethoxy)phenyl]pyridin-3-yl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (R-69)
Compounds of Table 3
Synthesis of R-122 (Scheme 4A)
(6R)-2-Nitro-6-[(prop-2-yn-1-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (121)
Procedure J: (6R)-2-Nitro-6-({3-[4-(trifluoromethoxy)phenyl]prop-2-yn-1-yl}oxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (R-122)
Synthesis of R-136 (Scheme 4D)
(6R)-2-Nitro-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (R-136)
Synthesis of R-140 (Scheme 4E)
Procedure K: (6R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl [4-(Trifluoromethoxy)phenyl]carbamate (R-140)
Syntheses of R-147 and R-151 (Scheme 5A)
(6S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 4-Methylbenzene-1-sulfonate (144)
(6R)-6-Azido-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (145)
(6R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine Hydrochloride (146)
Procedure L: (6R)-2-Nitro-N-[4-(trifluoromethoxy)benzyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine (R-147)
Procedure M: N-[(6R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl]-3-(trifluoromethoxy)benzamide (R-151)
Synthesis of R-155 (Scheme 5B)
Procedure N: N-[(6R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl]-N′-[2-(trifluoromethoxy)phenyl]urea (R-155)
Compounds of Table 4
Synthesis of R-168 (Scheme 5D)
(2R)-2-[(6-Bromopyridin-3-yl)oxy]-3-[(4-methoxybenzyl)oxy]propan-1-ol (163)
Procedure O: 2-Bromo-5-({(2S)-1-iodo-3-[(4-methoxybenzyl)oxy]propan-2-yl}oxy)pyridine (164)
2-Bromo-5-({(2R)-1-(2-bromo-4-nitro-1H-imidazol-1-yl)-3-[(4-methoxybenzyl)oxy]propan-2-yl}oxy)pyridine (165)
(2R)-3-(2-Bromo-4-nitro-1H-imidazol-1-yl)-2-[(6-bromopyridin-3-yl)oxy]propan-1-ol (166)
(6R)-6-[(6-Bromopyridin-3-yl)oxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (167)
(6R)-2-Nitro-6-({6-[4-(trifluoromethoxy)phenyl]pyridin-3-yl}oxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (R-168)
Minimum Inhibitory Concentration Assays (MABA and LORA)
In Vitro Parasite Growth Inhibition Assays
Solubility Determinations
Method A
Method B
Microsomal Stability Assays
Distribution Coefficient
Permeability Assay
Plasma Protein Binding Assays
Ames Test
hERG Assay
CYP3A4 Inhibition Assay
In Vivo Experiments
Acute VL Infection Assay (mouse model, LSHTM)
Chronic VL Infection Assay (hamster model, LMPH)
Mouse Pharmacokinetics
Rat and Hamster Pharmacokinetics
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b01581.
Additional biological assay data, synthetic schemes, graphs of PK data, experimental procedures and characterizations for compounds, combustion analytical data, and representative NMR spectra (PDF)
Molecular formula strings spreadsheet (CSV)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgments
The authors thank the Global Alliance for TB Drug Development (TB Alliance) and the Drugs for Neglected Diseases initiative (DNDi) for financial support through collaborative research agreements. For this project, the TB Alliance acknowledges grant funding from the Bill & Melinda Gates Foundation (OPP40827), while DNDi received financial support from the following donors: Department for International Development (DFID), of the U.K.; Federal Ministry of Education and Research (BMBF), through KfW Germany; Directorate-General for International Cooperation (DGIS), of The Netherlands; Bill & Melinda Gates Foundation (grant OPP48262); and Médecins Sans Frontières (MSF) International. The donors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors also thank Drs. Jakir Pinjari and Rao Mukkavilli (Advinus Therapeutics Ltd., Bangalore, India) for some PK data, Sisira Kumara (ACSRC) for the kinetic solubility measurements, and Dr. Beatrice Bonnet (DNDi) for providing some new data and comments on the large scale synthesis of the lead.
VL | visceral leishmaniasis |
TPP | target product profile |
M. tb | M. tuberculosis |
TB | tuberculosis |
L. inf | L. infantum |
L. don | L. donovani |
HLM | human liver microsomes |
PK | pharmacokinetic |
DMPK | drug metabolism and pharmacokinetic |
MLM | mouse liver microsomes |
PD | pharmacodynamic |
HREIMS | high-resolution electron impact mass spectrometry |
HRCIMS | high-resolution chemical ionization mass spectrometry |
HRFABMS | high-resolution fast atom bombardment mass spectrometry |
HRESIMS | high-resolution electrospray ionization mass spectrometry |
APCI MS | atmospheric-pressure chemical ionization mass spectrometry |
DIPEA | N,N-diisopropylethylamine |
NMM | N-methylmorpholine |
CMC | carboxymethylcellulose |
MIL | miltefosine |
SD | standard deviation |
References
This article references 62 other publications.
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- 4Al-Salem, W.; Herricks, J. R.; Hotez, P. J. A review of visceral leishmaniasis during the conflict in South Sudan and the consequences for East African countries. Parasites Vectors 2016, 9, 460, DOI: 10.1186/s13071-016-1743-7Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szjtlGqtQ%253D%253D&md5=c3d84d763f71e186e9843b829492c45aA review of visceral leishmaniasis during the conflict in South Sudan and the consequences for East African countriesAl-Salem Waleed; Herricks Jennifer R; Hotez Peter J; Herricks Jennifer R; Hotez Peter J; Hotez Peter J; Hotez Peter JParasites & vectors (2016), 9 (), 460 ISSN:.BACKGROUND: Visceral leishmaniasis (VL), caused predominantly by Leishmania donovani and transmitted by both Phlebotomus orientalis and Phlebotomus martini, is highly endemic in East Africa where approximately 30 thousands VL cases are reported annually. The largest numbers of cases are found in Sudan - where Phlebotomus orientalis proliferate in Acacia forests especially on Sudan's eastern border with Ethiopia, followed by South Sudan, Ethiopia, Somalia, Kenya and Uganda. Long-standing civil war and unrest is a dominant determinant of VL in East African countries. Here we attempt to identify the correlation between VL epidemics and civil unrest. OBJECTIVE AND METHODOLOGY: In this review, literature published between 1955 and 2016 have been gathered from MSF, UNICEF, OCHA, UNHCR, PubMed and Google Scholar to analyse the correlation between conflict and human suffering from VL, which is especially apparent in South Sudan. FINDINGS: Waves of forced migration as a consequence of civil wars between 1983 and 2005 have resulted in massive and lethal epidemics in southern Sudan. Following a comprehensive peace agreement, but especially with increased allocation of resources for disease treatment and prevention in 2011, cases of VL declined reaching the lowest levels after South Sudan declared independence. However, in the latest epidemic that began in 2014 after the onset of a civil war in South Sudan, more than 1.5 million displaced refugees have migrated internally to states highly endemic for VL, while 800,000 have fled to neighboring countries. CONCLUSION: We find a strong relationship between civil unrest and VL epidemics which tend to occur among immunologically naive migrants entering VL-endemic areas and when Leishmania-infected individuals migrate to new areas and establish additional foci of disease. Further complicating factors in East Africa's VL epidemics include severe lack of access to diagnosis and treatment, HIV/AIDS co-infection, food insecurity and malnutrition. Moreover, cases of post-kala-azar dermal leishmaniasis (PKDL) can serve as important reservoirs of anthroponotic Leishmania parasites.
- 5Sunyoto, T.; Potet, J.; Boelaert, M. Visceral leishmaniasis in Somalia: A review of epidemiology and access to care. PLoS Neglected Trop. Dis. 2017, 11 (3), e0005231, DOI: 10.1371/journal.pntd.0005231Google ScholarThere is no corresponding record for this reference.
- 6Kimutai, R.; Musa, A. M.; Njoroge, S.; Omollo, R.; Alves, F.; Hailu, A.; Khalil, E. A. G.; Diro, E.; Soipei, P.; Musa, B.; Salman, K.; Ritmeijer, K.; Chappuis, F.; Rashid, J.; Mohammed, R.; Jameneh, A.; Makonnen, E.; Olobo, J.; Okello, L.; Sagaki, P.; Strub, N.; Ellis, S.; Alvar, J.; Balasegaram, M.; Alirol, E.; Wasunna, M. Safety and effectiveness of sodium stibogluconate and paromomycin combination for the treatment of visceral leishmaniasis in Eastern Africa: Results from a pharmacovigilance programme. Clin. Drug Invest. 2017, 37, 259– 272, DOI: 10.1007/s40261-016-0481-0Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnslChug%253D%253D&md5=f31bfd47e626755fc4fad5b705b1a237Safety and Effectiveness of Sodium Stibogluconate and Paromomycin Combination for the Treatment of Visceral Leishmaniasis in Eastern Africa: Results from a Pharmacovigilance ProgrammeKimutai, Robert; Musa, Ahmed M.; Njoroge, Simon; Omollo, Raymond; Alves, Fabiana; Hailu, Asrat; Khalil, Eltahir A. G.; Diro, Ermias; Soipei, Peninah; Musa, Brima; Salman, Khalid; Ritmeijer, Koert; Chappuis, Francois; Rashid, Juma; Mohammed, Rezika; Jameneh, Asfaw; Makonnen, Eyasu; Olobo, Joseph; Okello, Lawrence; Sagaki, Patrick; Strub, Nathalie; Ellis, Sally; Alvar, Jorge; Balasegaram, Manica; Alirol, Emilie; Wasunna, MoniqueClinical Drug Investigation (2017), 37 (3), 259-272CODEN: CDINFR; ISSN:1173-2563. (Springer International Publishing AG)Introduction: In 2010, WHO recommended a new first-line treatment for visceral leishmaniasis (VL) in Eastern Africa. The new treatment, a combination of i.v. (IV) or i.m. (IM) sodium stibogluconate (SSG) and IM paromomycin (PM) was an improvement over SSG monotherapy, the previous first-line VL treatment in the region. To monitor the new treatment's safety and effectiveness in routine clin. practice a pharmacovigilance (PV) program was developed. Methods: A prospective PV cohort was developed. Regulatory approval was obtained in Sudan, Kenya, Uganda and Ethiopia. Twelve sentinel sites sponsored by the Ministries of Health, Me´decins Sans Frontie´res (MSF) and Drugs for Neglected Diseases initiative (DNDi) participated. VL patients treated using the new treatment were consented and included in a common registry that collected demographics, baseline clin. characteristics, adverse events, serious adverse events and treatment outcomes. Six-monthly periodic safety update reports (PSUR) were prepd. and reviewed by a PV steering committee. Results: Overall 3126 patients were enrolled: 1962 (62.7%) from Sudan, 652 (20.9%) from Kenya, 322 (10.3%) from Ethiopia and 190 (6.1%) from Uganda. Patients were mostly male children (68.1%, median age 11 years) with primary VL (97.8%). SSG-PM initial cure rate was 95.1%; no geog. differences were noted. HIV/VL co-infected patients and patients older than 50 years had initial cure rates of 56 and 81.4%, resp., while 1063 (34%) patients had at least one adverse event (AE) during treatment and 1.92% (n = 60) had a serious adverse event (SAE) with a mortality of 1.0% (n = 32). There were no serious unexpected adverse drug reactions. Conclusions: This first regional PV program in VL supports SSG-PM combination as first-line treatment for primary VL in Eastern Africa. SSG-PM was effective and safe except in HIV/VL co-infected or older patients. Active PV surveillance of targeted safety, effectiveness and key VL outcomes such us VL relapse, PKDL and HIV/VL co-infection should continue and PV data integrated to national and WHO PV databases.
- 7Wasunna, M.; Njenga, S.; Balasegaram, M.; Alexander, N.; Omollo, R.; Edwards, T.; Dorlo, T. P. C.; Musa, B.; Ali, M. H. S.; Elamin, M. Y.; Kirigi, G.; Juma, R.; Kip, A. E.; Schoone, G. J.; Hailu, A.; Olobo, J.; Ellis, S.; Kimutai, R.; Wells, S.; Khalil, E. A. G.; Strub Wourgaft, N.; Alves, F.; Musa, A. Efficacy and safety of AmBisome in combination with sodium stibogluconate or miltefosine and miltefosine monotherapy for African visceral leishmaniasis: Phase II randomized trial. PLoS Neglected Trop. Dis. 2016, 10 (9), e0004880, DOI: 10.1371/journal.pntd.0004880Google ScholarThere is no corresponding record for this reference.
- 8Fexinidazole/Miltefosine Combination (VL). DNDi, 2016. https://www.dndi.org/diseases-projects/portfolio/completed-projects/fexinidazole-vl/ (accessed June 22, 2017).Google ScholarThere is no corresponding record for this reference.
- 9Singh, N.; Mishra, B. B.; Bajpai, S.; Singh, R. K.; Tiwari, V. K. Natural product based leads to fight against leishmaniasis. Bioorg. Med. Chem. 2014, 22, 18– 45, DOI: 10.1016/j.bmc.2013.11.048Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOgtrjL&md5=d3f82091638d595b388c6f65080ce8d9Natural product based leads to fight against leishmaniasisSingh, Nisha; Mishra, Bhuwan B.; Bajpai, Surabhi; Singh, Rakesh K.; Tiwari, Vinod K.Bioorganic & Medicinal Chemistry (2014), 22 (1), 18-45CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A review. The growing incidence of parasitic resistance against generic pentavalent antimonials, specifically for visceral disease in Indian subcontinent, is a serious issue in Leishmania control. Notwithstanding the two treatment alternatives, that is amphotericin B and miltefosine are being effectively used but their high cost and therapeutic complications limit their use in endemic areas. In the absence of a vaccine candidate, identification, and characterization of novel drugs and targets is a major requirement of leishmanial research. This review describes current drug regimens, putative drug targets, numerous natural products that have shown promising antileishmanial activity along with some key issues and strategies for future research to control leishmaniasis worldwide.
- 10Target Product Profile for Visceral Leishmaniasis. DNDi, 2017. https://www.dndi.org/diseases-projects/leishmaniasis/tpp-vl/ (accessed December 7, 2017).Google ScholarThere is no corresponding record for this reference.
- 11Nagle, A. S.; Khare, S.; Kumar, A. B.; Supek, F.; Buchynskyy, A.; Mathison, C. J. N.; Chennamaneni, N. K.; Pendem, N.; Buckner, F. S.; Gelb, M. H.; Molteni, V. Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Chem. Rev. 2014, 114, 11305– 11347, DOI: 10.1021/cr500365fGoogle Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVGls7jM&md5=560ffc9063472316ad1706e4a4caa1dfRecent Developments in Drug Discovery for Leishmaniasis and Human African TrypanosomiasisNagle, Advait S.; Khare, Shilpi; Kumar, Arun Babu; Supek, Frantisek; Buchynskyy, Andriy; Mathison, Casey J. N.; Chennamaneni, Naveen Kumar; Pendem, Nagendar; Buckner, Frederick S.; Gelb, Michael H.; Molteni, ValentinaChemical Reviews (Washington, DC, United States) (2014), 114 (22), 11305-11347CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Leishmaniasis is a parasitic disease that presents four main clin. syndromes: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), visceral leishmaniasis/kala azar(VL), and post kala azar dermal leishmaniasis (PKDL). Causative Leishmania are protozoan parasites that are transmitted among mammalian hosts by phlebotomine sandiflies. In spite of the high prevalence, currently available treatments for leishmaniasis are inadequate. Several new VL treatment shave emerged during the past 10-15 years, but each has serious short comings. These include paromomycin (injectable, long treatment, region-dependente efficacy), miltefosine (cost, teratogenicity, long treatment), and liposomal amphotericin B (cost, hospitalization, region-dependent efficacy). An addnl. challenge is represented by patients with HIV/VL coinfections who are more difficult to cure (lower initial and final cure rates), have greater susceptibility to drug toxicity, and have higher rates of death and relapse. Due to the limitations of the existing treatments, better drugs are urgently needed. Ideally, new VL drugs would be efficacious across all endemic regions, would affect cure in ≤10 days, and would cost <$10 per course (for a complete target product profile for new VL drugs, which was formulated by DNDi, see Table 4). Here we describe the disease history and parasite biol. followed by a summary of the currently available treatments and, finally, review reports of novel small mols. with antileishmanial activity.
- 12Field, M. C.; Horn, D.; Fairlamb, A. H.; Ferguson, M. A. J.; Gray, D. W.; Read, K. D.; De Rycker, M.; Torrie, L. S.; Wyatt, P. G.; Wyllie, S.; Gilbert, I. H. Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need. Nat. Rev. Microbiol. 2017, 15, 217– 231, DOI: 10.1038/nrmicro.2016.193Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsVSms7Y%253D&md5=1585d954d6eb695196a6c8921a84e300Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing needField, Mark C.; Horn, David; Fairlamb, Alan H.; Ferguson, Michael A. J.; Gray, David W.; Read, Kevin D.; De Rycker, Manu; Torrie, Leah S.; Wyatt, Paul G.; Wyllie, Susan; Gilbert, Ian H.Nature Reviews Microbiology (2017), 15 (4), 217-231CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)A review. The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addn., we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.
- 13Don, R.; Ioset, J.-R. Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections. Parasitology 2014, 141, 140– 146, DOI: 10.1017/S003118201300142XGoogle Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sbjtFGmsA%253D%253D&md5=ae473acad2714a482e5acc926b8fe85fScreening strategies to identify new chemical diversity for drug development to treat kinetoplastid infectionsDon Rob; Ioset Jean-RobertParasitology (2014), 141 (1), 140-6 ISSN:.The Drugs for Neglected Diseases initiative (DNDi) has defined and implemented an early discovery strategy over the last few years, in fitting with its virtual R&D business model. This strategy relies on a medium- to high-throughput phenotypic assay platform to expedite the screening of compound libraries accessed through its collaborations with partners from the pharmaceutical industry. We review the pragmatic approaches used to select compound libraries for screening against kinetoplastids, taking into account screening capacity. The advantages, limitations and current achievements in identifying new quality series for further development into preclinical candidates are critically discussed, together with attractive new approaches currently under investigation.
- 14Liévin-Le Moal, V.; Loiseau, P. M. Leishmania hijacking of the macrophage intracellular compartments. FEBS J. 2016, 283, 598– 607, DOI: 10.1111/febs.13601Google ScholarThere is no corresponding record for this reference.
- 15Naderer, T.; Vince, J. E.; McConville, M. J. Surface determinants of Leishmania parasites and their role in infectivity in the mammalian host. Curr. Mol. Med. 2004, 4, 649– 665, DOI: 10.2174/1566524043360069Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvVKmt78%253D&md5=4b595d691a6454482cb4a802cfc363e6Surface determinants of Leishmania parasites and their role in infectivity in the mammalian hostNaderer, Thomas; Vince, James E.; McConville, Malcolm J.Current Molecular Medicine (2004), 4 (6), 649-665CODEN: CMMUBP; ISSN:1566-5240. (Bentham Science Publishers Ltd.)A review. Leishmania are intracellular protozoan parasites that reside primarily in host mononuclear phagocytes. Infection of host macrophages is initiated by infective promastigote stages and perpetuated by an obligate intracellular amastigote stage. Studies undertaken over the last decade have shown that the compn. of the complex surface glycocalyx of these stages (comprising lipophosphoglycan, GPI-anchored glycoproteins, proteophosphoglycans and free GPI glycolipids) changes dramatically as promastigotes differentiate into amastigotes. Marked stage-specific changes also occur in the expression of other plasma membrane components, including type-1, polytopic and peripheral membrane proteins, reflecting the distinct microbicidal responses and nutritional environments encountered by these stages. More recently, a no. of Leishmania mutants lacking single or multiple surface components have been generated. While some of these mutants are less virulent than wild type parasites, many of these mutants exhibit only mild or no loss of virulence. These studies suggest that (1) the major surface glycocalyx components of the promastigote stage (i.e. LPG, GPI-anchored proteins) only have a transient or minor role in macrophage invasion, (2) that there is considerable functional redundancy in the surface glycocalyx and/or loss of some components can be compensated for by the acquisition of equiv. host glycolipids, (3) the expression of specific nutrient transporters is essential for life in the macrophage, and (4) the role(s) of some surface components differ markedly in different Leishmania species. These mutants will be useful for identifying other surface or intracellular components that are required for virulence in macrophages.
- 16Katsuno, K.; Burrows, J. N.; Duncan, K.; Hooft van Huijsduijnen, R.; Kaneko, T.; Kita, K.; Mowbray, C. E.; Schmatz, D.; Warner, P.; Slingsby, B. T. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discovery 2015, 14, 751– 758, DOI: 10.1038/nrd4683Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1SitL7O&md5=6cd6d7c8ca3a85d64f24915da8e1120cHit and lead criteria in drug discovery for infectious diseases of the developing worldKatsuno, Kei; Burrows, Jeremy N.; Duncan, Ken; van Huijsduijnen, Rob Hooft; Kaneko, Takushi; Kita, Kiyoshi; Mowbray, Charles E.; Schmatz, Dennis; Warner, Peter; Slingsby, B. T.Nature Reviews Drug Discovery (2015), 14 (11), 751-758CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chem. starting points for such projects is a key factor in improving the likelihood of clin. success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compds. With this in mind, the Japanese Global Health Innovative Technol. (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill & Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.
- 17Burrows, J. N.; Elliott, R. L.; Kaneko, T.; Mowbray, C. E.; Waterson, D. The role of modern drug discovery in the fight against neglected and tropical diseases. MedChemComm 2014, 5, 688– 700, DOI: 10.1039/c4md00011kGoogle Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXovVanu7k%253D&md5=314051c267239b24f6f98b2405e624b9The role of modern drug discovery in the fight against neglected and tropical diseasesBurrows, Jeremy N.; Elliott, Richard L.; Kaneko, Takushi; Mowbray, Charles E.; Waterson, DavidMedChemComm (2014), 5 (6), 688-700CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. Neglected and tropical diseases affect a large proportion of the world's population and impose a huge economic and health burden on developing countries. Despite this, there is a dearth of safe, effective, suitable medications for treatment of these diseases, largely as a result of an underinvestment in developing new drugs against these diseases by the majority of research-based pharmaceutical companies. In the past 12 years, the situation has begun to improve with the emergence of public-private product development partnerships (PDPs), which foster a collaborative approach to drug discovery and have established strong drug development pipelines for neglected and tropical diseases. Some large pharmaceutical companies have also now established dedicated research sites for developing world diseases and are working closely with PDPs on drug development activities. However, drug discovery in this field is still hampered by a lack of sufficient funding and technol. investment, and there is a shortage of the tools, assays, and well-validated targets needed to ensure strong drug development pipelines in the future. The availability of high-quality chem. diverse compd. libraries to enable lead discovery remains one of the crit. bottlenecks. The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners. The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate together and will require sustained resourcing and focus.
- 18Mowbray, C. E.; Braillard, S.; Speed, W.; Glossop, P. A.; Whitlock, G. A.; Gibson, K. R.; Mills, J. E. J.; Brown, A. D.; Gardner, J. M. F.; Cao, Y.; Hua, W.; Morgans, G. L.; Feijens, P.-B.; Matheeussen, A.; Maes, L. J. Novel amino-pyrazole ureas with potent in vitro and in vivo antileishmanial activity. J. Med. Chem. 2015, 58, 9615– 9624, DOI: 10.1021/acs.jmedchem.5b01456Google ScholarThere is no corresponding record for this reference.
- 19Khare, S.; Nagle, A. S.; Biggart, A.; Lai, Y. H.; Liang, F.; Davis, L. C.; Barnes, S. W.; Mathison, C. J. N.; Myburgh, E.; Gao, M.-Y.; Gillespie, J. R.; Liu, X.; Tan, J. L.; Stinson, M.; Rivera, I. C.; Ballard, J.; Yeh, V.; Groessl, T.; Federe, G.; Koh, H. X. Y.; Venable, J. D.; Bursulaya, B.; Shapiro, M.; Mishra, P. K.; Spraggon, G.; Brock, A.; Mottram, J. C.; Buckner, F. S.; Rao, S. P. S.; Wen, B. G.; Walker, J. R.; Tuntland, T.; Molteni, V.; Glynne, R. J.; Supek, F. Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature 2016, 537, 229– 233, DOI: 10.1038/nature19339Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyhtr%252FL&md5=a05e7ce0f6b912b3003c5b3f42a005bbProteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sicknessKhare, Shilpi; Nagle, Advait S.; Biggart, Agnes; Lai, Yin H.; Liang, Fang; Davis, Lauren C.; Barnes, S. Whitney; Mathison, Casey J. N.; Myburgh, Elmarie; Gao, Mu-Yun; Gillespie, J. Robert; Liu, Xianzhong; Tan, Jocelyn L.; Stinson, Monique; Rivera, Ianne C.; Ballard, Jaime; Yeh, Vince; Groessl, Todd; Federe, Glenn; Koh, Hazel X. Y.; Venable, John D.; Bursulaya, Badry; Shapiro, Michael; Mishra, Pranab K.; Spraggon, Glen; Brock, Ansgar; Mottram, Jeremy C.; Buckner, Frederick S.; Rao, Srinivasa P. S.; Wen, Ben G.; Walker, John R.; Tuntland, Tove; Molteni, Valentina; Glynne, Richard J.; Supek, FrantisekNature (London, United Kingdom) (2016), 537 (7619), 229-233CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., resp. These parasites have similar biol. and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such mol. targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chem. validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
- 20Mukherjee, T.; Boshoff, H. Nitroimidazoles for the treatment of TB: past, present and future. Future Med. Chem. 2011, 3, 1427– 1454, DOI: 10.4155/fmc.11.90Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFSktr%252FN&md5=44739c4906d7b9e1ffeaa76f65acb16cNitroimidazoles for the treatment of TB: past, present and futureMukherjee, Tathagata; Boshoff, HelenaFuture Medicinal Chemistry (2011), 3 (11), 1427-1454CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review. Tuberculosis remains a leading cause of death resulting from an infectious agent, and the spread of multi- and extensively drug-resistant strains of Mycobacterium tuberculosis poses a threat to management of global health. New drugs that effectively shorten the duration of treatment and are active against drug-resistant strains of this pathogen are urgently required to develop effective chemotherapies to combat this disease. Two nitroimidazoles, PA-824 and OPC-67683, are currently in Phase II clin. trials for the treatment of TB and the outcome of these may det. the future directions of drug development for anti-tubercular nitroimidazoles. In this review we summarize the development of these nitroimidazoles and alternative analogs in these series that may offer attractive alternatives to PA-824 and OPC-67683 for further development in the drug-discovery pipeline. Lastly, the potential pitfalls in the development of nitroimidazoles as drugs for TB are discussed.
- 21Diacon, A. H.; Dawson, R.; du Bois, J.; Narunsky, K.; Venter, A.; Donald, P. R.; van Niekerk, C.; Erondu, N.; Ginsberg, A. M.; Becker, P.; Spigelman, M. K. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob. Agents Chemother. 2012, 56, 3027– 3031, DOI: 10.1128/AAC.06125-11Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnslWrtrk%253D&md5=5ab64eb6bc8d02e4e7b1bb6d9d112920Phase II dose-ranging trial of the early bactericidal activity of PA-824Diacon, Andreas H.; Dawson, Rodney; du Bois, Jeannine; Narunsky, Kim; Venter, Amour; Donald, Peter R.; van Niekerk, Christo; Erondu, Ngozi; Ginsberg, Ann M.; Becker, Piet; Spigelman, Melvin K.Antimicrobial Agents and Chemotherapy (2012), 56 (6), 3027-3031CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-pos. adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body wt. per day for 14 days. Eight subjects received once-daily std. antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a pos. control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/mL sputum (± std. deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, resp. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approx. dose proportional with respect to the area under the time-concn. curve. All doses were safe and well tolerated with no dose-limiting adverse events or clin. significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.
- 22Murray, S.; Mendel, C.; Spigelman, M. TB Alliance regimen development for multidrug-resistant tuberculosis. International Journal of Tuberculosis and Lung Disease 2016, 20 (Suppl. 1), S38– S41, DOI: 10.5588/ijtld.16.0069Google ScholarThere is no corresponding record for this reference.
- 23Upton, A. M.; Cho, S.; Yang, T. J.; Kim, Y.; Wang, Y.; Lu, Y.; Wang, B.; Xu, J.; Mdluli, K.; Ma, Z.; Franzblau, S. G. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2015, 59, 136– 144, DOI: 10.1128/AAC.03823-14Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1aisLk%253D&md5=3061f7349c1059a9514e5cd6ee42431cIn vitro and In Vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosisUpton, A. M.; Cho, S. M.; Yang, T. J.; Kim, Y.; Wang, Y.; Lu, Y.; Wang, B.; Xu, J.; Mdluli, K.; Ma, Z.; Franzblau, S. G.Antimicrobial Agents and Chemotherapy (2015), 59 (1), 136-144/1-136-144/9, 9 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid OPC-67683, Deltyba is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 SN31354 S-2-nitro-6-6-4-trifluoromethoxyphenyl pyridine-3-ylmethoxy-6,7-dihydro-5H-imidazo 2,1-b 1,3 oxazine is a pyridine-contg. biaryl compd. with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chem. effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addn. of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clin. drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10-7. In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.
- 24Thompson, A. M.; O’Connor, P. D.; Marshall, A. J.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Braillard, S.; Chatelain, E.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Cooper, C. B.; Denny, W. A. 7-Substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: novel antitubercular agents lead to a new preclinical candidate for visceral leishmaniasis. J. Med. Chem. 2017, 60, 4212– 4233, DOI: 10.1021/acs.jmedchem.7b00034Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVentbw%253D&md5=ccb6e45ed81213d05527071e095bd6517-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral LeishmaniasisThompson, Andrew M.; O'Connor, Patrick D.; Marshall, Andrew J.; Yardley, Vanessa; Maes, Louis; Gupta, Suman; Launay, Delphine; Braillard, Stephanie; Chatelain, Eric; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Cooper, Christopher B.; Denny, William A.Journal of Medicinal Chemistry (2017), 60 (10), 4212-4233CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Within a backup program for the clin. investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analog DNDI-VL-2098 as a VL preclin. candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compds. with improved soly. and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one Ph by pyridine or pyrimidine showed improved soly. and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.
- 25Thompson, A. M.; O’Connor, P. D.; Blaser, A.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Martin, D.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Repositioning antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for neglected tropical diseases: structure-activity studies on a preclinical candidate for visceral leishmaniasis. J. Med. Chem. 2016, 59, 2530– 2550, DOI: 10.1021/acs.jmedchem.5b01699Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivFGmtbY%253D&md5=9eebc55cc434cc4dec0692bef5bbed98Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral LeishmaniasisThompson, Andrew M.; O'Connor, Patrick D.; Blaser, Adrian; Yardley, Vanessa; Maes, Louis; Gupta, Suman; Launay, Delphine; Martin, Denis; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.Journal of Medicinal Chemistry (2016), 59 (6), 2530-2550CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivs. were initially studied for tuberculosis within a backup program for the clin. trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Addnl. work was then conducted to delineate its essential structural features, aiming to improve soly. and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of Ph rings by pyridine. Several less lipophilic analogs displayed improved aq. soly., particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection,phenylpyridine deriv. I stood out, providing efficacy surpassing that of the original preclin. lead.
- 26Gupta, S.; Yardley, V.; Vishwakarma, P.; Shivahare, R.; Sharma, B.; Launay, D.; Martin, D.; Puri, S. K. Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis. J. Antimicrob. Chemother. 2015, 70, 518– 527, DOI: 10.1093/jac/dku422Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFGmur8%253D&md5=179ae312a4efef99059577223650641aNitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasisGupta, Suman; Yardley, Vanessa; Vishwakarma, Preeti; Shivahare, Rahul; Sharma, Bhawna; Launay, Delphine; Martin, Denis; Puri, Sunil K.Journal of Antimicrobial Chemotherapy (2015), 70 (2), 518-527CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)Objectives: The objective of this study was to identify a nitroimidazo-oxazole lead mol. for the treatment of visceral leishmaniasis (VL). Methods: A library of 72 nitroimidazo-oxazoles was evaluated in vitro for their antileishmanial activity against luciferase-transfected DD8 amastigotes of Leishmania donovani. On the basis of their in vitro potency and pharmacokinetic properties, the promising compds. were tested in acute BALB/c mouse and chronic hamster models of VL via oral administration and efficacy was evaluated by microscopic counting of amastigotes after Giemsa staining. The best antileishmanial candidates (racemate DNDI-VL-2001) and its R enantiomer (DNDI-VL-2098) were evaluated in vitro against a range of Leishmania strains. These candidates were further studied in a hamster model using various dose regimens. Cytokine and inducible nitric oxide synthase estns. by real-time PCR and nitric oxide generation by Griess assay were also carried out for DNDI-VL-2098. Results: In vitro screening of nitroimidazo-oxazole compds. identified the racemate DNDI-VL-2001 (6-nitroimidazo-oxazole deriv.) and its enantiomers as candidates for further evaluation in in vivo models of VL. DNDI-VL-2098 (IC50 of 0.03 μM for the DD8 strain) showed excellent in vivo activity in both mouse and hamster models, with an ED90 value of 3.7 and <25 mg/kg, resp., and was also found to be very effective against high-grade infection in the hamster model. Our studies revealed that, along with leishmanicidal activity, DNDI-VL-2098 was also capable of inducing host-protective immune cells to suppress Leishmania parasites in hamsters. Conclusions: These studies led to the identification of compd. DNDI-VL-2098 as a preclin. candidate for further drug development as an oral treatment for VL.
- 27Wyllie, S.; Roberts, A. J.; Norval, S.; Patterson, S.; Foth, B. J.; Berriman, M.; Read, K. D.; Fairlamb, A. H. Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in Leishmania. PLoS Pathog. 2016, 12 (11), e1005971, DOI: 10.1371/journal.ppat.1005971Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitV2mt7g%253D&md5=0506a45a0a29a613f96c1b874af54b96Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in LeishmaniaWyllie, Susan; Roberts, Adam J.; Norval, Suzanne; Patterson, Stephen; Foth, Bernardo J.; Berriman, Matthew; Read, Kevin D.; Fairlamb, Alan H.PLoS Pathogens (2016), 12 (11), e1005971/1-e1005971/22CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)Drug discovery pipelines for the "neglected diseases" are now heavily populated with nitroheterocyclic compds. Recently, the bicyclic nitro-compds. (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quant. proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein. Susceptibility of leishmania was restored by reintroduction of the wild-type gene into the resistant line, which was accompanied by the ability to metabolise these compds. Overexpression of NTR2 in wild-type parasites rendered cells hyper-sensitive to bicyclic nitro-compds., but only marginally to the monocyclic nitro-drugs, nifurtimox and fexinidazole sulfone, known to be activated by a mitochondrial oxygen-insensitive nitroreductase (NTR1). Conversely, a double knockout NTR2 null cell line was completely resistant to bicyclic nitro-compds. and only marginally resistant to nifurtimox. Sensitivity was fully restored on expression of NTR2 in the null background. Thus, NTR2 is necessary and sufficient for activation of these bicyclic nitro-drugs. Recombinant NTR2 was capable of reducing bicyclic nitro-compds. in the same rank order as drug sensitivity in vitro. These findings may aid the future development of better, novel anti-leishmanial drugs. Moreover, the discovery of anti-leishmanial nitro-drugs with independent modes of activation and independent mechanisms of resistance alleviates many of the concerns over the continued development of these compd. series.
- 28Patterson, S.; Wyllie, S.; Norval, S.; Stojanovski, L.; Simeons, F. R. C.; Auer, J. L.; Osuna-Cabello, M.; Read, K. D.; Fairlamb, A. H. The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. eLife 2016, 5, e09744, DOI: 10.7554/eLife.09744Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmsFamtLw%253D&md5=1a704d1acb52b08cae5f73cf625f293aThe anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasisPatterson, Stephen; Wyllie, Susan; Norval, Suzanne; Stojanovski, Laste; Simeons, Frederick R. C.; Auer, Jennifer L.; Osuna-Cabello, Maria; Read, Kevin D.; Fairlamb, Alan H.eLife (2016), 5 (), e09744/1-e09744/21CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmaniadonovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg-1 for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg-1 than at 3 mg kg-1 (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.
- 29Thompson, A. M.; Denny, W. A.; Blaser, A.; Ma, Z. Nitroimidazooxazine and Nitroimidazooxazole Analogues and Their Uses. Patent WO 2011/014776 A1, 2011, and U.S. Patent 8293734 B2, 2012.Google ScholarThere is no corresponding record for this reference.
- 30Thompson, A. M.; Blaser, A.; Palmer, B. D.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Biarylmethoxy 2-nitroimidazooxazine antituberculosis agents: Effects of proximal ring substitution and linker reversal on metabolism and efficacy. Bioorg. Med. Chem. Lett. 2015, 25, 3804– 3809, DOI: 10.1016/j.bmcl.2015.07.084Google ScholarThere is no corresponding record for this reference.
- 31Li, X.; Manjunatha, U. H.; Goodwin, M. B.; Knox, J. E.; Lipinski, C. A.; Keller, T. H.; Barry, C. E.; Dowd, C. S. Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines, analogues of PA-824. Bioorg. Med. Chem. Lett. 2008, 18, 2256– 2262, DOI: 10.1016/j.bmcl.2008.03.011Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjvFyksbw%253D&md5=660a69bf91fe7949b9c90349f4530ed0Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines, analogues of PA-824Li, Xiaojin; Manjunatha, Ujjini H.; Goodwin, Michael B.; Knox, John E.; Lipinski, Christopher A.; Keller, Thomas H.; Barry, Clifton E., III; Dowd, Cynthia S.Bioorganic & Medicinal Chemistry Letters (2008), 18 (7), 2256-2262CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Nitroimidazoles, such as I (R1 = R2 = H) (PA-824) or OPC-67683, are currently in clin. development as members of a promising new class of therapeutics for tuberculosis. While the antitubercular activity of these compds. is high, they both suffer from poor water soly. thus complicating development. The single crystal X-ray structure of I (R1 = R2 = H) was detd. and showed a close packing of the nitroimidazoles facilitated by a pseudoaxial conformation of the p-trifluoromethoxybenzyl ether. In an attempt to disrupt this tight packing by destabilizing the axial preference of this side chain, the two diastereomers I (R1 = Me, R2 = H) and I (R1 = H; R2 = Me) were synthesized. Detn. of the crystal structure of the (S)-I (R1 = Me; R2 = H) revealed that the benzylic side chain remained pseudoaxial while the (R)-I (R1 = H; R2 = Me) adopted the desired pseudoequatorial conformation. Both derivs. displayed similar activities against Mycobacterium tuberculosis, but neither showed improved aq. soly., suggesting that inherent lattice stability is not likely to be a major factor in limiting soly. Conformational anal. revealed that all three compds. have similar energetically accessible conformations in soln. Addnl., these results suggest that the nitroreductase that initially recognizes PA-824 is somewhat insensitive to substitutions at the 7-position.
- 32Baker, W. R.; Shaopei, C.; Keeler, E. L. Nitro-[2,1-b]imidazopyran Compounds and Antibacterial Uses Thereof. U.S. Patent 6087358, 2000.Google ScholarThere is no corresponding record for this reference.
- 33Hirata, M.; Fujimoto, R.; Mikami, M. Preparation of 2-Methylglycidyl Ethers from 3-Halogeno-2-methyl-1,2-propanediols or 2-Methylepihalohydrins. Patent JP 2007297330, 2007.Google ScholarThere is no corresponding record for this reference.
- 34Elbert, B. L.; Lim, D. S. W.; Gudmundsson, H. G.; O’Hanlon, J. A.; Anderson, E. A. Synthesis of cyclic alkenylsiloxanes by semihydrogenation: a stereospecific route to (Z)-alkenyl polyenes. Chem. - Eur. J. 2014, 20, 8594– 8598, DOI: 10.1002/chem.201403255Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptlKrsbs%253D&md5=8fc0c25bc10fe28ca302e79f3a9767fbSynthesis of Cyclic Alkenylsiloxanes by Semihydrogenation: A Stereospecific Route to (Z)-Alkenyl PolyenesElbert, Bryony L.; Lim, Diane S. W.; Gudmundsson, Haraldur G.; O'Hanlon, Jack A.; Anderson, Edward A.Chemistry - A European Journal (2014), 20 (28), 8594-8598CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Cyclic alkenylsiloxanes were synthesized by a semi-hydrogenation (partial hydrogenation) of alkynylsilanes which is a reaction previously plagued by poor stereoselectivity. The silanes, which can be synthesized on multi-gram scale, undergo Hiyama-Denmark coupling to give (Z)-alkenyl polyene motifs found in bioactive natural products [i.e., bitungolide C, fostriecin, phoslactomycin B, 6-[(1E,3R,4R,6R,7Z,9Z)-3-(2-aminoethyl)-10-cyclohexyl-3,6-dihydroxy-4-(phosphonooxy)-1,7,9-decatriene-1-yl]-5-ethyl-5,6-dihydro-2H-pyran-2-one]. The ring size of the silane is crucial: five-membered cyclic siloxanes also couple under fluoride-free conditions, while their six-membered homologs do not, enabling orthogonality within this structural motif. Under optimized conditions the synthesis of the target compds. was achieved by a palladium-catalyzed cyclization of [[bis(alkoxy)alkyl]silyl]alkynol derivs. and the title compds. thus formed included 1-oxa-2-silacyclopent-3-ene derivs. and 1-oxa-2-silacyclohex-3-ene derivs. (cyclic alkenylsiloxanes).
- 35Ginsberg, A. M.; Laurenzi, M. W.; Rouse, D. J.; Whitney, K. D.; Spigelman, M. K. Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects. Antimicrob. Agents Chemother. 2009, 53, 3720– 3725, DOI: 10.1128/AAC.00106-09Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFCjsr7E&md5=b1a66b6df94526f21a3873747ad54487Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjectsGinsberg, Ann M.; Laurenzi, Martino W.; Rouse, Doris J.; Whitney, Karl D.; Spigelman, Melvin K.Antimicrobial Agents and Chemotherapy (2009), 53 (9), 3720-3725CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compd.'s MIC is between 0.015 and 0.25 μg/mL for drug-sensitive strains and between 0.03 and 0.53 μg/mL for drug-resistant strains. In addn., it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clin. studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approx. 3 μg/mL (1,500-mg dose) in the single-dose study and 3.8 μg/mL (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approx. 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compd. for the treatment of tuberculosis.
- 36Thompson, A. M.; Marshall, A. J.; Maes, L.; Yarlett, N.; Bacchi, C. J.; Gaukel, E.; Wring, S. A.; Launay, D.; Braillard, S.; Chatelain, E.; Mowbray, C. E.; Denny, W. A. Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides. Bioorg. Med. Chem. Lett. 2018, 28, 207– 213, DOI: 10.1016/j.bmcl.2017.10.067Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvV2lsr7N&md5=00573f41d0ae4882b316c5ed36199ef5Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxidesThompson, Andrew M.; Marshall, Andrew J.; Maes, Louis; Yarlett, Nigel; Bacchi, Cyrus J.; Gaukel, Eric; Wring, Stephen A.; Launay, Delphine; Braillard, Stephanie; Chatelain, Eric; Mowbray, Charles E.; Denny, William A.Bioorganic & Medicinal Chemistry Letters (2018), 28 (2), 207-213CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A 900 compd. nitroimidazole-based library derived from the authors' pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and detn. of the most active chiral form, a thiazine oxide counterpart of pretomanid (24 ((6S)-2-Nitro-6-[[4-(trifluoromethoxy)benzyl]oxy]-6,7-dihydro-5H-imidazo[2,1-6][1,3]thiazine 8-oxide)) was identified as the best lead. With once daily oral dosing, this compd. delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.
- 37Gurumurthy, M.; Mukherjee, T.; Dowd, C. S.; Singh, R.; Niyomrattanakit, P.; Tay, J. A.; Nayyar, A.; Lee, Y. S.; Cherian, J.; Boshoff, H. I.; Dick, T.; Barry, C. E., III; Manjunatha, U. H. Substrate specificity of the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles. FEBS J. 2012, 279, 113– 125, DOI: 10.1111/j.1742-4658.2011.08404.xGoogle Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xit1Smsw%253D%253D&md5=ad91d6afcc9a4d3b715a1e7dacf1f9fdSubstrate specificity of the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazolesGurumurthy, Meera; Mukherjee, Tathagata; Dowd, Cynthia S.; Singh, Ramandeep; Niyomrattanakit, Pornwaratt; Tay, Jo Ann; Nayyar, Amit; Lee, Yong Sok; Cherian, Joseph; Boshoff, Helena I.; Dick, Thomas; Barry, Clifton E., III; Manjunatha, Ujjini H.FEBS Journal (2012), 279 (1), 113-125CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)The bicyclic 4-nitroimidazoles PA-824 and OPC-67683 represent a promising novel class of therapeutics for tuberculosis and are currently in phase II clin. development. Both compds. are pro-drugs that are reductively activated by a deazaflavin (F420) dependent nitroreductase (Ddn). Herein we describe the biochem. properties of Ddn including the optimal enzymic turnover conditions and substrate specificity. The preference of the enzyme for the (S) isomer of PA-824 over the (R) isomer is directed by the presence of a long hydrophobic tail. Nitroimidazo-oxazoles bearing only short alkyl substituents at the C-7 position of the oxazole were reduced by Ddn without any stereochem. preference. However, with bulkier substitutions on the tail of the oxazole, Ddn displayed stereospecificity. Ddn mediated metab. of PA-824 results in the release of reactive nitrogen species. We have employed a direct chemiluminescence based nitric oxide (NO) detection assay to measure the kinetics of NO prodn. by Ddn. Binding affinity of PA-824 to Ddn was monitored through intrinsic fluorescence quenching of the protein facilitating a turnover-independent assessment of affinity. Our results indicate that (R)-PA-824, despite not being turned over by Ddn, binds to the enzyme with the same affinity as the active (S) isomer. This result, in combination with docking studies in the active site, suggests that the (R) isomer probably has a different binding mode than the (S) with the C-3 of the imidazole ring orienting in a non-productive position with respect to the incoming hydride from F420. The results presented provide insight into the biochem. mechanism of redn. and elucidate structural features important for understanding substrate binding.
- 38Patterson, S.; Wyllie, S.; Stojanovski, L.; Perry, M. R.; Simeons, F. R. C.; Norval, S.; Osuna-Cabello, M.; De Rycker, M.; Read, K. D.; Fairlamb, A. H. The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral leishmaniasis. Antimicrob. Agents Chemother. 2013, 57, 4699– 4706, DOI: 10.1128/AAC.00722-13Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVygtb7I&md5=401760844c66c37003791c9dcf83392bThe R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral leishmaniasisPatterson, Stephen; Wyllie, Susan; Stojanovski, Laste; Perry, Meghan R.; Simeons, Frederick R. C.; Norval, Suzanne; Osuna-Cabello, Maria; De Rycker, Manu; Read, Kevin D.; Fairlamb, Alan H.Antimicrobial Agents and Chemotherapy (2013), 57 (10), 4699-4706CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)The novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is currently in phase II clin. trials for tuberculosis (TB). In contrast to M. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity against Leishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogs are inactive, underlining the importance of the nitro group in the mechanism of action. Although the in vitro and in vivo pharmacol. profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body wt.-1, twice daily for 5 days. In M. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent in Leishmania spp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compds. Drug combination studies in vitro indicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clin. trials against VL.
- 39Kmentova, I.; Sutherland, H. S.; Palmer, B. D.; Blaser, A.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A.; Thompson, A. M. Synthesis and structure-activity relationships of aza- and diazabiphenyl analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2010, 53, 8421– 8439, DOI: 10.1021/jm101288tGoogle ScholarThere is no corresponding record for this reference.
- 40Thompson, A. M.; Blaser, A.; Anderson, R. F.; Shinde, S. S.; Franzblau, S. G.; Ma, Z.; Denny, W. A.; Palmer, B. D. Synthesis, reduction potentials, and antitubercular activity of ring A/B analogues of the bioreductive drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2009, 52, 637– 645, DOI: 10.1021/jm801087eGoogle Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFais7%252FK&md5=a9fe7edce4c538f14ddec49942a1e9a0Synthesis, Reduction Potentials, and Antitubercular Activity of Ring A/B Analogues of the Bioreductive Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)Thompson, Andrew M.; Blaser, Adrian; Anderson, Robert F.; Shinde, Sujata S.; Franzblau, Scott G.; Ma, Zhenkun; Denny, William A.; Palmer, Brian D.Journal of Medicinal Chemistry (2009), 52 (3), 637-645CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The nitroimidazooxazine I (PA-824) is a new class of bioreductive drug for tuberculosis. A series of related bicyclic nitroheterocycles was synthesized, designed to have a wide range of one-electron redn. potentials E(1) (from -570 to -338 mV, compared with -534 mV for I). The obsd. E(1) values closely correlated with the σm values of the heteroatom at the 4/8-position of the adjacent six-membered ring. Although the compds. spanned a range of E(1) values around that of I, only the nitroimidazothiazines showed significant antitubercular activity (at a similar level of potency), suggesting that E(1) is not the main driver of efficacy. Furthermore, there was a correlation between activity and the formation of imidazole ring-reduced products at the two-electron level, pointing to the potential importance of this redn. pathway, which is detd. by the nature of the substituent at the 2-position of the 4-nitroimidazole ring.
- 41Bom, D.; Curran, D. P.; Kruszewski, S.; Zimmer, S. G.; Thompson Strode, J.; Kohlhagen, G.; Du, W.; Chavan, A. J.; Fraley, K. A.; Bingcang, A. L.; Latus, L. J.; Pommier, Y.; Burke, T. G. The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J. Med. Chem. 2000, 43, 3970– 3980, DOI: 10.1021/jm000144oGoogle Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmsFeitL0%253D&md5=07aa6c0159366ff9685892c10a6fc959The Novel Silatecan 7-tert-Butyldimethylsilyl-10-hydroxycamptothecin Displays High Lipophilicity, Improved Human Blood Stability, and Potent Anticancer ActivityBom, David; Curran, Dennis P.; Kruszewski, Stefan; Zimmer, Stephen G.; Strode, J. Thompson; Kohlhagen, Glenda; Du, Wu; Chavan, Ashok J.; Fraley, Kimberly A.; Bingcang, Alex L.; Latus, Lori J.; Pommier, Yves; Burke, Thomas G.Journal of Medicinal Chemistry (2000), 43 (21), 3970-3980CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The rational design and synthesis of B- and A,B-ring-modified camptothecins are described. The key α-hydroxy-δ-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, I) displays superior stability in human blood when compared with clin. relevant camptothecin analogs. In human blood I displayed a t1/2 of 130 min and a percent lactone at equil. value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and I is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addn., the dual 7-alkylsilyl and 10-hydroxy substitution in I enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that I is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogs topotecan and CPT-11. In addn., cell-free cleavage assays reveal that I is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for I strongly suggest that it is an excellent candidate for addnl. in vivo pharmacol. and efficacy studies.
- 42Thompson, A. M.; Sutherland, H. S.; Palmer, B. D.; Kmentova, I.; Blaser, A.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Synthesis and structure-activity relationships of varied ether linker analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2011, 54, 6563– 6585, DOI: 10.1021/jm200377rGoogle ScholarThere is no corresponding record for this reference.
- 43Alberati-Giani, D.; Jolidon, S.; Narquizian, R.; Nettekoven, M. H.; Norcross, R. D.; Pinard, E.; Stalder, H. Preparation of 1-(2-Aminobenzoyl)-piperazine Derivatives as Glycine Transporter 1 (GlyT-1) Inhibitors for Treating Psychoses. Patent WO 2005023260 A1, 2005.Google ScholarThere is no corresponding record for this reference.
- 44Kaiser, M.; Maes, L.; Tadoori, L. P.; Spangenberg, T.; Ioset, J.-R. Repurposing of the open access malaria box for kinetoplastid diseases identifies novel active scaffolds against trypanosomatids. J. Biomol. Screening 2015, 20, 634– 645, DOI: 10.1177/1087057115569155Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlWlu7nM&md5=64a9cd3add4e2b1b6682422018f0c61bRepurposing of the open access malaria box for kinetoplastid diseases identifies novel active scaffolds against trypanosomatidsKaiser, Marcel; Maes, Louis; Tadoori, Leela Pavan; Spangenberg, Thomas; Ioset, Jean-RobertJournal of Biomolecular Screening (2015), 20 (5), 634-645CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)Phenotypic screening had successfully been used for hit generation, esp. in the field of neglected diseases, in which feeding the drug pipeline with new chemotypes remains a const. challenge. Here, we catalyze drug discovery research using a publicly available screening tool to boost drug discovery. The Malaria Box, assembled by the Medicines for Malaria Venture, is a structurally diverse set of 200 druglike and 200 probelike compds. distd. from more than 20,000 antimalarial hits from corporate and academic libraries. Repurposing such compds. has already identified new scaffolds against cryptosporidiosis and schistosomiasis. In addn. to initiating new hit- to- lead activities, screening the Malaria Box against a plethora of other parasites would enable the community to better understand the similarities and differences between them. We describe the screening of the Malaria Box and triaging of the identified hits against kinetoplastids responsible for human African trypanosomiasis (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and visceral leishmaniasis (Leishmania donovani and Leishmania infantum). The in vitro and in vivo profiling of the most promising active compds. with respect to efficacy, toxicity, pharmacokinetics, and complementary druggable properties are presented and a collaborative model used as a way to accelerate the discovery process discussed.
- 45Siqueira-Neto, J. L.; Song, O.-R.; Oh, H.; Sohn, J.-H.; Yang, G.; Nam, J.; Jang, J.; Cechetto, J.; Lee, C. B.; Moon, S.; Genovesio, A.; Chatelain, E.; Christophe, T.; Freitas-Junior, L. H. Antileishmanial high-throughput drug screening reveals drug candidates with new scaffolds. PLoS Neglected Trop. Dis. 2010, 4 (5), e675, DOI: 10.1371/journal.pntd.0000675Google ScholarThere is no corresponding record for this reference.
- 46Palmer, B. D.; Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A.; Thompson, A. M. Synthesis and structure-activity relationships for extended side chain analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2015, 58, 3036– 3059, DOI: 10.1021/jm501608qGoogle Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVOrtrY%253D&md5=2ce7144ac56b5ec156d83a09d4d6af90Synthesis and Structure-Activity Relationships for Extended Side Chain Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)Palmer, Brian D.; Sutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.; Thompson, Andrew M.Journal of Medicinal Chemistry (2015), 58 (7), 3036-3059CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Novel extended side chain nitroimidazooxazine analogs featuring diverse linker groups between two aryl rings, e.g., I, were studied as a potential strategy to improve soly. and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some soly. improvements, particularly in combination with pyridine rings. Most of the 18 compds. further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-contg. acetylene derivs. (5-fold and >933-fold) gave in vivo efficacies notably superior to the clin. stage compd. pretomanid (PA-824). The most efficacious analog, I, also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.
- 47Palmer, B. D.; Thompson, A. M.; Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2010, 53, 282– 294, DOI: 10.1021/jm901207nGoogle Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVKhs7rL&md5=1ff5a8bd11f095f428898ec13f884259Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)Palmer, Brian D.; Thompson, Andrew M.; Sutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.Journal of Medicinal Chemistry (2010), 53 (1), 282-294CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of biphenyl analogs of the new tuberculosis drug PA-824 e. g. , I was prepd., primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki coupling of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side chain prior to coupling with the above alc. Antitubercular activity was detd. under both replicating (MABA) and nonreplicating (LORA) conditions. Para-Linked biaryls were the most active, followed by meta-linked and then ortho-linked analogs. A more detailed study of a larger group of para-linked analogs showed a significant correlation between potency (MABA) and both lipophilicity (CLOGP) and the electron-withdrawing properties of terminal ring substituents (.sum.σ). Selected compds. were evaluated for their efficacy in a mouse model of acute Mycobacterium tuberculosis infection. In vivo activity correlated well with the stability of compds. to microsomal metab. Three compds. bearing combinations of lipophilic, electron-withdrawing groups achieved >200-fold higher efficacies than the parent drug.
- 48Blaser, A.; Palmer, B. D.; Sutherland, H. S.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Thompson, A. M.; Denny, W. A. Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2012, 55, 312– 326, DOI: 10.1021/jm2012276Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFylurrE&md5=b515998cf44ca9998fc3434def6f82d4Structure-Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)Blaser, Adrian; Palmer, Brian D.; Sutherland, Hamish S.; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Thompson, Andrew M.; Denny, William A.Journal of Medicinal Chemistry (2012), 55 (1), 312-326CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Analogs of clin. tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824, I), in which the OCH2 linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metab., reduce lipophilicity, and improve aq. soly. Several sol. monoaryl examples displayed moderately improved (∼2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivs. mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly sol. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a sol., orally bioavailable carbamate analog providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.
- 49Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Palmer, B. D.; Denny, W. A.; Thompson, A. M. Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains. J. Med. Chem. 2010, 53, 855– 866, DOI: 10.1021/jm901378uGoogle Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFaisrrN&md5=f9b6518612795cc55e5f9b8ad784c8c6Synthesis and Structure-activity Relationships of Antitubercular 2-Nitroimidazooxazines Bearing Heterocyclic Side ChainsSutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Palmer, Brian D.; Denny, William A.; Thompson, Andrew M.Journal of Medicinal Chemistry (2010), 53 (2), 855-866CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Previously, biphenyl analogs of the antituberculosis drug PA-824 were found to display improved potencies against M. tuberculosis but were poorly sol. Heterobiaryl analogs of these, e.g., I (X = 2,5-thiophenediyl, R = 4-F), in which the first Ph ring was replaced with various 5-membered ring heterocycles, were prepd. with the aim of identifying potent new candidates with improved aq. soly. The compds. were constructed by coupling the chiral 2-nitroimidazooxazine II with various halomethyl-substituted arylheterocycles, by cycloaddns. to a propargyl ether deriv. of this alc., or by Suzuki couplings on haloheterocyclic Me ether derivs. The arylheterocyclic compds. were all more hydrophilic than their corresponding biphenyl analogs, and several showed soly. improvements. 1-Methylpyrazole, e.g., I (X = 1-methyl-3,5-pyrazolediyl, R = 4-F3C), 1,3-linked-pyrazole, e.g., I (X = 1,3-pyrazolediyl, R = 4-F), 2,4-linked-triazole, e.g., I [X = 1,2,3-triazole-2,4-diyl, R = 4-(CF3O)] and tetrazole analogs, e.g., I (X = 2,5-tetrazolediyl, R = H) had 3- to 7-fold higher MIC potencies against replicating M. tuberculosis than predicted by their lipophilicities. Two pyrazole analogs were >10-fold more efficacious than the parent drug in a mouse model of acute M. tuberculosis infection, and one displayed a 2-fold higher soly.
- 50Kataoka, M.; Fukahori, M.; Ikemura, A.; Kubota, A.; Higashino, H.; Sakuma, S.; Yamashita, S. Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process. Eur. J. Pharm. Biopharm. 2016, 101, 103– 111, DOI: 10.1016/j.ejpb.2016.02.002Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisVGgtr0%253D&md5=0db9d87ed2bd62f8234c34acbdc97306Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution processKataoka, Makoto; Fukahori, Miho; Ikemura, Atsumi; Kubota, Ayaka; Higashino, Haruki; Sakuma, Shinji; Yamashita, ShinjiEuropean Journal of Pharmaceutics and Biopharmaceutics (2016), 101 (), 103-111CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)The aim of the present study was to evaluate the effects of gastric pH on the oral absorption of poorly water-sol. drugs using an in vitro system. A dissoln./permeation system (D/P system) equipped with a Caco-2 cell monolayer was used as the in vitro system to evaluate oral drug absorption, while a small vessel filled with simulated gastric fluid (SGF) was used to reflect the gastric dissoln. phase. After applying drugs in their solid forms to SGF, SGF soln. contg. a 1/100 clin. dose of each drug was mixed with the apical soln. of the D/P system, which was changed to fasted state-simulated intestinal fluid. Dissolved and permeated amts. on applied amt. of drugs were then monitored for 2 h. Similar expts. were performed using the same drugs, but without the gastric phase. Oral absorption with or without the gastric phase was predicted in humans based on the amt. of the drug that permeated in the D/P system, assuming that the system without the gastric phase reflected human absorption with an elevated gastric pH. The dissolved amts. of basic drugs with poor water soly., namely albendazole, dipyridamole, and ketoconazole, in the apical soln. and their permeation across a Caco-2 cell monolayer were significantly enhanced when the gastric dissoln. process was reflected due to the physicochem. properties of basic drugs. These amts. resulted in the prediction of higher oral absorption with normal gastric pH than with high gastric pH. On the other hand, when diclofenac sodium, the salt form of an acidic drug, was applied to the D/P system with the gastric phase, its dissolved and permeated amts. were significantly lower than those without the gastric phase. However, the oral absorption of diclofenac was predicted to be complete (96-98%) irresp. of gastric pH because the permeated amts. of diclofenac under both conditions were sufficiently high to achieve complete absorption. These estns. of the effects of gastric pH on the oral absorption of poorly water-sol. drugs were consistent with observations in humans. In conclusion, the D/P system with the gastric phase may be a useful tool for better predicting the oral absorption of poorly water-sol. basic drugs. In addn., the effects of gastric pH on the oral absorption of poorly water-sol. drugs may be evaluated by the D/P system with and without the gastric phase.
- 51Rouault, E.; Lecoeur, H.; Meriem, A. B.; Minoprio, P.; Goyard, S.; Lang, T. Imaging visceral leishmaniasis in real time with golden hamster model: Monitoring the parasite burden and hamster transcripts to further characterize the immunological responses of the host. Parasitol. Int. 2017, 66, 933– 939, DOI: 10.1016/j.parint.2016.10.020Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKmsbvJ&md5=6ebdf4b36b8fda8dcf3e9a08b6ac5bd3Imaging visceral leishmaniasis in real time with golden hamster model: Monitoring the parasite burden and hamster transcripts to further characterize the immunological responses of the hostRouault, Eline; Lecoeur, Herve; Meriem, Asma Ben; Minoprio, Paola; Goyard, Sophie; Lang, ThierryParasitology International (2017), 66 (1), 933-939CODEN: PAINFD; ISSN:1383-5769. (Elsevier Ireland Ltd.)Characterizing the clin., immunol. and parasitol. features assocd. with visceral leishmaniasis is complex. It involves recording in real time and integrating quant. multi-parametric data sets from parasite infected host tissues. Although several models have been used, hamsters are considered the bona fide exptl. model for Leishmania donovani studies. To study visceral leishmaniasis in hamsters we generated virulent transgenic L. donovani that stably express a reporter luciferase protein. Two complementary methodologies were combined to follow the infectious process: in vivo imaging using luciferase-expressing Leishmania and real time RT-PCR to quantify both Leishmania and host transcripts. This approach allows us: (i) to assess the clin. outcome of visceral leishmaniasis by individual monitoring of hamster wt., (ii) to follow the parasite load in several organs by real time anal. of the bioluminescence in vivo and through real time quant. PCR anal. of amastigote parasite transcript abundance ex vivo, (iii) to evaluate the immunol. responses triggered by the infection by quantifying hamster transcripts on the same samples and (iv) to limit the no. of hamsters selected for further anal. The overall data highlight a correlation between the transcriptional cytokine signatures of hamster affected tissues and the amastigote burden fluctuations, thus providing new insights into the immunopathol. process driven by L. donovani in the tissues of mammalian hosts. Finally, they suggest organ-specific immune responses.
- 52Yao, X.; Anderson, D. L.; Ross, S. A.; Lang, D. G.; Desai, B. Z.; Cooper, D. C.; Wheelan, P.; McIntyre, M. S.; Bergquist, M. L.; MacKenzie, K. I.; Becherer, J. D.; Hashim, M. A. Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model. Br. J. Pharmacol. 2008, 154, 1446– 1456, DOI: 10.1038/bjp.2008.267Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptVajsLw%253D&md5=1dbf4f50957b26496c4efa213e3f7e5cPredicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig modelYao, X.; Anderson, D. L.; Ross, S. A.; Lang, D. G.; Desai, B. Z.; Cooper, D. C.; Wheelan, P.; McIntyre, M. S.; Bergquist, M. L.; MacKenzie, K. I.; Becherer, J. D.; Hashim, M. A.British Journal of Pharmacology (2008), 154 (7), 1446-1456CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclin. development, the propensity of drugs to prolong the QT interval in humans. Sixteen marketed drugs from various pharmacol. classes with a known incidence-or lack thereof-of QT prolongation in humans were examd. in hERG (human ether a-go-go-related gene) patch-clamp assay and an anesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concns. in perfusates from hERG assays and plasma samples from guinea-pigs were detd. using liq. chromatog.-mass spectrometry. Various pharmacol. agents that inhibit hERG currents prolong the QT interval in anesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compds. not assocd. with QT prolongation in humans failed to prolong the QT interval in this model. Anal. of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anesthetized guinea-pigs can reliably predict, during preclin. drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chem. entities during early lead optimization.
- 53Nwaka, S.; Ramirez, B.; Brun, R.; Maes, L.; Douglas, F.; Ridley, R. Advancing drug innovation for neglected diseases - criteria for lead progression. PLoS Neglected Trop. Dis. 2009, 3 (8), e440, DOI: 10.1371/journal.pntd.0000440Google ScholarThere is no corresponding record for this reference.
- 54Freitas-Junior, L. H.; Chatelain, E.; Kim, H. A.; Siqueira-Neto, J. L. Visceral leishmaniasis treatment: What do we have, what do we need and how to deliver it?. Int. J. Parasitol.: Drugs Drug Resist. 2012, 2, 11– 19, DOI: 10.1016/j.ijpddr.2012.01.003Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1KmtLY%253D&md5=bc79e6a916e0dac45ec0879ecdc27e03Visceral leishmaniasis treatment: what do we have, what do we need and how to deliver it?Freitas-Junior, Lucio H.; Chatelain, Eric; Kim, Helena Andrade; Siqueira-Neto, Jair L.International Journal of Parasitology: Drugs and Drug Resistance (2012), 2 (), 11-19CODEN: IJPDAX; ISSN:2211-3207. (Elsevier Ltd.)A review. Leishmaniasis is one of the most neglected tropical disease in terms of drug discovery and development. Most antileishmanial drugs are highly toxic, present resistance issues or require hospitalization, being therefore not adequate to the field. Recently improvements have been achieved by combination therapy, reducing the time and cost of treatment. Nonetheless, new drugs are still urgently needed. In this review, we describe the current visceral leishmaniasis (VL) treatments and their limitations. We also discuss the new strategies in the drug discovery field including the development and implementation of high-throughput screening (HTS) assays and the joint efforts of international teams to deliver clin. candidates.
- 55Tweats, D.; Bourdin Trunz, B.; Torreele, E. Genotoxicity profile of fexinidazole - a drug candidate in clinical development for human African trypanomiasis (sleeping sickness). Mutagenesis 2012, 27, 523– 532, DOI: 10.1093/mutage/ges015Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1KjsbvO&md5=d46d69b6bd96c3e483c25f0f29e4b3aaGenotoxicity profile of fexinidazole-a drug candidate in clinical development for human African trypanomiasis (sleeping sickness)Tweats, David; Bourdin Trunz, Bernadette; Torreele, ElsMutagenesis (2012), 27 (5), 523-532CODEN: MUTAEX; ISSN:0267-8357. (Oxford University Press)The parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as tinidazole are used to treat trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness. Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compd. mining of public and pharmaceutical company databases, has the potential to become a short-course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of fexinidazole and its two active metabolites, the sulfoxide and sulfone derivs. All the three compds. are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s). It is known that these enzymes can nitroreduce compds. with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions. Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled DNA synthesis in rats; bone marrow micronucleus test in mice), were neg. Thus, fexinidazole does not pose a genotoxic hazard to patients and represents a promising drug candidate for HAT. Fexinidazole is expected to enter Phase II clin. trials in 2012.
- 56Pilkington, L. I.; Barker, D. Total synthesis of (−)-isoamericanin A and (+)-isoamericanol A. Eur. J. Org. Chem. 2014, 2014, 1037– 1046, DOI: 10.1002/ejoc.201301363Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFSktbbE&md5=66ad43bcbe6fb78f3833ff7162a2a2e2Total Synthesis of (-)-isoamericanin A and (+)-isoamericanol APilkington, Lisa I.; Barker, DavidEuropean Journal of Organic Chemistry (2014), 2014 (5), 1037-1046CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)An enantioselective total synthesis of the biol. active 1,4-benzodioxan lignans isoamericanin A and isoamericanol A was designed and the synthesis of the target compds. was n achieved in 11 and 12 steps, resp. These benzodioxane lignan natural products and others that contain a 9-hydroxymethyl group, show a wide range of biol. properties. The 1,4-benzodioxane ring was formed by an acid-catalyzed cyclization, which gave the desired trans-isomer exclusively. This method will allow the synthesis of a no. of benzodioxane compds. contg. a 9-hydroxymethyl group. The title compds. thus formed included (2E)-3-[(2S,3S)-3-(3,4-dihydroxyphenyl)-2,3-dihydro-2-(hydroxymethyl)-1,4-benzodioxin-6-yl]-2-propenal [(-)-isoamericanin A] and (2E)-3-[(2S,3S)-3-(3,4-dihydroxyphenyl)-2,3-dihydro-2-(hydroxymethyl)-1,4-benzodioxin-6-yl]-2-propen-1-ol [(+)-isoamericanol A].
- 57Andresen, T. L.; Jensen, S. S.; Madsen, R.; Jørgensen, K. Synthesis and biological activity of anticancer ether lipids that are specifically released by phospholipase A2 in tumor tissue. J. Med. Chem. 2005, 48, 7305– 7314, DOI: 10.1021/jm049006fGoogle Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFCltb3K&md5=845fed4894abdaa1e9d72801314f35b7Synthesis and Biological Activity of Anticancer Ether Lipids That Are Specifically Released by Phospholipase A2 in Tumor TissueAndresen, Thomas L.; Jensen, Simon S.; Madsen, Robert; Jorgensen, KentJournal of Medicinal Chemistry (2005), 48 (23), 7305-7314CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The clin. use of anticancer lipids is severely limited by their ability to cause lysis of red blood cells prohibiting i.v. injection. Novel delivery systems are therefore required in order to develop anticancer ether lipids (AELs) into clin. useful anticancer drugs. In a recent article (J. Med. Chem. 2004, 47, 1694) we showed that it is possible to construct liposome systems composed of masked AELs that are activated by secretory phospholipase A2 in cancerous tissue. We present here the synthesis of six AELs and evaluate the biol. activity of these bioactive lipids. The synthesized AEL 1-6 were tested against three different cancer cell lines. It was found that the stereochem. of the glycerol headgroup in AEL-2 and 3 has a dramatic effect on the cytotoxicity of the lipids. AEL 1-4 were furthermore evaluated for their ability to prevent phosphorylation of the apoptosis regulating kinase Akt, and a correlation was found between their cytotoxic activity and their ability to inhibit Akt phosphorylation.
- 58Patterson, S.; Wyllie, S. Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends Parasitol. 2014, 30, 289– 298, DOI: 10.1016/j.pt.2014.04.003Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnsVWlsL4%253D&md5=041606bd13d4f709723aa61f1100873bNitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospectsPatterson, Stephen; Wyllie, SusanTrends in Parasitology (2014), 30 (6), 289-298CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)A review. There is an urgent need for new, safer, and effective treatments for the diseases caused by the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. In the search for more effective drugs to treat these 'neglected diseases' researchers have chosen to reassess the therapeutic value of nitroarom. compds. Previously avoided in drug discovery programs owing to potential toxicity issues, a nitro drug is now being used successfully as part of a combination therapy for human African trypanosomiasis. We describe here the rehabilitation of nitro drugs for the treatment of trypanosomatid diseases and discuss the future prospects for this compd. class.
- 59Falzari, K.; Zhu, Z.; Pan, D.; Liu, H.; Hongmanee, P.; Franzblau, S. G. In vitro and in vivo activities of macrolide derivatives against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2005, 49, 1447– 1454, DOI: 10.1128/AAC.49.4.1447-1454.2005Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjt1GjsL0%253D&md5=b137071813f92948d563e489dbaf14a3In vitro and in vivo activities of macrolide derivatives against Mycobacterium tuberculosisFalzari, Kanakeshwari; Zhu, Zhaohai; Pan, Dahua; Liu, Huiwen; Hongmanee, Poonpilas; Franzblau, Scott G.Antimicrobial Agents and Chemotherapy (2005), 49 (4), 1447-1454CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Existing macrolides have never shown definitive clin. efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-pos. bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of ≤4 μM were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compds. with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compds. with low MICs and low cytotoxicity also effected significant redns. in CFU in infected macrophages. Active compds. were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10- to 20-fold redn. of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clin. useful agent for tuberculosis.
- 60Cho, S. H.; Warit, S.; Wan, B.; Hwang, C. H.; Pauli, G. F.; Franzblau, S. G. Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2007, 51, 1380– 1385, DOI: 10.1128/AAC.00055-06Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXktlOjtLg%253D&md5=43c83b44c7a5fdac907463530d4aaad5Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosisCho, Sang Hyun; Warit, Saradee; Wan, Baojie; Hwang, Chang Hwa; Pauli, Guido F.; Franzblau, Scott G.Antimicrobial Agents and Chemotherapy (2007), 51 (4), 1380-1385CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Screening for new antimicrobial agents is routinely conducted only against actively replicating bacteria. However, it is now widely accepted that a physiol. state of nonreplicating persistence (NRP) is responsible for antimicrobial tolerance in many bacterial infections. In tuberculosis, the key to shortening the 6-mo regimen lies in targeting this NRP subpopulation. Therefore, a high-throughput, luminescence-based low-oxygen-recovery assay (LORA) was developed to screen antimicrobial agents against NRP Mycobacterium tuberculosis. M. tuberculosis H37Rv contg. a plasmid with an acetamidase promoter driving a bacterial luciferase gene was adapted to low oxygen conditions by extended culture in a fermentor with a 0.5 headspace ratio. The MICs of 31 established antimicrobial agents were detd. in microplate cultures maintained under anaerobic conditions for 10 days and, for comparative purposes, under aerobic conditions for 7 days. Cultures exposed to drugs under anaerobic conditions followed by 28 h of "recovery" under ambient oxygen produced a luminescent signal that was, for most compds., proportional to the no. of CFU detd. prior to the recovery phase. No agents targeting the cell wall were active against NRP M. tuberculosis, whereas drugs hitting other cellular targets had a range of activities. The calcd. Z' factor was in the range of 0.58 to 0.84, indicating the suitability of the use of LORA for high-throughput assays. This LORA is sufficiently robust for use for primary high-throughput screening of compds. against NRP M. tuberculosis.
- 61Mukkavilli, R.; Pinjari, J.; Patel, B.; Sengottuvelan, S.; Mondal, S.; Gadekar, A.; Verma, M.; Patel, J.; Pothuri, L.; Chandrashekar, G.; Koiram, P.; Harisudhan, T.; Moinuddin, A.; Launay, D.; Vachharajani, N.; Ramanathan, V.; Martin, D. In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral Leishmaniasis. Eur. J. Pharm. Sci. 2014, 65, 147– 155, DOI: 10.1016/j.ejps.2014.09.006Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Gms73N&md5=9d351c194ceba25f2dc23be54bb1ba33In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral LeishmaniasisMukkavilli, Rao; Pinjari, Jakir; Patel, Bhavesh; Sengottuvelan, Shankar; Mondal, Subodh; Gadekar, Ajit; Verma, Manas; Patel, Jignesh; Pothuri, Lavanya; Chandrashekar, Gopu; Koiram, Prabhakar; Harisudhan, Tanukrishnan; Moinuddin, Ansari; Launay, Delphine; Vachharajani, Nimish; Ramanathan, Vikram; Martin, DenisEuropean Journal of Pharmaceutical Sciences (2014), 65 (), 147-155CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)The in vitro metab. and in vivo pharmacokinetic (PK) properties of DNDI-VL-2098, a potential oral agent for Visceral Leishmaniasis (VL) were studied and used to predict its human pharmacokinetics. DNDI-VL-2098 showed a low soly. (10 μM) and was highly permeable (>200 nm/s) in the Caco-2 model. It was stable in vitro in liver microsomes and hepatocytes and no metabolite was detectable in circulating plasma from dosed animals suggesting very slow, if any, metab. of the compd. DNDI-VL-2098 was moderate to highly bound to plasma proteins across the species tested (94-98%). DNDI-VL-2098 showed satisfactory PK properties in mouse, hamster, rat and dog with a low blood clearance (<15% of hepatic blood flow except hamster), a vol. of distribution of about 3 times total body water, acceptable half-life (1-6 h across the species) and good oral bioavailability (37-100%). Allometric scaling of the preclin. PK data to human gave a blood half-life of approx. 20 h suggesting that the compd. could be a once-a-day drug. Based on the above assumptions, the min. efficacious dose predicted for a 50 kg human was 150 mg and 300 mg, using efficacy results in the mouse and hamster, resp.
- 62Hendrickx, S.; Van den Kerkhof, M.; Mabille, D.; Cos, P.; Delputte, P.; Maes, L.; Caljon, G. Combined treatment of miltefosine and paromomycin delays the onset of experimental drug resistance in Leishmania infantum. PLoS Neglected Trop. Dis. 2017, 11 (5), e0005620, DOI: 10.1371/journal.pntd.0005620Google ScholarThere is no corresponding record for this reference.
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Abstract
Figure 1
Figure 1. Structures of antitubercular or antileishmanial agents.
Scheme 1
Scheme 1. a
aReagents and conditions: (i) 70–75 or 95 °C, 18–23 h; (ii) 3,4-dihydro-2H-pyran, PPTS, CH2Cl2, 20 °C, 3.5–24 h; (iii) TBAF, THF, 20 °C, 1–4.5 h, or 0–20 °C, 14 h (for 47); (iv) MsOH, MeOH, 20 °C, 1–2 h; (v) 4-OCF3BnBr or 4-BnOBnCl or 4-BnOBnI, NaH, DMF, 20 °C for 3–20 h or 0–20 °C for 0.7–2.2 h; (vi) TBSOTf, Et3N, CH2Cl2, 20 °C, 3 h; (vii) m-CPBA, CH2Cl2, 20 °C, 18 h; (viii) NaH, DMF, 20 °C for 18 h or 0–20 °C for 3.5 h; (ix) 3.3 M HCl, MeOH, 20 °C, 5 h; (x) DIPEA, toluene, 89–105 °C, 67 h.
Scheme 2
Scheme 2. a
aReagents and conditions: (i) NaH, DMF, 0–20 °C, 2.3–3.5 h; (ii) ArB(OH)2, DMF, (toluene, EtOH), 2 M Na2CO3 or 2 M KHCO3, Pd(dppf)Cl2 under N2, 70–88 °C, 2.2–4 h; (iii) NBS, PPh3, CH2Cl2, 20 °C, 3.5 h.
Scheme 3
Scheme 3. a
aReagents and conditions: (i) NaH, DMF, 0–20 °C (or 0–8 °C), 2–2.7 h; (ii) ArB(OH)2, DMF, (toluene, EtOH), 2 M Na2CO3 or 2 M KHCO3, Pd(dppf)Cl2 under N2, 80–89 °C for 2–4 h or 70 °C for 16 h; (iii) m-CPBA, Na2HPO4, CH2Cl2, 20 °C, 16 h.
Scheme 4
Scheme 4. a
aReagents and conditions: (i) NaH, DMF, 0–20 °C, 0.25–5.5 h; (ii) TBAF, THF, 20 °C, 0.5–18 h; (iii) ArI or ArBr, Et3N, DMF, CuI, Pd(PPh3)2Cl2 under N2, 70 °C for 0.25–1 h or 20 °C for 16 h; (iv) 4-OCF3PhOH, DEAD, PPh3, THF, 0–20 °C, 60 h; (v) DDQ, CH2Cl2, 20 °C, 10–28 h (then TsOH, MeOH, 20 °C, 12 h for 135); (vi) I2, PPh3, imidazole, CH2Cl2, 20 °C, 12–35 h; (vii) 128 or 133, K2CO3, DMF, 85–92 °C, 64–111 h; (viii) CuCl, DMF, 20 °C, 33–43 h; (ix) triphosgene, Et3N, THF, 0–20 °C, 1.7 h, then 142, THF, 20 °C, 3.5 h.
Scheme 5
Scheme 5. a
aReagents and conditions: (i) TsCl, pyridine, 49 °C, 17 h; (ii) NaN3, DMSO, 64 °C, 3.5 days; (iii) HS(CH2)3SH, Et3N, MeOH, 20 °C, 0.5 h, then HCl, dioxane; (iv) NaBH3CN, AcOH, DMF, 0–20 °C, 7–20 h; (v) DIPEA, DMF, 20 °C, 10–25 h; (vi) NMM or DIPEA, Bu2Sn(OAc)2, DMF, 20 °C, 4–18 h; (vii) NaH, DMF, 0–20 °C, 2.7–3.4 h; (viii) ArB(OH)2, DMF, toluene, EtOH, 2 M Na2CO3, Pd(dppf)Cl2 under N2, 84–89 °C, 1.3–3.5 h; (ix) 6-bromopyridin-3-ol, DEAD, PPh3, THF, 0–20 °C, 89 h; (x) TBAF, THF, 20 °C, 13 h; (xi) I2, PPh3, imidazole, CH2Cl2, 20 °C, 41 h; (xii) 164, K2CO3, DMF, 88 °C, 122 h; (xiii) DDQ, CH2Cl2, 20 °C, 98 h, then TsOH, MeOH, CH2Cl2, 20 °C, 10 h.
Figure 2
Figure 2. Schematic diagram of the two lead optimization approaches (A and B) employed.
Figure 3
Figure 3. Potencies of 17 selected phenotypic screening hits (30,39,42,46−49) against L. don (percent inhibition data from IPK, IC50s from CDRI).
Figure 4
Figure 4. Comparative in vivo efficacy in the L. don mouse model: (a) 25 mg/kg and (b) 6.25 mg/kg. All compounds except racemates 24, 116, and 117 are the 6R form.
Figure 5
Figure 5. Comparative in vivo efficacy in the L. inf hamster model. All compounds are the 6R form.
References
This article references 62 other publications.
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- 3den Boer, M.; Argaw, D.; Jannin, J.; Alvar, J. Leishmaniasis impact and treatment access. Clin. Microbiol. Infect. 2011, 17, 1471– 1477, DOI: 10.1111/j.1469-0691.2011.03635.x3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVWrsb3E&md5=46ebcc981f2320c64eedaff317d660e7Leishmaniasis impact and treatment accessden Boer, M.; Argaw, D.; Jannin, J.; Alvar, J.Clinical Microbiology and Infection (2011), 17 (10), 1471-1477CODEN: CMINFM; ISSN:1198-743X. (Wiley-Blackwell)A review. According to disease burden ests., leishmaniasis ranks third in disease burden in disability-adjusted life years caused by neglected tropical diseases and is the second cause of parasite-related deaths after malaria; but for a variety of reasons, it is not receiving the attention that would be justified seeing its importance. This is esp. apparent in the unnecessarily and unacceptably poor access to timely and appropriate treatment for patients. To our knowledge, this is the first publication that addresses the major issues assocd. with poor access to drugs for leishmaniasis and that outlines a no. of feasible and practical solns.
- 4Al-Salem, W.; Herricks, J. R.; Hotez, P. J. A review of visceral leishmaniasis during the conflict in South Sudan and the consequences for East African countries. Parasites Vectors 2016, 9, 460, DOI: 10.1186/s13071-016-1743-74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szjtlGqtQ%253D%253D&md5=c3d84d763f71e186e9843b829492c45aA review of visceral leishmaniasis during the conflict in South Sudan and the consequences for East African countriesAl-Salem Waleed; Herricks Jennifer R; Hotez Peter J; Herricks Jennifer R; Hotez Peter J; Hotez Peter J; Hotez Peter JParasites & vectors (2016), 9 (), 460 ISSN:.BACKGROUND: Visceral leishmaniasis (VL), caused predominantly by Leishmania donovani and transmitted by both Phlebotomus orientalis and Phlebotomus martini, is highly endemic in East Africa where approximately 30 thousands VL cases are reported annually. The largest numbers of cases are found in Sudan - where Phlebotomus orientalis proliferate in Acacia forests especially on Sudan's eastern border with Ethiopia, followed by South Sudan, Ethiopia, Somalia, Kenya and Uganda. Long-standing civil war and unrest is a dominant determinant of VL in East African countries. Here we attempt to identify the correlation between VL epidemics and civil unrest. OBJECTIVE AND METHODOLOGY: In this review, literature published between 1955 and 2016 have been gathered from MSF, UNICEF, OCHA, UNHCR, PubMed and Google Scholar to analyse the correlation between conflict and human suffering from VL, which is especially apparent in South Sudan. FINDINGS: Waves of forced migration as a consequence of civil wars between 1983 and 2005 have resulted in massive and lethal epidemics in southern Sudan. Following a comprehensive peace agreement, but especially with increased allocation of resources for disease treatment and prevention in 2011, cases of VL declined reaching the lowest levels after South Sudan declared independence. However, in the latest epidemic that began in 2014 after the onset of a civil war in South Sudan, more than 1.5 million displaced refugees have migrated internally to states highly endemic for VL, while 800,000 have fled to neighboring countries. CONCLUSION: We find a strong relationship between civil unrest and VL epidemics which tend to occur among immunologically naive migrants entering VL-endemic areas and when Leishmania-infected individuals migrate to new areas and establish additional foci of disease. Further complicating factors in East Africa's VL epidemics include severe lack of access to diagnosis and treatment, HIV/AIDS co-infection, food insecurity and malnutrition. Moreover, cases of post-kala-azar dermal leishmaniasis (PKDL) can serve as important reservoirs of anthroponotic Leishmania parasites.
- 5Sunyoto, T.; Potet, J.; Boelaert, M. Visceral leishmaniasis in Somalia: A review of epidemiology and access to care. PLoS Neglected Trop. Dis. 2017, 11 (3), e0005231, DOI: 10.1371/journal.pntd.0005231There is no corresponding record for this reference.
- 6Kimutai, R.; Musa, A. M.; Njoroge, S.; Omollo, R.; Alves, F.; Hailu, A.; Khalil, E. A. G.; Diro, E.; Soipei, P.; Musa, B.; Salman, K.; Ritmeijer, K.; Chappuis, F.; Rashid, J.; Mohammed, R.; Jameneh, A.; Makonnen, E.; Olobo, J.; Okello, L.; Sagaki, P.; Strub, N.; Ellis, S.; Alvar, J.; Balasegaram, M.; Alirol, E.; Wasunna, M. Safety and effectiveness of sodium stibogluconate and paromomycin combination for the treatment of visceral leishmaniasis in Eastern Africa: Results from a pharmacovigilance programme. Clin. Drug Invest. 2017, 37, 259– 272, DOI: 10.1007/s40261-016-0481-06https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnslChug%253D%253D&md5=f31bfd47e626755fc4fad5b705b1a237Safety and Effectiveness of Sodium Stibogluconate and Paromomycin Combination for the Treatment of Visceral Leishmaniasis in Eastern Africa: Results from a Pharmacovigilance ProgrammeKimutai, Robert; Musa, Ahmed M.; Njoroge, Simon; Omollo, Raymond; Alves, Fabiana; Hailu, Asrat; Khalil, Eltahir A. G.; Diro, Ermias; Soipei, Peninah; Musa, Brima; Salman, Khalid; Ritmeijer, Koert; Chappuis, Francois; Rashid, Juma; Mohammed, Rezika; Jameneh, Asfaw; Makonnen, Eyasu; Olobo, Joseph; Okello, Lawrence; Sagaki, Patrick; Strub, Nathalie; Ellis, Sally; Alvar, Jorge; Balasegaram, Manica; Alirol, Emilie; Wasunna, MoniqueClinical Drug Investigation (2017), 37 (3), 259-272CODEN: CDINFR; ISSN:1173-2563. (Springer International Publishing AG)Introduction: In 2010, WHO recommended a new first-line treatment for visceral leishmaniasis (VL) in Eastern Africa. The new treatment, a combination of i.v. (IV) or i.m. (IM) sodium stibogluconate (SSG) and IM paromomycin (PM) was an improvement over SSG monotherapy, the previous first-line VL treatment in the region. To monitor the new treatment's safety and effectiveness in routine clin. practice a pharmacovigilance (PV) program was developed. Methods: A prospective PV cohort was developed. Regulatory approval was obtained in Sudan, Kenya, Uganda and Ethiopia. Twelve sentinel sites sponsored by the Ministries of Health, Me´decins Sans Frontie´res (MSF) and Drugs for Neglected Diseases initiative (DNDi) participated. VL patients treated using the new treatment were consented and included in a common registry that collected demographics, baseline clin. characteristics, adverse events, serious adverse events and treatment outcomes. Six-monthly periodic safety update reports (PSUR) were prepd. and reviewed by a PV steering committee. Results: Overall 3126 patients were enrolled: 1962 (62.7%) from Sudan, 652 (20.9%) from Kenya, 322 (10.3%) from Ethiopia and 190 (6.1%) from Uganda. Patients were mostly male children (68.1%, median age 11 years) with primary VL (97.8%). SSG-PM initial cure rate was 95.1%; no geog. differences were noted. HIV/VL co-infected patients and patients older than 50 years had initial cure rates of 56 and 81.4%, resp., while 1063 (34%) patients had at least one adverse event (AE) during treatment and 1.92% (n = 60) had a serious adverse event (SAE) with a mortality of 1.0% (n = 32). There were no serious unexpected adverse drug reactions. Conclusions: This first regional PV program in VL supports SSG-PM combination as first-line treatment for primary VL in Eastern Africa. SSG-PM was effective and safe except in HIV/VL co-infected or older patients. Active PV surveillance of targeted safety, effectiveness and key VL outcomes such us VL relapse, PKDL and HIV/VL co-infection should continue and PV data integrated to national and WHO PV databases.
- 7Wasunna, M.; Njenga, S.; Balasegaram, M.; Alexander, N.; Omollo, R.; Edwards, T.; Dorlo, T. P. C.; Musa, B.; Ali, M. H. S.; Elamin, M. Y.; Kirigi, G.; Juma, R.; Kip, A. E.; Schoone, G. J.; Hailu, A.; Olobo, J.; Ellis, S.; Kimutai, R.; Wells, S.; Khalil, E. A. G.; Strub Wourgaft, N.; Alves, F.; Musa, A. Efficacy and safety of AmBisome in combination with sodium stibogluconate or miltefosine and miltefosine monotherapy for African visceral leishmaniasis: Phase II randomized trial. PLoS Neglected Trop. Dis. 2016, 10 (9), e0004880, DOI: 10.1371/journal.pntd.0004880There is no corresponding record for this reference.
- 8Fexinidazole/Miltefosine Combination (VL). DNDi, 2016. https://www.dndi.org/diseases-projects/portfolio/completed-projects/fexinidazole-vl/ (accessed June 22, 2017).There is no corresponding record for this reference.
- 9Singh, N.; Mishra, B. B.; Bajpai, S.; Singh, R. K.; Tiwari, V. K. Natural product based leads to fight against leishmaniasis. Bioorg. Med. Chem. 2014, 22, 18– 45, DOI: 10.1016/j.bmc.2013.11.0489https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOgtrjL&md5=d3f82091638d595b388c6f65080ce8d9Natural product based leads to fight against leishmaniasisSingh, Nisha; Mishra, Bhuwan B.; Bajpai, Surabhi; Singh, Rakesh K.; Tiwari, Vinod K.Bioorganic & Medicinal Chemistry (2014), 22 (1), 18-45CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A review. The growing incidence of parasitic resistance against generic pentavalent antimonials, specifically for visceral disease in Indian subcontinent, is a serious issue in Leishmania control. Notwithstanding the two treatment alternatives, that is amphotericin B and miltefosine are being effectively used but their high cost and therapeutic complications limit their use in endemic areas. In the absence of a vaccine candidate, identification, and characterization of novel drugs and targets is a major requirement of leishmanial research. This review describes current drug regimens, putative drug targets, numerous natural products that have shown promising antileishmanial activity along with some key issues and strategies for future research to control leishmaniasis worldwide.
- 10Target Product Profile for Visceral Leishmaniasis. DNDi, 2017. https://www.dndi.org/diseases-projects/leishmaniasis/tpp-vl/ (accessed December 7, 2017).There is no corresponding record for this reference.
- 11Nagle, A. S.; Khare, S.; Kumar, A. B.; Supek, F.; Buchynskyy, A.; Mathison, C. J. N.; Chennamaneni, N. K.; Pendem, N.; Buckner, F. S.; Gelb, M. H.; Molteni, V. Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Chem. Rev. 2014, 114, 11305– 11347, DOI: 10.1021/cr500365f11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVGls7jM&md5=560ffc9063472316ad1706e4a4caa1dfRecent Developments in Drug Discovery for Leishmaniasis and Human African TrypanosomiasisNagle, Advait S.; Khare, Shilpi; Kumar, Arun Babu; Supek, Frantisek; Buchynskyy, Andriy; Mathison, Casey J. N.; Chennamaneni, Naveen Kumar; Pendem, Nagendar; Buckner, Frederick S.; Gelb, Michael H.; Molteni, ValentinaChemical Reviews (Washington, DC, United States) (2014), 114 (22), 11305-11347CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Leishmaniasis is a parasitic disease that presents four main clin. syndromes: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), visceral leishmaniasis/kala azar(VL), and post kala azar dermal leishmaniasis (PKDL). Causative Leishmania are protozoan parasites that are transmitted among mammalian hosts by phlebotomine sandiflies. In spite of the high prevalence, currently available treatments for leishmaniasis are inadequate. Several new VL treatment shave emerged during the past 10-15 years, but each has serious short comings. These include paromomycin (injectable, long treatment, region-dependente efficacy), miltefosine (cost, teratogenicity, long treatment), and liposomal amphotericin B (cost, hospitalization, region-dependent efficacy). An addnl. challenge is represented by patients with HIV/VL coinfections who are more difficult to cure (lower initial and final cure rates), have greater susceptibility to drug toxicity, and have higher rates of death and relapse. Due to the limitations of the existing treatments, better drugs are urgently needed. Ideally, new VL drugs would be efficacious across all endemic regions, would affect cure in ≤10 days, and would cost <$10 per course (for a complete target product profile for new VL drugs, which was formulated by DNDi, see Table 4). Here we describe the disease history and parasite biol. followed by a summary of the currently available treatments and, finally, review reports of novel small mols. with antileishmanial activity.
- 12Field, M. C.; Horn, D.; Fairlamb, A. H.; Ferguson, M. A. J.; Gray, D. W.; Read, K. D.; De Rycker, M.; Torrie, L. S.; Wyatt, P. G.; Wyllie, S.; Gilbert, I. H. Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need. Nat. Rev. Microbiol. 2017, 15, 217– 231, DOI: 10.1038/nrmicro.2016.19312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsVSms7Y%253D&md5=1585d954d6eb695196a6c8921a84e300Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing needField, Mark C.; Horn, David; Fairlamb, Alan H.; Ferguson, Michael A. J.; Gray, David W.; Read, Kevin D.; De Rycker, Manu; Torrie, Leah S.; Wyatt, Paul G.; Wyllie, Susan; Gilbert, Ian H.Nature Reviews Microbiology (2017), 15 (4), 217-231CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)A review. The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addn., we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.
- 13Don, R.; Ioset, J.-R. Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections. Parasitology 2014, 141, 140– 146, DOI: 10.1017/S003118201300142X13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sbjtFGmsA%253D%253D&md5=ae473acad2714a482e5acc926b8fe85fScreening strategies to identify new chemical diversity for drug development to treat kinetoplastid infectionsDon Rob; Ioset Jean-RobertParasitology (2014), 141 (1), 140-6 ISSN:.The Drugs for Neglected Diseases initiative (DNDi) has defined and implemented an early discovery strategy over the last few years, in fitting with its virtual R&D business model. This strategy relies on a medium- to high-throughput phenotypic assay platform to expedite the screening of compound libraries accessed through its collaborations with partners from the pharmaceutical industry. We review the pragmatic approaches used to select compound libraries for screening against kinetoplastids, taking into account screening capacity. The advantages, limitations and current achievements in identifying new quality series for further development into preclinical candidates are critically discussed, together with attractive new approaches currently under investigation.
- 14Liévin-Le Moal, V.; Loiseau, P. M. Leishmania hijacking of the macrophage intracellular compartments. FEBS J. 2016, 283, 598– 607, DOI: 10.1111/febs.13601There is no corresponding record for this reference.
- 15Naderer, T.; Vince, J. E.; McConville, M. J. Surface determinants of Leishmania parasites and their role in infectivity in the mammalian host. Curr. Mol. Med. 2004, 4, 649– 665, DOI: 10.2174/156652404336006915https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvVKmt78%253D&md5=4b595d691a6454482cb4a802cfc363e6Surface determinants of Leishmania parasites and their role in infectivity in the mammalian hostNaderer, Thomas; Vince, James E.; McConville, Malcolm J.Current Molecular Medicine (2004), 4 (6), 649-665CODEN: CMMUBP; ISSN:1566-5240. (Bentham Science Publishers Ltd.)A review. Leishmania are intracellular protozoan parasites that reside primarily in host mononuclear phagocytes. Infection of host macrophages is initiated by infective promastigote stages and perpetuated by an obligate intracellular amastigote stage. Studies undertaken over the last decade have shown that the compn. of the complex surface glycocalyx of these stages (comprising lipophosphoglycan, GPI-anchored glycoproteins, proteophosphoglycans and free GPI glycolipids) changes dramatically as promastigotes differentiate into amastigotes. Marked stage-specific changes also occur in the expression of other plasma membrane components, including type-1, polytopic and peripheral membrane proteins, reflecting the distinct microbicidal responses and nutritional environments encountered by these stages. More recently, a no. of Leishmania mutants lacking single or multiple surface components have been generated. While some of these mutants are less virulent than wild type parasites, many of these mutants exhibit only mild or no loss of virulence. These studies suggest that (1) the major surface glycocalyx components of the promastigote stage (i.e. LPG, GPI-anchored proteins) only have a transient or minor role in macrophage invasion, (2) that there is considerable functional redundancy in the surface glycocalyx and/or loss of some components can be compensated for by the acquisition of equiv. host glycolipids, (3) the expression of specific nutrient transporters is essential for life in the macrophage, and (4) the role(s) of some surface components differ markedly in different Leishmania species. These mutants will be useful for identifying other surface or intracellular components that are required for virulence in macrophages.
- 16Katsuno, K.; Burrows, J. N.; Duncan, K.; Hooft van Huijsduijnen, R.; Kaneko, T.; Kita, K.; Mowbray, C. E.; Schmatz, D.; Warner, P.; Slingsby, B. T. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discovery 2015, 14, 751– 758, DOI: 10.1038/nrd468316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1SitL7O&md5=6cd6d7c8ca3a85d64f24915da8e1120cHit and lead criteria in drug discovery for infectious diseases of the developing worldKatsuno, Kei; Burrows, Jeremy N.; Duncan, Ken; van Huijsduijnen, Rob Hooft; Kaneko, Takushi; Kita, Kiyoshi; Mowbray, Charles E.; Schmatz, Dennis; Warner, Peter; Slingsby, B. T.Nature Reviews Drug Discovery (2015), 14 (11), 751-758CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chem. starting points for such projects is a key factor in improving the likelihood of clin. success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compds. With this in mind, the Japanese Global Health Innovative Technol. (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill & Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.
- 17Burrows, J. N.; Elliott, R. L.; Kaneko, T.; Mowbray, C. E.; Waterson, D. The role of modern drug discovery in the fight against neglected and tropical diseases. MedChemComm 2014, 5, 688– 700, DOI: 10.1039/c4md00011k17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXovVanu7k%253D&md5=314051c267239b24f6f98b2405e624b9The role of modern drug discovery in the fight against neglected and tropical diseasesBurrows, Jeremy N.; Elliott, Richard L.; Kaneko, Takushi; Mowbray, Charles E.; Waterson, DavidMedChemComm (2014), 5 (6), 688-700CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. Neglected and tropical diseases affect a large proportion of the world's population and impose a huge economic and health burden on developing countries. Despite this, there is a dearth of safe, effective, suitable medications for treatment of these diseases, largely as a result of an underinvestment in developing new drugs against these diseases by the majority of research-based pharmaceutical companies. In the past 12 years, the situation has begun to improve with the emergence of public-private product development partnerships (PDPs), which foster a collaborative approach to drug discovery and have established strong drug development pipelines for neglected and tropical diseases. Some large pharmaceutical companies have also now established dedicated research sites for developing world diseases and are working closely with PDPs on drug development activities. However, drug discovery in this field is still hampered by a lack of sufficient funding and technol. investment, and there is a shortage of the tools, assays, and well-validated targets needed to ensure strong drug development pipelines in the future. The availability of high-quality chem. diverse compd. libraries to enable lead discovery remains one of the crit. bottlenecks. The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners. The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate together and will require sustained resourcing and focus.
- 18Mowbray, C. E.; Braillard, S.; Speed, W.; Glossop, P. A.; Whitlock, G. A.; Gibson, K. R.; Mills, J. E. J.; Brown, A. D.; Gardner, J. M. F.; Cao, Y.; Hua, W.; Morgans, G. L.; Feijens, P.-B.; Matheeussen, A.; Maes, L. J. Novel amino-pyrazole ureas with potent in vitro and in vivo antileishmanial activity. J. Med. Chem. 2015, 58, 9615– 9624, DOI: 10.1021/acs.jmedchem.5b01456There is no corresponding record for this reference.
- 19Khare, S.; Nagle, A. S.; Biggart, A.; Lai, Y. H.; Liang, F.; Davis, L. C.; Barnes, S. W.; Mathison, C. J. N.; Myburgh, E.; Gao, M.-Y.; Gillespie, J. R.; Liu, X.; Tan, J. L.; Stinson, M.; Rivera, I. C.; Ballard, J.; Yeh, V.; Groessl, T.; Federe, G.; Koh, H. X. Y.; Venable, J. D.; Bursulaya, B.; Shapiro, M.; Mishra, P. K.; Spraggon, G.; Brock, A.; Mottram, J. C.; Buckner, F. S.; Rao, S. P. S.; Wen, B. G.; Walker, J. R.; Tuntland, T.; Molteni, V.; Glynne, R. J.; Supek, F. Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature 2016, 537, 229– 233, DOI: 10.1038/nature1933919https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyhtr%252FL&md5=a05e7ce0f6b912b3003c5b3f42a005bbProteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sicknessKhare, Shilpi; Nagle, Advait S.; Biggart, Agnes; Lai, Yin H.; Liang, Fang; Davis, Lauren C.; Barnes, S. Whitney; Mathison, Casey J. N.; Myburgh, Elmarie; Gao, Mu-Yun; Gillespie, J. Robert; Liu, Xianzhong; Tan, Jocelyn L.; Stinson, Monique; Rivera, Ianne C.; Ballard, Jaime; Yeh, Vince; Groessl, Todd; Federe, Glenn; Koh, Hazel X. Y.; Venable, John D.; Bursulaya, Badry; Shapiro, Michael; Mishra, Pranab K.; Spraggon, Glen; Brock, Ansgar; Mottram, Jeremy C.; Buckner, Frederick S.; Rao, Srinivasa P. S.; Wen, Ben G.; Walker, John R.; Tuntland, Tove; Molteni, Valentina; Glynne, Richard J.; Supek, FrantisekNature (London, United Kingdom) (2016), 537 (7619), 229-233CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., resp. These parasites have similar biol. and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such mol. targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chem. validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
- 20Mukherjee, T.; Boshoff, H. Nitroimidazoles for the treatment of TB: past, present and future. Future Med. Chem. 2011, 3, 1427– 1454, DOI: 10.4155/fmc.11.9020https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFSktr%252FN&md5=44739c4906d7b9e1ffeaa76f65acb16cNitroimidazoles for the treatment of TB: past, present and futureMukherjee, Tathagata; Boshoff, HelenaFuture Medicinal Chemistry (2011), 3 (11), 1427-1454CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review. Tuberculosis remains a leading cause of death resulting from an infectious agent, and the spread of multi- and extensively drug-resistant strains of Mycobacterium tuberculosis poses a threat to management of global health. New drugs that effectively shorten the duration of treatment and are active against drug-resistant strains of this pathogen are urgently required to develop effective chemotherapies to combat this disease. Two nitroimidazoles, PA-824 and OPC-67683, are currently in Phase II clin. trials for the treatment of TB and the outcome of these may det. the future directions of drug development for anti-tubercular nitroimidazoles. In this review we summarize the development of these nitroimidazoles and alternative analogs in these series that may offer attractive alternatives to PA-824 and OPC-67683 for further development in the drug-discovery pipeline. Lastly, the potential pitfalls in the development of nitroimidazoles as drugs for TB are discussed.
- 21Diacon, A. H.; Dawson, R.; du Bois, J.; Narunsky, K.; Venter, A.; Donald, P. R.; van Niekerk, C.; Erondu, N.; Ginsberg, A. M.; Becker, P.; Spigelman, M. K. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob. Agents Chemother. 2012, 56, 3027– 3031, DOI: 10.1128/AAC.06125-1121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnslWrtrk%253D&md5=5ab64eb6bc8d02e4e7b1bb6d9d112920Phase II dose-ranging trial of the early bactericidal activity of PA-824Diacon, Andreas H.; Dawson, Rodney; du Bois, Jeannine; Narunsky, Kim; Venter, Amour; Donald, Peter R.; van Niekerk, Christo; Erondu, Ngozi; Ginsberg, Ann M.; Becker, Piet; Spigelman, Melvin K.Antimicrobial Agents and Chemotherapy (2012), 56 (6), 3027-3031CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-pos. adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body wt. per day for 14 days. Eight subjects received once-daily std. antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a pos. control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/mL sputum (± std. deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, resp. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approx. dose proportional with respect to the area under the time-concn. curve. All doses were safe and well tolerated with no dose-limiting adverse events or clin. significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.
- 22Murray, S.; Mendel, C.; Spigelman, M. TB Alliance regimen development for multidrug-resistant tuberculosis. International Journal of Tuberculosis and Lung Disease 2016, 20 (Suppl. 1), S38– S41, DOI: 10.5588/ijtld.16.0069There is no corresponding record for this reference.
- 23Upton, A. M.; Cho, S.; Yang, T. J.; Kim, Y.; Wang, Y.; Lu, Y.; Wang, B.; Xu, J.; Mdluli, K.; Ma, Z.; Franzblau, S. G. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2015, 59, 136– 144, DOI: 10.1128/AAC.03823-1423https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1aisLk%253D&md5=3061f7349c1059a9514e5cd6ee42431cIn vitro and In Vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosisUpton, A. M.; Cho, S. M.; Yang, T. J.; Kim, Y.; Wang, Y.; Lu, Y.; Wang, B.; Xu, J.; Mdluli, K.; Ma, Z.; Franzblau, S. G.Antimicrobial Agents and Chemotherapy (2015), 59 (1), 136-144/1-136-144/9, 9 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid OPC-67683, Deltyba is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 SN31354 S-2-nitro-6-6-4-trifluoromethoxyphenyl pyridine-3-ylmethoxy-6,7-dihydro-5H-imidazo 2,1-b 1,3 oxazine is a pyridine-contg. biaryl compd. with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chem. effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addn. of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clin. drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10-7. In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.
- 24Thompson, A. M.; O’Connor, P. D.; Marshall, A. J.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Braillard, S.; Chatelain, E.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Cooper, C. B.; Denny, W. A. 7-Substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: novel antitubercular agents lead to a new preclinical candidate for visceral leishmaniasis. J. Med. Chem. 2017, 60, 4212– 4233, DOI: 10.1021/acs.jmedchem.7b0003424https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVentbw%253D&md5=ccb6e45ed81213d05527071e095bd6517-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral LeishmaniasisThompson, Andrew M.; O'Connor, Patrick D.; Marshall, Andrew J.; Yardley, Vanessa; Maes, Louis; Gupta, Suman; Launay, Delphine; Braillard, Stephanie; Chatelain, Eric; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Cooper, Christopher B.; Denny, William A.Journal of Medicinal Chemistry (2017), 60 (10), 4212-4233CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Within a backup program for the clin. investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analog DNDI-VL-2098 as a VL preclin. candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compds. with improved soly. and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one Ph by pyridine or pyrimidine showed improved soly. and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.
- 25Thompson, A. M.; O’Connor, P. D.; Blaser, A.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Martin, D.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Repositioning antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for neglected tropical diseases: structure-activity studies on a preclinical candidate for visceral leishmaniasis. J. Med. Chem. 2016, 59, 2530– 2550, DOI: 10.1021/acs.jmedchem.5b0169925https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivFGmtbY%253D&md5=9eebc55cc434cc4dec0692bef5bbed98Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral LeishmaniasisThompson, Andrew M.; O'Connor, Patrick D.; Blaser, Adrian; Yardley, Vanessa; Maes, Louis; Gupta, Suman; Launay, Delphine; Martin, Denis; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.Journal of Medicinal Chemistry (2016), 59 (6), 2530-2550CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivs. were initially studied for tuberculosis within a backup program for the clin. trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Addnl. work was then conducted to delineate its essential structural features, aiming to improve soly. and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of Ph rings by pyridine. Several less lipophilic analogs displayed improved aq. soly., particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection,phenylpyridine deriv. I stood out, providing efficacy surpassing that of the original preclin. lead.
- 26Gupta, S.; Yardley, V.; Vishwakarma, P.; Shivahare, R.; Sharma, B.; Launay, D.; Martin, D.; Puri, S. K. Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis. J. Antimicrob. Chemother. 2015, 70, 518– 527, DOI: 10.1093/jac/dku42226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFGmur8%253D&md5=179ae312a4efef99059577223650641aNitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasisGupta, Suman; Yardley, Vanessa; Vishwakarma, Preeti; Shivahare, Rahul; Sharma, Bhawna; Launay, Delphine; Martin, Denis; Puri, Sunil K.Journal of Antimicrobial Chemotherapy (2015), 70 (2), 518-527CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)Objectives: The objective of this study was to identify a nitroimidazo-oxazole lead mol. for the treatment of visceral leishmaniasis (VL). Methods: A library of 72 nitroimidazo-oxazoles was evaluated in vitro for their antileishmanial activity against luciferase-transfected DD8 amastigotes of Leishmania donovani. On the basis of their in vitro potency and pharmacokinetic properties, the promising compds. were tested in acute BALB/c mouse and chronic hamster models of VL via oral administration and efficacy was evaluated by microscopic counting of amastigotes after Giemsa staining. The best antileishmanial candidates (racemate DNDI-VL-2001) and its R enantiomer (DNDI-VL-2098) were evaluated in vitro against a range of Leishmania strains. These candidates were further studied in a hamster model using various dose regimens. Cytokine and inducible nitric oxide synthase estns. by real-time PCR and nitric oxide generation by Griess assay were also carried out for DNDI-VL-2098. Results: In vitro screening of nitroimidazo-oxazole compds. identified the racemate DNDI-VL-2001 (6-nitroimidazo-oxazole deriv.) and its enantiomers as candidates for further evaluation in in vivo models of VL. DNDI-VL-2098 (IC50 of 0.03 μM for the DD8 strain) showed excellent in vivo activity in both mouse and hamster models, with an ED90 value of 3.7 and <25 mg/kg, resp., and was also found to be very effective against high-grade infection in the hamster model. Our studies revealed that, along with leishmanicidal activity, DNDI-VL-2098 was also capable of inducing host-protective immune cells to suppress Leishmania parasites in hamsters. Conclusions: These studies led to the identification of compd. DNDI-VL-2098 as a preclin. candidate for further drug development as an oral treatment for VL.
- 27Wyllie, S.; Roberts, A. J.; Norval, S.; Patterson, S.; Foth, B. J.; Berriman, M.; Read, K. D.; Fairlamb, A. H. Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in Leishmania. PLoS Pathog. 2016, 12 (11), e1005971, DOI: 10.1371/journal.ppat.100597127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitV2mt7g%253D&md5=0506a45a0a29a613f96c1b874af54b96Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in LeishmaniaWyllie, Susan; Roberts, Adam J.; Norval, Suzanne; Patterson, Stephen; Foth, Bernardo J.; Berriman, Matthew; Read, Kevin D.; Fairlamb, Alan H.PLoS Pathogens (2016), 12 (11), e1005971/1-e1005971/22CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)Drug discovery pipelines for the "neglected diseases" are now heavily populated with nitroheterocyclic compds. Recently, the bicyclic nitro-compds. (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quant. proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein. Susceptibility of leishmania was restored by reintroduction of the wild-type gene into the resistant line, which was accompanied by the ability to metabolise these compds. Overexpression of NTR2 in wild-type parasites rendered cells hyper-sensitive to bicyclic nitro-compds., but only marginally to the monocyclic nitro-drugs, nifurtimox and fexinidazole sulfone, known to be activated by a mitochondrial oxygen-insensitive nitroreductase (NTR1). Conversely, a double knockout NTR2 null cell line was completely resistant to bicyclic nitro-compds. and only marginally resistant to nifurtimox. Sensitivity was fully restored on expression of NTR2 in the null background. Thus, NTR2 is necessary and sufficient for activation of these bicyclic nitro-drugs. Recombinant NTR2 was capable of reducing bicyclic nitro-compds. in the same rank order as drug sensitivity in vitro. These findings may aid the future development of better, novel anti-leishmanial drugs. Moreover, the discovery of anti-leishmanial nitro-drugs with independent modes of activation and independent mechanisms of resistance alleviates many of the concerns over the continued development of these compd. series.
- 28Patterson, S.; Wyllie, S.; Norval, S.; Stojanovski, L.; Simeons, F. R. C.; Auer, J. L.; Osuna-Cabello, M.; Read, K. D.; Fairlamb, A. H. The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. eLife 2016, 5, e09744, DOI: 10.7554/eLife.0974428https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmsFamtLw%253D&md5=1a704d1acb52b08cae5f73cf625f293aThe anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasisPatterson, Stephen; Wyllie, Susan; Norval, Suzanne; Stojanovski, Laste; Simeons, Frederick R. C.; Auer, Jennifer L.; Osuna-Cabello, Maria; Read, Kevin D.; Fairlamb, Alan H.eLife (2016), 5 (), e09744/1-e09744/21CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmaniadonovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg-1 for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg-1 than at 3 mg kg-1 (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.
- 29Thompson, A. M.; Denny, W. A.; Blaser, A.; Ma, Z. Nitroimidazooxazine and Nitroimidazooxazole Analogues and Their Uses. Patent WO 2011/014776 A1, 2011, and U.S. Patent 8293734 B2, 2012.There is no corresponding record for this reference.
- 30Thompson, A. M.; Blaser, A.; Palmer, B. D.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Biarylmethoxy 2-nitroimidazooxazine antituberculosis agents: Effects of proximal ring substitution and linker reversal on metabolism and efficacy. Bioorg. Med. Chem. Lett. 2015, 25, 3804– 3809, DOI: 10.1016/j.bmcl.2015.07.084There is no corresponding record for this reference.
- 31Li, X.; Manjunatha, U. H.; Goodwin, M. B.; Knox, J. E.; Lipinski, C. A.; Keller, T. H.; Barry, C. E.; Dowd, C. S. Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines, analogues of PA-824. Bioorg. Med. Chem. Lett. 2008, 18, 2256– 2262, DOI: 10.1016/j.bmcl.2008.03.01131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjvFyksbw%253D&md5=660a69bf91fe7949b9c90349f4530ed0Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines, analogues of PA-824Li, Xiaojin; Manjunatha, Ujjini H.; Goodwin, Michael B.; Knox, John E.; Lipinski, Christopher A.; Keller, Thomas H.; Barry, Clifton E., III; Dowd, Cynthia S.Bioorganic & Medicinal Chemistry Letters (2008), 18 (7), 2256-2262CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Nitroimidazoles, such as I (R1 = R2 = H) (PA-824) or OPC-67683, are currently in clin. development as members of a promising new class of therapeutics for tuberculosis. While the antitubercular activity of these compds. is high, they both suffer from poor water soly. thus complicating development. The single crystal X-ray structure of I (R1 = R2 = H) was detd. and showed a close packing of the nitroimidazoles facilitated by a pseudoaxial conformation of the p-trifluoromethoxybenzyl ether. In an attempt to disrupt this tight packing by destabilizing the axial preference of this side chain, the two diastereomers I (R1 = Me, R2 = H) and I (R1 = H; R2 = Me) were synthesized. Detn. of the crystal structure of the (S)-I (R1 = Me; R2 = H) revealed that the benzylic side chain remained pseudoaxial while the (R)-I (R1 = H; R2 = Me) adopted the desired pseudoequatorial conformation. Both derivs. displayed similar activities against Mycobacterium tuberculosis, but neither showed improved aq. soly., suggesting that inherent lattice stability is not likely to be a major factor in limiting soly. Conformational anal. revealed that all three compds. have similar energetically accessible conformations in soln. Addnl., these results suggest that the nitroreductase that initially recognizes PA-824 is somewhat insensitive to substitutions at the 7-position.
- 32Baker, W. R.; Shaopei, C.; Keeler, E. L. Nitro-[2,1-b]imidazopyran Compounds and Antibacterial Uses Thereof. U.S. Patent 6087358, 2000.There is no corresponding record for this reference.
- 33Hirata, M.; Fujimoto, R.; Mikami, M. Preparation of 2-Methylglycidyl Ethers from 3-Halogeno-2-methyl-1,2-propanediols or 2-Methylepihalohydrins. Patent JP 2007297330, 2007.There is no corresponding record for this reference.
- 34Elbert, B. L.; Lim, D. S. W.; Gudmundsson, H. G.; O’Hanlon, J. A.; Anderson, E. A. Synthesis of cyclic alkenylsiloxanes by semihydrogenation: a stereospecific route to (Z)-alkenyl polyenes. Chem. - Eur. J. 2014, 20, 8594– 8598, DOI: 10.1002/chem.20140325534https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptlKrsbs%253D&md5=8fc0c25bc10fe28ca302e79f3a9767fbSynthesis of Cyclic Alkenylsiloxanes by Semihydrogenation: A Stereospecific Route to (Z)-Alkenyl PolyenesElbert, Bryony L.; Lim, Diane S. W.; Gudmundsson, Haraldur G.; O'Hanlon, Jack A.; Anderson, Edward A.Chemistry - A European Journal (2014), 20 (28), 8594-8598CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Cyclic alkenylsiloxanes were synthesized by a semi-hydrogenation (partial hydrogenation) of alkynylsilanes which is a reaction previously plagued by poor stereoselectivity. The silanes, which can be synthesized on multi-gram scale, undergo Hiyama-Denmark coupling to give (Z)-alkenyl polyene motifs found in bioactive natural products [i.e., bitungolide C, fostriecin, phoslactomycin B, 6-[(1E,3R,4R,6R,7Z,9Z)-3-(2-aminoethyl)-10-cyclohexyl-3,6-dihydroxy-4-(phosphonooxy)-1,7,9-decatriene-1-yl]-5-ethyl-5,6-dihydro-2H-pyran-2-one]. The ring size of the silane is crucial: five-membered cyclic siloxanes also couple under fluoride-free conditions, while their six-membered homologs do not, enabling orthogonality within this structural motif. Under optimized conditions the synthesis of the target compds. was achieved by a palladium-catalyzed cyclization of [[bis(alkoxy)alkyl]silyl]alkynol derivs. and the title compds. thus formed included 1-oxa-2-silacyclopent-3-ene derivs. and 1-oxa-2-silacyclohex-3-ene derivs. (cyclic alkenylsiloxanes).
- 35Ginsberg, A. M.; Laurenzi, M. W.; Rouse, D. J.; Whitney, K. D.; Spigelman, M. K. Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects. Antimicrob. Agents Chemother. 2009, 53, 3720– 3725, DOI: 10.1128/AAC.00106-0935https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFCjsr7E&md5=b1a66b6df94526f21a3873747ad54487Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjectsGinsberg, Ann M.; Laurenzi, Martino W.; Rouse, Doris J.; Whitney, Karl D.; Spigelman, Melvin K.Antimicrobial Agents and Chemotherapy (2009), 53 (9), 3720-3725CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compd.'s MIC is between 0.015 and 0.25 μg/mL for drug-sensitive strains and between 0.03 and 0.53 μg/mL for drug-resistant strains. In addn., it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clin. studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approx. 3 μg/mL (1,500-mg dose) in the single-dose study and 3.8 μg/mL (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approx. 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compd. for the treatment of tuberculosis.
- 36Thompson, A. M.; Marshall, A. J.; Maes, L.; Yarlett, N.; Bacchi, C. J.; Gaukel, E.; Wring, S. A.; Launay, D.; Braillard, S.; Chatelain, E.; Mowbray, C. E.; Denny, W. A. Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides. Bioorg. Med. Chem. Lett. 2018, 28, 207– 213, DOI: 10.1016/j.bmcl.2017.10.06736https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvV2lsr7N&md5=00573f41d0ae4882b316c5ed36199ef5Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxidesThompson, Andrew M.; Marshall, Andrew J.; Maes, Louis; Yarlett, Nigel; Bacchi, Cyrus J.; Gaukel, Eric; Wring, Stephen A.; Launay, Delphine; Braillard, Stephanie; Chatelain, Eric; Mowbray, Charles E.; Denny, William A.Bioorganic & Medicinal Chemistry Letters (2018), 28 (2), 207-213CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A 900 compd. nitroimidazole-based library derived from the authors' pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and detn. of the most active chiral form, a thiazine oxide counterpart of pretomanid (24 ((6S)-2-Nitro-6-[[4-(trifluoromethoxy)benzyl]oxy]-6,7-dihydro-5H-imidazo[2,1-6][1,3]thiazine 8-oxide)) was identified as the best lead. With once daily oral dosing, this compd. delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.
- 37Gurumurthy, M.; Mukherjee, T.; Dowd, C. S.; Singh, R.; Niyomrattanakit, P.; Tay, J. A.; Nayyar, A.; Lee, Y. S.; Cherian, J.; Boshoff, H. I.; Dick, T.; Barry, C. E., III; Manjunatha, U. H. Substrate specificity of the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles. FEBS J. 2012, 279, 113– 125, DOI: 10.1111/j.1742-4658.2011.08404.x37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xit1Smsw%253D%253D&md5=ad91d6afcc9a4d3b715a1e7dacf1f9fdSubstrate specificity of the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazolesGurumurthy, Meera; Mukherjee, Tathagata; Dowd, Cynthia S.; Singh, Ramandeep; Niyomrattanakit, Pornwaratt; Tay, Jo Ann; Nayyar, Amit; Lee, Yong Sok; Cherian, Joseph; Boshoff, Helena I.; Dick, Thomas; Barry, Clifton E., III; Manjunatha, Ujjini H.FEBS Journal (2012), 279 (1), 113-125CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)The bicyclic 4-nitroimidazoles PA-824 and OPC-67683 represent a promising novel class of therapeutics for tuberculosis and are currently in phase II clin. development. Both compds. are pro-drugs that are reductively activated by a deazaflavin (F420) dependent nitroreductase (Ddn). Herein we describe the biochem. properties of Ddn including the optimal enzymic turnover conditions and substrate specificity. The preference of the enzyme for the (S) isomer of PA-824 over the (R) isomer is directed by the presence of a long hydrophobic tail. Nitroimidazo-oxazoles bearing only short alkyl substituents at the C-7 position of the oxazole were reduced by Ddn without any stereochem. preference. However, with bulkier substitutions on the tail of the oxazole, Ddn displayed stereospecificity. Ddn mediated metab. of PA-824 results in the release of reactive nitrogen species. We have employed a direct chemiluminescence based nitric oxide (NO) detection assay to measure the kinetics of NO prodn. by Ddn. Binding affinity of PA-824 to Ddn was monitored through intrinsic fluorescence quenching of the protein facilitating a turnover-independent assessment of affinity. Our results indicate that (R)-PA-824, despite not being turned over by Ddn, binds to the enzyme with the same affinity as the active (S) isomer. This result, in combination with docking studies in the active site, suggests that the (R) isomer probably has a different binding mode than the (S) with the C-3 of the imidazole ring orienting in a non-productive position with respect to the incoming hydride from F420. The results presented provide insight into the biochem. mechanism of redn. and elucidate structural features important for understanding substrate binding.
- 38Patterson, S.; Wyllie, S.; Stojanovski, L.; Perry, M. R.; Simeons, F. R. C.; Norval, S.; Osuna-Cabello, M.; De Rycker, M.; Read, K. D.; Fairlamb, A. H. The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral leishmaniasis. Antimicrob. Agents Chemother. 2013, 57, 4699– 4706, DOI: 10.1128/AAC.00722-1338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVygtb7I&md5=401760844c66c37003791c9dcf83392bThe R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral leishmaniasisPatterson, Stephen; Wyllie, Susan; Stojanovski, Laste; Perry, Meghan R.; Simeons, Frederick R. C.; Norval, Suzanne; Osuna-Cabello, Maria; De Rycker, Manu; Read, Kevin D.; Fairlamb, Alan H.Antimicrobial Agents and Chemotherapy (2013), 57 (10), 4699-4706CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)The novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is currently in phase II clin. trials for tuberculosis (TB). In contrast to M. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity against Leishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogs are inactive, underlining the importance of the nitro group in the mechanism of action. Although the in vitro and in vivo pharmacol. profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body wt.-1, twice daily for 5 days. In M. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent in Leishmania spp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compds. Drug combination studies in vitro indicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clin. trials against VL.
- 39Kmentova, I.; Sutherland, H. S.; Palmer, B. D.; Blaser, A.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A.; Thompson, A. M. Synthesis and structure-activity relationships of aza- and diazabiphenyl analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2010, 53, 8421– 8439, DOI: 10.1021/jm101288tThere is no corresponding record for this reference.
- 40Thompson, A. M.; Blaser, A.; Anderson, R. F.; Shinde, S. S.; Franzblau, S. G.; Ma, Z.; Denny, W. A.; Palmer, B. D. Synthesis, reduction potentials, and antitubercular activity of ring A/B analogues of the bioreductive drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2009, 52, 637– 645, DOI: 10.1021/jm801087e40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFais7%252FK&md5=a9fe7edce4c538f14ddec49942a1e9a0Synthesis, Reduction Potentials, and Antitubercular Activity of Ring A/B Analogues of the Bioreductive Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)Thompson, Andrew M.; Blaser, Adrian; Anderson, Robert F.; Shinde, Sujata S.; Franzblau, Scott G.; Ma, Zhenkun; Denny, William A.; Palmer, Brian D.Journal of Medicinal Chemistry (2009), 52 (3), 637-645CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The nitroimidazooxazine I (PA-824) is a new class of bioreductive drug for tuberculosis. A series of related bicyclic nitroheterocycles was synthesized, designed to have a wide range of one-electron redn. potentials E(1) (from -570 to -338 mV, compared with -534 mV for I). The obsd. E(1) values closely correlated with the σm values of the heteroatom at the 4/8-position of the adjacent six-membered ring. Although the compds. spanned a range of E(1) values around that of I, only the nitroimidazothiazines showed significant antitubercular activity (at a similar level of potency), suggesting that E(1) is not the main driver of efficacy. Furthermore, there was a correlation between activity and the formation of imidazole ring-reduced products at the two-electron level, pointing to the potential importance of this redn. pathway, which is detd. by the nature of the substituent at the 2-position of the 4-nitroimidazole ring.
- 41Bom, D.; Curran, D. P.; Kruszewski, S.; Zimmer, S. G.; Thompson Strode, J.; Kohlhagen, G.; Du, W.; Chavan, A. J.; Fraley, K. A.; Bingcang, A. L.; Latus, L. J.; Pommier, Y.; Burke, T. G. The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J. Med. Chem. 2000, 43, 3970– 3980, DOI: 10.1021/jm000144o41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmsFeitL0%253D&md5=07aa6c0159366ff9685892c10a6fc959The Novel Silatecan 7-tert-Butyldimethylsilyl-10-hydroxycamptothecin Displays High Lipophilicity, Improved Human Blood Stability, and Potent Anticancer ActivityBom, David; Curran, Dennis P.; Kruszewski, Stefan; Zimmer, Stephen G.; Strode, J. Thompson; Kohlhagen, Glenda; Du, Wu; Chavan, Ashok J.; Fraley, Kimberly A.; Bingcang, Alex L.; Latus, Lori J.; Pommier, Yves; Burke, Thomas G.Journal of Medicinal Chemistry (2000), 43 (21), 3970-3980CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The rational design and synthesis of B- and A,B-ring-modified camptothecins are described. The key α-hydroxy-δ-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, I) displays superior stability in human blood when compared with clin. relevant camptothecin analogs. In human blood I displayed a t1/2 of 130 min and a percent lactone at equil. value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and I is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addn., the dual 7-alkylsilyl and 10-hydroxy substitution in I enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that I is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogs topotecan and CPT-11. In addn., cell-free cleavage assays reveal that I is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for I strongly suggest that it is an excellent candidate for addnl. in vivo pharmacol. and efficacy studies.
- 42Thompson, A. M.; Sutherland, H. S.; Palmer, B. D.; Kmentova, I.; Blaser, A.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Synthesis and structure-activity relationships of varied ether linker analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2011, 54, 6563– 6585, DOI: 10.1021/jm200377rThere is no corresponding record for this reference.
- 43Alberati-Giani, D.; Jolidon, S.; Narquizian, R.; Nettekoven, M. H.; Norcross, R. D.; Pinard, E.; Stalder, H. Preparation of 1-(2-Aminobenzoyl)-piperazine Derivatives as Glycine Transporter 1 (GlyT-1) Inhibitors for Treating Psychoses. Patent WO 2005023260 A1, 2005.There is no corresponding record for this reference.
- 44Kaiser, M.; Maes, L.; Tadoori, L. P.; Spangenberg, T.; Ioset, J.-R. Repurposing of the open access malaria box for kinetoplastid diseases identifies novel active scaffolds against trypanosomatids. J. Biomol. Screening 2015, 20, 634– 645, DOI: 10.1177/108705711556915544https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlWlu7nM&md5=64a9cd3add4e2b1b6682422018f0c61bRepurposing of the open access malaria box for kinetoplastid diseases identifies novel active scaffolds against trypanosomatidsKaiser, Marcel; Maes, Louis; Tadoori, Leela Pavan; Spangenberg, Thomas; Ioset, Jean-RobertJournal of Biomolecular Screening (2015), 20 (5), 634-645CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)Phenotypic screening had successfully been used for hit generation, esp. in the field of neglected diseases, in which feeding the drug pipeline with new chemotypes remains a const. challenge. Here, we catalyze drug discovery research using a publicly available screening tool to boost drug discovery. The Malaria Box, assembled by the Medicines for Malaria Venture, is a structurally diverse set of 200 druglike and 200 probelike compds. distd. from more than 20,000 antimalarial hits from corporate and academic libraries. Repurposing such compds. has already identified new scaffolds against cryptosporidiosis and schistosomiasis. In addn. to initiating new hit- to- lead activities, screening the Malaria Box against a plethora of other parasites would enable the community to better understand the similarities and differences between them. We describe the screening of the Malaria Box and triaging of the identified hits against kinetoplastids responsible for human African trypanosomiasis (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and visceral leishmaniasis (Leishmania donovani and Leishmania infantum). The in vitro and in vivo profiling of the most promising active compds. with respect to efficacy, toxicity, pharmacokinetics, and complementary druggable properties are presented and a collaborative model used as a way to accelerate the discovery process discussed.
- 45Siqueira-Neto, J. L.; Song, O.-R.; Oh, H.; Sohn, J.-H.; Yang, G.; Nam, J.; Jang, J.; Cechetto, J.; Lee, C. B.; Moon, S.; Genovesio, A.; Chatelain, E.; Christophe, T.; Freitas-Junior, L. H. Antileishmanial high-throughput drug screening reveals drug candidates with new scaffolds. PLoS Neglected Trop. Dis. 2010, 4 (5), e675, DOI: 10.1371/journal.pntd.0000675There is no corresponding record for this reference.
- 46Palmer, B. D.; Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A.; Thompson, A. M. Synthesis and structure-activity relationships for extended side chain analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2015, 58, 3036– 3059, DOI: 10.1021/jm501608q46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVOrtrY%253D&md5=2ce7144ac56b5ec156d83a09d4d6af90Synthesis and Structure-Activity Relationships for Extended Side Chain Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)Palmer, Brian D.; Sutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.; Thompson, Andrew M.Journal of Medicinal Chemistry (2015), 58 (7), 3036-3059CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Novel extended side chain nitroimidazooxazine analogs featuring diverse linker groups between two aryl rings, e.g., I, were studied as a potential strategy to improve soly. and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some soly. improvements, particularly in combination with pyridine rings. Most of the 18 compds. further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-contg. acetylene derivs. (5-fold and >933-fold) gave in vivo efficacies notably superior to the clin. stage compd. pretomanid (PA-824). The most efficacious analog, I, also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.
- 47Palmer, B. D.; Thompson, A. M.; Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2010, 53, 282– 294, DOI: 10.1021/jm901207n47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVKhs7rL&md5=1ff5a8bd11f095f428898ec13f884259Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)Palmer, Brian D.; Thompson, Andrew M.; Sutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.Journal of Medicinal Chemistry (2010), 53 (1), 282-294CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of biphenyl analogs of the new tuberculosis drug PA-824 e. g. , I was prepd., primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki coupling of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side chain prior to coupling with the above alc. Antitubercular activity was detd. under both replicating (MABA) and nonreplicating (LORA) conditions. Para-Linked biaryls were the most active, followed by meta-linked and then ortho-linked analogs. A more detailed study of a larger group of para-linked analogs showed a significant correlation between potency (MABA) and both lipophilicity (CLOGP) and the electron-withdrawing properties of terminal ring substituents (.sum.σ). Selected compds. were evaluated for their efficacy in a mouse model of acute Mycobacterium tuberculosis infection. In vivo activity correlated well with the stability of compds. to microsomal metab. Three compds. bearing combinations of lipophilic, electron-withdrawing groups achieved >200-fold higher efficacies than the parent drug.
- 48Blaser, A.; Palmer, B. D.; Sutherland, H. S.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Thompson, A. M.; Denny, W. A. Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2012, 55, 312– 326, DOI: 10.1021/jm201227648https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFylurrE&md5=b515998cf44ca9998fc3434def6f82d4Structure-Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)Blaser, Adrian; Palmer, Brian D.; Sutherland, Hamish S.; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Thompson, Andrew M.; Denny, William A.Journal of Medicinal Chemistry (2012), 55 (1), 312-326CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Analogs of clin. tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824, I), in which the OCH2 linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metab., reduce lipophilicity, and improve aq. soly. Several sol. monoaryl examples displayed moderately improved (∼2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivs. mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly sol. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a sol., orally bioavailable carbamate analog providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.
- 49Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Palmer, B. D.; Denny, W. A.; Thompson, A. M. Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains. J. Med. Chem. 2010, 53, 855– 866, DOI: 10.1021/jm901378u49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFaisrrN&md5=f9b6518612795cc55e5f9b8ad784c8c6Synthesis and Structure-activity Relationships of Antitubercular 2-Nitroimidazooxazines Bearing Heterocyclic Side ChainsSutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Palmer, Brian D.; Denny, William A.; Thompson, Andrew M.Journal of Medicinal Chemistry (2010), 53 (2), 855-866CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Previously, biphenyl analogs of the antituberculosis drug PA-824 were found to display improved potencies against M. tuberculosis but were poorly sol. Heterobiaryl analogs of these, e.g., I (X = 2,5-thiophenediyl, R = 4-F), in which the first Ph ring was replaced with various 5-membered ring heterocycles, were prepd. with the aim of identifying potent new candidates with improved aq. soly. The compds. were constructed by coupling the chiral 2-nitroimidazooxazine II with various halomethyl-substituted arylheterocycles, by cycloaddns. to a propargyl ether deriv. of this alc., or by Suzuki couplings on haloheterocyclic Me ether derivs. The arylheterocyclic compds. were all more hydrophilic than their corresponding biphenyl analogs, and several showed soly. improvements. 1-Methylpyrazole, e.g., I (X = 1-methyl-3,5-pyrazolediyl, R = 4-F3C), 1,3-linked-pyrazole, e.g., I (X = 1,3-pyrazolediyl, R = 4-F), 2,4-linked-triazole, e.g., I [X = 1,2,3-triazole-2,4-diyl, R = 4-(CF3O)] and tetrazole analogs, e.g., I (X = 2,5-tetrazolediyl, R = H) had 3- to 7-fold higher MIC potencies against replicating M. tuberculosis than predicted by their lipophilicities. Two pyrazole analogs were >10-fold more efficacious than the parent drug in a mouse model of acute M. tuberculosis infection, and one displayed a 2-fold higher soly.
- 50Kataoka, M.; Fukahori, M.; Ikemura, A.; Kubota, A.; Higashino, H.; Sakuma, S.; Yamashita, S. Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process. Eur. J. Pharm. Biopharm. 2016, 101, 103– 111, DOI: 10.1016/j.ejpb.2016.02.00250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisVGgtr0%253D&md5=0db9d87ed2bd62f8234c34acbdc97306Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution processKataoka, Makoto; Fukahori, Miho; Ikemura, Atsumi; Kubota, Ayaka; Higashino, Haruki; Sakuma, Shinji; Yamashita, ShinjiEuropean Journal of Pharmaceutics and Biopharmaceutics (2016), 101 (), 103-111CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)The aim of the present study was to evaluate the effects of gastric pH on the oral absorption of poorly water-sol. drugs using an in vitro system. A dissoln./permeation system (D/P system) equipped with a Caco-2 cell monolayer was used as the in vitro system to evaluate oral drug absorption, while a small vessel filled with simulated gastric fluid (SGF) was used to reflect the gastric dissoln. phase. After applying drugs in their solid forms to SGF, SGF soln. contg. a 1/100 clin. dose of each drug was mixed with the apical soln. of the D/P system, which was changed to fasted state-simulated intestinal fluid. Dissolved and permeated amts. on applied amt. of drugs were then monitored for 2 h. Similar expts. were performed using the same drugs, but without the gastric phase. Oral absorption with or without the gastric phase was predicted in humans based on the amt. of the drug that permeated in the D/P system, assuming that the system without the gastric phase reflected human absorption with an elevated gastric pH. The dissolved amts. of basic drugs with poor water soly., namely albendazole, dipyridamole, and ketoconazole, in the apical soln. and their permeation across a Caco-2 cell monolayer were significantly enhanced when the gastric dissoln. process was reflected due to the physicochem. properties of basic drugs. These amts. resulted in the prediction of higher oral absorption with normal gastric pH than with high gastric pH. On the other hand, when diclofenac sodium, the salt form of an acidic drug, was applied to the D/P system with the gastric phase, its dissolved and permeated amts. were significantly lower than those without the gastric phase. However, the oral absorption of diclofenac was predicted to be complete (96-98%) irresp. of gastric pH because the permeated amts. of diclofenac under both conditions were sufficiently high to achieve complete absorption. These estns. of the effects of gastric pH on the oral absorption of poorly water-sol. drugs were consistent with observations in humans. In conclusion, the D/P system with the gastric phase may be a useful tool for better predicting the oral absorption of poorly water-sol. basic drugs. In addn., the effects of gastric pH on the oral absorption of poorly water-sol. drugs may be evaluated by the D/P system with and without the gastric phase.
- 51Rouault, E.; Lecoeur, H.; Meriem, A. B.; Minoprio, P.; Goyard, S.; Lang, T. Imaging visceral leishmaniasis in real time with golden hamster model: Monitoring the parasite burden and hamster transcripts to further characterize the immunological responses of the host. Parasitol. Int. 2017, 66, 933– 939, DOI: 10.1016/j.parint.2016.10.02051https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKmsbvJ&md5=6ebdf4b36b8fda8dcf3e9a08b6ac5bd3Imaging visceral leishmaniasis in real time with golden hamster model: Monitoring the parasite burden and hamster transcripts to further characterize the immunological responses of the hostRouault, Eline; Lecoeur, Herve; Meriem, Asma Ben; Minoprio, Paola; Goyard, Sophie; Lang, ThierryParasitology International (2017), 66 (1), 933-939CODEN: PAINFD; ISSN:1383-5769. (Elsevier Ireland Ltd.)Characterizing the clin., immunol. and parasitol. features assocd. with visceral leishmaniasis is complex. It involves recording in real time and integrating quant. multi-parametric data sets from parasite infected host tissues. Although several models have been used, hamsters are considered the bona fide exptl. model for Leishmania donovani studies. To study visceral leishmaniasis in hamsters we generated virulent transgenic L. donovani that stably express a reporter luciferase protein. Two complementary methodologies were combined to follow the infectious process: in vivo imaging using luciferase-expressing Leishmania and real time RT-PCR to quantify both Leishmania and host transcripts. This approach allows us: (i) to assess the clin. outcome of visceral leishmaniasis by individual monitoring of hamster wt., (ii) to follow the parasite load in several organs by real time anal. of the bioluminescence in vivo and through real time quant. PCR anal. of amastigote parasite transcript abundance ex vivo, (iii) to evaluate the immunol. responses triggered by the infection by quantifying hamster transcripts on the same samples and (iv) to limit the no. of hamsters selected for further anal. The overall data highlight a correlation between the transcriptional cytokine signatures of hamster affected tissues and the amastigote burden fluctuations, thus providing new insights into the immunopathol. process driven by L. donovani in the tissues of mammalian hosts. Finally, they suggest organ-specific immune responses.
- 52Yao, X.; Anderson, D. L.; Ross, S. A.; Lang, D. G.; Desai, B. Z.; Cooper, D. C.; Wheelan, P.; McIntyre, M. S.; Bergquist, M. L.; MacKenzie, K. I.; Becherer, J. D.; Hashim, M. A. Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model. Br. J. Pharmacol. 2008, 154, 1446– 1456, DOI: 10.1038/bjp.2008.26752https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptVajsLw%253D&md5=1dbf4f50957b26496c4efa213e3f7e5cPredicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig modelYao, X.; Anderson, D. L.; Ross, S. A.; Lang, D. G.; Desai, B. Z.; Cooper, D. C.; Wheelan, P.; McIntyre, M. S.; Bergquist, M. L.; MacKenzie, K. I.; Becherer, J. D.; Hashim, M. A.British Journal of Pharmacology (2008), 154 (7), 1446-1456CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclin. development, the propensity of drugs to prolong the QT interval in humans. Sixteen marketed drugs from various pharmacol. classes with a known incidence-or lack thereof-of QT prolongation in humans were examd. in hERG (human ether a-go-go-related gene) patch-clamp assay and an anesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concns. in perfusates from hERG assays and plasma samples from guinea-pigs were detd. using liq. chromatog.-mass spectrometry. Various pharmacol. agents that inhibit hERG currents prolong the QT interval in anesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compds. not assocd. with QT prolongation in humans failed to prolong the QT interval in this model. Anal. of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anesthetized guinea-pigs can reliably predict, during preclin. drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chem. entities during early lead optimization.
- 53Nwaka, S.; Ramirez, B.; Brun, R.; Maes, L.; Douglas, F.; Ridley, R. Advancing drug innovation for neglected diseases - criteria for lead progression. PLoS Neglected Trop. Dis. 2009, 3 (8), e440, DOI: 10.1371/journal.pntd.0000440There is no corresponding record for this reference.
- 54Freitas-Junior, L. H.; Chatelain, E.; Kim, H. A.; Siqueira-Neto, J. L. Visceral leishmaniasis treatment: What do we have, what do we need and how to deliver it?. Int. J. Parasitol.: Drugs Drug Resist. 2012, 2, 11– 19, DOI: 10.1016/j.ijpddr.2012.01.00354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1KmtLY%253D&md5=bc79e6a916e0dac45ec0879ecdc27e03Visceral leishmaniasis treatment: what do we have, what do we need and how to deliver it?Freitas-Junior, Lucio H.; Chatelain, Eric; Kim, Helena Andrade; Siqueira-Neto, Jair L.International Journal of Parasitology: Drugs and Drug Resistance (2012), 2 (), 11-19CODEN: IJPDAX; ISSN:2211-3207. (Elsevier Ltd.)A review. Leishmaniasis is one of the most neglected tropical disease in terms of drug discovery and development. Most antileishmanial drugs are highly toxic, present resistance issues or require hospitalization, being therefore not adequate to the field. Recently improvements have been achieved by combination therapy, reducing the time and cost of treatment. Nonetheless, new drugs are still urgently needed. In this review, we describe the current visceral leishmaniasis (VL) treatments and their limitations. We also discuss the new strategies in the drug discovery field including the development and implementation of high-throughput screening (HTS) assays and the joint efforts of international teams to deliver clin. candidates.
- 55Tweats, D.; Bourdin Trunz, B.; Torreele, E. Genotoxicity profile of fexinidazole - a drug candidate in clinical development for human African trypanomiasis (sleeping sickness). Mutagenesis 2012, 27, 523– 532, DOI: 10.1093/mutage/ges01555https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1KjsbvO&md5=d46d69b6bd96c3e483c25f0f29e4b3aaGenotoxicity profile of fexinidazole-a drug candidate in clinical development for human African trypanomiasis (sleeping sickness)Tweats, David; Bourdin Trunz, Bernadette; Torreele, ElsMutagenesis (2012), 27 (5), 523-532CODEN: MUTAEX; ISSN:0267-8357. (Oxford University Press)The parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as tinidazole are used to treat trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness. Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compd. mining of public and pharmaceutical company databases, has the potential to become a short-course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of fexinidazole and its two active metabolites, the sulfoxide and sulfone derivs. All the three compds. are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s). It is known that these enzymes can nitroreduce compds. with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions. Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled DNA synthesis in rats; bone marrow micronucleus test in mice), were neg. Thus, fexinidazole does not pose a genotoxic hazard to patients and represents a promising drug candidate for HAT. Fexinidazole is expected to enter Phase II clin. trials in 2012.
- 56Pilkington, L. I.; Barker, D. Total synthesis of (−)-isoamericanin A and (+)-isoamericanol A. Eur. J. Org. Chem. 2014, 2014, 1037– 1046, DOI: 10.1002/ejoc.20130136356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFSktbbE&md5=66ad43bcbe6fb78f3833ff7162a2a2e2Total Synthesis of (-)-isoamericanin A and (+)-isoamericanol APilkington, Lisa I.; Barker, DavidEuropean Journal of Organic Chemistry (2014), 2014 (5), 1037-1046CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)An enantioselective total synthesis of the biol. active 1,4-benzodioxan lignans isoamericanin A and isoamericanol A was designed and the synthesis of the target compds. was n achieved in 11 and 12 steps, resp. These benzodioxane lignan natural products and others that contain a 9-hydroxymethyl group, show a wide range of biol. properties. The 1,4-benzodioxane ring was formed by an acid-catalyzed cyclization, which gave the desired trans-isomer exclusively. This method will allow the synthesis of a no. of benzodioxane compds. contg. a 9-hydroxymethyl group. The title compds. thus formed included (2E)-3-[(2S,3S)-3-(3,4-dihydroxyphenyl)-2,3-dihydro-2-(hydroxymethyl)-1,4-benzodioxin-6-yl]-2-propenal [(-)-isoamericanin A] and (2E)-3-[(2S,3S)-3-(3,4-dihydroxyphenyl)-2,3-dihydro-2-(hydroxymethyl)-1,4-benzodioxin-6-yl]-2-propen-1-ol [(+)-isoamericanol A].
- 57Andresen, T. L.; Jensen, S. S.; Madsen, R.; Jørgensen, K. Synthesis and biological activity of anticancer ether lipids that are specifically released by phospholipase A2 in tumor tissue. J. Med. Chem. 2005, 48, 7305– 7314, DOI: 10.1021/jm049006f57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFCltb3K&md5=845fed4894abdaa1e9d72801314f35b7Synthesis and Biological Activity of Anticancer Ether Lipids That Are Specifically Released by Phospholipase A2 in Tumor TissueAndresen, Thomas L.; Jensen, Simon S.; Madsen, Robert; Jorgensen, KentJournal of Medicinal Chemistry (2005), 48 (23), 7305-7314CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The clin. use of anticancer lipids is severely limited by their ability to cause lysis of red blood cells prohibiting i.v. injection. Novel delivery systems are therefore required in order to develop anticancer ether lipids (AELs) into clin. useful anticancer drugs. In a recent article (J. Med. Chem. 2004, 47, 1694) we showed that it is possible to construct liposome systems composed of masked AELs that are activated by secretory phospholipase A2 in cancerous tissue. We present here the synthesis of six AELs and evaluate the biol. activity of these bioactive lipids. The synthesized AEL 1-6 were tested against three different cancer cell lines. It was found that the stereochem. of the glycerol headgroup in AEL-2 and 3 has a dramatic effect on the cytotoxicity of the lipids. AEL 1-4 were furthermore evaluated for their ability to prevent phosphorylation of the apoptosis regulating kinase Akt, and a correlation was found between their cytotoxic activity and their ability to inhibit Akt phosphorylation.
- 58Patterson, S.; Wyllie, S. Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends Parasitol. 2014, 30, 289– 298, DOI: 10.1016/j.pt.2014.04.00358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnsVWlsL4%253D&md5=041606bd13d4f709723aa61f1100873bNitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospectsPatterson, Stephen; Wyllie, SusanTrends in Parasitology (2014), 30 (6), 289-298CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)A review. There is an urgent need for new, safer, and effective treatments for the diseases caused by the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. In the search for more effective drugs to treat these 'neglected diseases' researchers have chosen to reassess the therapeutic value of nitroarom. compds. Previously avoided in drug discovery programs owing to potential toxicity issues, a nitro drug is now being used successfully as part of a combination therapy for human African trypanosomiasis. We describe here the rehabilitation of nitro drugs for the treatment of trypanosomatid diseases and discuss the future prospects for this compd. class.
- 59Falzari, K.; Zhu, Z.; Pan, D.; Liu, H.; Hongmanee, P.; Franzblau, S. G. In vitro and in vivo activities of macrolide derivatives against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2005, 49, 1447– 1454, DOI: 10.1128/AAC.49.4.1447-1454.200559https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjt1GjsL0%253D&md5=b137071813f92948d563e489dbaf14a3In vitro and in vivo activities of macrolide derivatives against Mycobacterium tuberculosisFalzari, Kanakeshwari; Zhu, Zhaohai; Pan, Dahua; Liu, Huiwen; Hongmanee, Poonpilas; Franzblau, Scott G.Antimicrobial Agents and Chemotherapy (2005), 49 (4), 1447-1454CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Existing macrolides have never shown definitive clin. efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-pos. bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of ≤4 μM were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compds. with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compds. with low MICs and low cytotoxicity also effected significant redns. in CFU in infected macrophages. Active compds. were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10- to 20-fold redn. of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clin. useful agent for tuberculosis.
- 60Cho, S. H.; Warit, S.; Wan, B.; Hwang, C. H.; Pauli, G. F.; Franzblau, S. G. Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2007, 51, 1380– 1385, DOI: 10.1128/AAC.00055-0660https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXktlOjtLg%253D&md5=43c83b44c7a5fdac907463530d4aaad5Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosisCho, Sang Hyun; Warit, Saradee; Wan, Baojie; Hwang, Chang Hwa; Pauli, Guido F.; Franzblau, Scott G.Antimicrobial Agents and Chemotherapy (2007), 51 (4), 1380-1385CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Screening for new antimicrobial agents is routinely conducted only against actively replicating bacteria. However, it is now widely accepted that a physiol. state of nonreplicating persistence (NRP) is responsible for antimicrobial tolerance in many bacterial infections. In tuberculosis, the key to shortening the 6-mo regimen lies in targeting this NRP subpopulation. Therefore, a high-throughput, luminescence-based low-oxygen-recovery assay (LORA) was developed to screen antimicrobial agents against NRP Mycobacterium tuberculosis. M. tuberculosis H37Rv contg. a plasmid with an acetamidase promoter driving a bacterial luciferase gene was adapted to low oxygen conditions by extended culture in a fermentor with a 0.5 headspace ratio. The MICs of 31 established antimicrobial agents were detd. in microplate cultures maintained under anaerobic conditions for 10 days and, for comparative purposes, under aerobic conditions for 7 days. Cultures exposed to drugs under anaerobic conditions followed by 28 h of "recovery" under ambient oxygen produced a luminescent signal that was, for most compds., proportional to the no. of CFU detd. prior to the recovery phase. No agents targeting the cell wall were active against NRP M. tuberculosis, whereas drugs hitting other cellular targets had a range of activities. The calcd. Z' factor was in the range of 0.58 to 0.84, indicating the suitability of the use of LORA for high-throughput assays. This LORA is sufficiently robust for use for primary high-throughput screening of compds. against NRP M. tuberculosis.
- 61Mukkavilli, R.; Pinjari, J.; Patel, B.; Sengottuvelan, S.; Mondal, S.; Gadekar, A.; Verma, M.; Patel, J.; Pothuri, L.; Chandrashekar, G.; Koiram, P.; Harisudhan, T.; Moinuddin, A.; Launay, D.; Vachharajani, N.; Ramanathan, V.; Martin, D. In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral Leishmaniasis. Eur. J. Pharm. Sci. 2014, 65, 147– 155, DOI: 10.1016/j.ejps.2014.09.00661https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Gms73N&md5=9d351c194ceba25f2dc23be54bb1ba33In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral LeishmaniasisMukkavilli, Rao; Pinjari, Jakir; Patel, Bhavesh; Sengottuvelan, Shankar; Mondal, Subodh; Gadekar, Ajit; Verma, Manas; Patel, Jignesh; Pothuri, Lavanya; Chandrashekar, Gopu; Koiram, Prabhakar; Harisudhan, Tanukrishnan; Moinuddin, Ansari; Launay, Delphine; Vachharajani, Nimish; Ramanathan, Vikram; Martin, DenisEuropean Journal of Pharmaceutical Sciences (2014), 65 (), 147-155CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)The in vitro metab. and in vivo pharmacokinetic (PK) properties of DNDI-VL-2098, a potential oral agent for Visceral Leishmaniasis (VL) were studied and used to predict its human pharmacokinetics. DNDI-VL-2098 showed a low soly. (10 μM) and was highly permeable (>200 nm/s) in the Caco-2 model. It was stable in vitro in liver microsomes and hepatocytes and no metabolite was detectable in circulating plasma from dosed animals suggesting very slow, if any, metab. of the compd. DNDI-VL-2098 was moderate to highly bound to plasma proteins across the species tested (94-98%). DNDI-VL-2098 showed satisfactory PK properties in mouse, hamster, rat and dog with a low blood clearance (<15% of hepatic blood flow except hamster), a vol. of distribution of about 3 times total body water, acceptable half-life (1-6 h across the species) and good oral bioavailability (37-100%). Allometric scaling of the preclin. PK data to human gave a blood half-life of approx. 20 h suggesting that the compd. could be a once-a-day drug. Based on the above assumptions, the min. efficacious dose predicted for a 50 kg human was 150 mg and 300 mg, using efficacy results in the mouse and hamster, resp.
- 62Hendrickx, S.; Van den Kerkhof, M.; Mabille, D.; Cos, P.; Delputte, P.; Maes, L.; Caljon, G. Combined treatment of miltefosine and paromomycin delays the onset of experimental drug resistance in Leishmania infantum. PLoS Neglected Trop. Dis. 2017, 11 (5), e0005620, DOI: 10.1371/journal.pntd.0005620There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b01581.
Additional biological assay data, synthetic schemes, graphs of PK data, experimental procedures and characterizations for compounds, combustion analytical data, and representative NMR spectra (PDF)
Molecular formula strings spreadsheet (CSV)
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