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LetterOctober 13, 2020

Synthesis and Structure–Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi
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Claire E. Sear
Claire E. Sear
Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
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Pauline Pieper
Pauline Pieper
Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
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Maiara Amaral
Maiara Amaral
Faculdade de Medicina, Universidade de São Paulo, São Paulo 05403-000, Brazil
Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil
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Maiara M. Romanelli
Maiara M. Romanelli
Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil
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Thais A. Costa-Silva
Thais A. Costa-Silva
Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil
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Marius M. Haugland
Marius M. Haugland
Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
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Joseph A. Tate
Joseph A. Tate
Syngenta Ltd., Jealott’s Hill International Research Centre, Bracknell RG42 6EY, United Kingdom
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João H. G. Lago
João H. G. Lago
Centre of Natural Sciences and Humanities, Federal University of ABC (UFBC), Avenida dos Estados 5001, Santo Andre, São Paulo 09210-580, Brazil
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Andre G. Tempone*
Andre G. Tempone
Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil
*Email: [email protected]
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http://orcid.org/0000-0003-2559-7344
Edward A. Anderson*
Edward A. Anderson
Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
*Email: [email protected]
More by Edward A. Anderson
http://orcid.org/0000-0002-4149-0494

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ACS Infectious Diseases

Cite this: ACS Infect. Dis. 2020, 6, 11, 2872–2878

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https://doi.org/10.1021/acsinfecdis.0c00523

Published October 13, 2020

Abstract

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Trypanosoma cruzi is the etiologic agent of Chagas disease, which affects over seven million people, especially in developing countries. Undesirable side effects are frequently associated with current therapies, which are typically ineffective in the treatment of all stages of the disease. Here, we report the first synthesis of the neolignan dehydrodieugenol B, a natural product recently shown to exhibit activity against T. cruzi. Using this strategy, a series of synthetic analogues were prepared to explore structure–activity relationships. The in vitro antiparasitic activities of these analogues revealed a wide tolerance of modifications and substituent deletions, with maintained or improved bioactivities against the amastigote forms of the parasite (50% inhibitory concentration (IC₅₀) of 4–63 μM) and no mammalian toxicity (50% cytotoxic concentration (CC₅₀) of >200 μM). Five of these analogues meet the Drugs for Neglected Disease Initiative (DNDi) “hit criteria” for Chagas disease. This work has enabled the identification of key structural features of the natural product and sites where scaffold modification is tolerated.

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Chagas disease, a neglected tropical disease caused by the kinetoplastid parasite Trypanosoma cruzi, affects 6–7 million people worldwide and causes ∼14 000 deaths per year. (1,2) It is endemic in Latin American countries and is spreading further worldwide due to human and vector migration. (3) The disease consists of a mostly asymptomatic acute stage, which is typified by the presence of parasites in the blood, and a chronic stage, where the level of parasite in the blood is low/undetectable due to their predominant location in the heart and digestive system. While the chronic phase can persist undetected for decades, (4) 30–40% of patients suffer severe failure of vital organs (e.g., cardiomyopathy and gastrointestinal disease), leading to major disability or death. (5) Current treatments (nifurtimox and benznidazole) cause severe side effects and are inefficient in the chronic stage of the disease, and parasite resistance is emerging. (6) Despite efforts to develop new antiparasitic agents, (7,8) the current pipeline for chemical entities against T. cruzi is limited, and as such, there is an ongoing need for new drug candidates. (9,10)

Natural products are a proven source of drugs, either in their natural form, as synthetic/semisynthetic derivatives, or as a basic pharmacophore. (11) Parasitic diseases are no exception, (12−15) with the frontline treatments for malaria (artemisinin) and visceral leishmaniasis (amphotericin B and paromomycin) themselves being natural products. (16,17) As part of a program to identify new antitrypanosomal agents, we previously reported the isolation of dehydrodieugenol B (1, Figure 1) and methyl dehydrodieugenol B (2) from the plant Nectandra leucantha and their bioactivity against T. cruzi. (18,19) A series of semisynthetic analogues was subsequently investigated, (20) which were accessed by modification of the phenol and allyl side chains of dehydrodieugenol B. This suggested that at least one nonpolar side chain is required for activity, as the introduction of polar functionalities onto both (a necessary consequence of this semisynthesis approach) resulted in a notable reduction in bioactivity.

Figure 1. Structures of the dehydrodieugenol natural products and planned SAR/synthesis strategy.

To establish a more detailed structure–activity relationship (SAR) for dehydrodieugenol B, we targeted a concise and robust strategy that would enable facile modification of the natural product core, including selective substitution/deletion of key structural features. We were attracted to a copper-catalyzed biaryl ether formation as a key disconnection (Ullmann coupling, Figure 1), as this would segment the natural product into the readily available eugenol (3) and eugenol-derived iodide (4); analogues would be accessed by the variation of either partner. From an SAR perspective, three sets of modifications were targeted: (1) the phenol/OMe group at C2 on the A-ring (substituent S1, green); (2) the allyl side chains (substituents S2, blue); (3) the methoxy groups (substituents S3, orange). Here, we describe the development of this synthetic strategy to access natural products 1 and 2, its application to prepare 21 analogues (5–25), and the evaluation of their bioactivity against T. cruzi.

Copper-catalyzed Ullmann coupling represents an attractive method to access biaryl ethers. (21−23) However, this particular C–O bond formation is challenged by the need for an electron-rich halide and steric hindrance (ortho-substitution) on both coupling partners. The need for basic reaction conditions leads to an additional concern, which has been encountered in work toward related natural products, (24) namely, isomerization of the allylic side chain to the more thermodynamically favored internal alkene.

The Ullmann coupling conditions described by Buck et al. were chosen as a starting point to study biaryl ether formation, (25) as they were successfully employed using electron-rich halides and sterically hindered substrates. In order to optimize the conditions for our system, commercially available 2-iodoanisole (26) was first used as a coupling partner with eugenol (Table 1). Under the reported conditions, (25) isomerization of the allylic side chain proved to be a significant problem (Entry 1), with desired product 27 being the minor component of the product mixture. The use of bromoanisole (Entry 2) exacerbated this problem due to the extended reaction time required. However, lowering the reaction temperature to 80 °C dramatically reduced the proportion of isomerized product 28 (Entry 3), and switching to a less polar solvent (dioxane, (26) Entry 4) eliminated this problem entirely but at the cost of a significantly reduced reaction rate. A solvent mixture of dioxane and NMP (1:1) resulted in shorter reaction times and greatly reduced the levels of isomerization (Entries 5 and 6). An increase in the proportion of dioxane (2:1) further reduced isomerization but also conversion (Entry 7), while a copper/ligand ratio of 1:1 maximized the reaction efficiency while maintaining minimal isomerization (Entry 8, 90%, <1% isomerization).

Table 1. Optimization of Ullmann Coupling Reaction Conditions

entry	CuCl (mol %)	TMHD (mol %)	solvent	temp (°C), time (h)	yield (%)^a	27:28^b
1	50	10	NMP	120, 16	33	1:2.5
2^c	50	10	NMP	120, 42	25	0:1
3	50	10	NMP	80, 16	63	1:0.07
4	50	10	dioxane	80, 64	37	1:<0.01
5	50	10	dioxane/NMP^d	80, 24	84	1:0.02
6	25	10	dioxane/NMP^d	80, 24	66	1:0.03
7	50	10	dioxane/NMP^e	80, 22	53	1:0.01
8	50	50	dioxane/NMP^e	80, 22	90	1:<0.01

^{^a}

Isolated yield.

^{^b}

Determined by ¹H NMR spectroscopic analysis of the crude reaction mixture.

^{^c}

Using 2-bromoanisole.

^{^d}

1:1 ratio.

^{^e}

2:1 ratio.

With optimized conditions in hand, attention turned to the natural products, which would require the coupling of a suitable iodinated derivative of eugenol (e.g., 4, Figure 1). This was prepared by straightforward ortho-lithiation/iodination of MOM-protected eugenol (Scheme 1). (27) The application of our optimized conditions to the coupling of 4 with eugenol resulted in low yields of product 5 due to the unexpected lability of the MOM protecting group under the reaction conditions. However, switching from MOM to PMB (30) or to Me (31, as required for natural product 2) overcame this problem, affording 6 and 2 in 59% and 58% yields, respectively. Interestingly, the more electron-rich “left-hand” side chain was found to be more prone to alkene isomerization during the coupling. Fortunately, the acidic conditions required for deprotection of the PMB group to deliver natural product 1 (67%) also removed any traces of this isomerized byproduct via selective hydration of the styrenyl double bond, which is activated to protonation by the electron-rich arene. This synthetic strategy could be scaled up to enable access to 1 in gram quantities. A series of synthetic derivatives of the natural products, featuring allyl or benzyl ethers at substituent S1 (7, 8) and/or double saturation at S3 (9, 10), was also prepared for reference, with 7–9 having been studied in our earlier work. (20)

Scheme 1. Synthesis of Natural Products 1 and 2 and Analogues 5–10^a

The modular nature of this route means it can readily be applied to the synthesis of a range of analogues not accessible from the natural products themselves in order to explore structure–activity relationships of dehydrodieugenol B. A series of 14 further compounds 11–25 was thus prepared, featuring systematic selective modification of substituents S1, S2, and S3 (Scheme 2). First, a variation of the B-ring was carried out by coupling of various aryl iodides (4, 30, and 31) with “saturated” eugenol (32). This gave analogues 11–13, which allowed the investigation of the importance of B-ring side chain unsaturation on bioactivity compared to 1, 2, and 6. The need for either the B-ring methoxy substituent or the three-carbon side chain was probed through analogues 14/15 and 16/17, respectively, which were prepared by coupling with the requisite partners 33 and 34 (we note in passing that 15 is itself a natural product, namely, 3-methylobovatol). (27−29) Equivalent variation of A-ring functionality was achieved by coupling of eugenol with n-propyl iodoarene 36, which gave analogues 18 and 19. Deletion of the A-ring three-carbon side chain and methoxy group was explored through analogues 20–22 and 23/24. Interestingly, when halide 40 (lacking a methoxy group ortho to the MOM ether) was used in the Ullmann coupling, no cleavage of the MOM group was observed as had been the case with the equivalent coupling of 3 with 4 (see Scheme 1). We suggest that this can be rationalized by a steric effect where the MOM group is now able to rotate away from the Lewis-acidic copper atom during the coupling reaction, presumably a more reactive conformation for the coupling process. Finally, deletion of the C1-phenol (25) was accomplished by coupling of 3,5-dibromoanisole with 3, followed by palladium-catalyzed Kumada coupling with allylmagnesium chloride.

Scheme 2. Synthesis of Analogues 11–25^a

Our attention next turned to an evaluation of the activity of the various natural product analogues against T. cruzi amastigotes (evaluated microscopically using an ex vivo intracellular model with mice macrophages) (20) and trypomastigotes (resazurin in vitro assay). (30) Among the compounds featuring sole modification of the S1 substituent (5–8 and 25, Table 2), four of the five presented improved activity against the amastigotes compared to the natural products, with 50% inhibitory concentration (IC₅₀) values of 4–24 μM, while only one demonstrated activity against the trypomastigotes (5, 6.5 ± 4.9 μM). Analogue 6 (OPMB) showed the most promising activity (4.0 ± 1.4 μM), being approximately 20-fold more potent than the natural product 1 against the amastigotes and with a selectivity index >50 and activity equivalent to benznidazole, a drug in clinical use against Chagas disease. Interestingly, in addition to the tolerance of functionalization of the phenol with a variety of groups, which offers a scope for future modification, the deletion of this S1 substituent also enhanced bioactivity compared to the parent natural products (25, 10.9 μM). It is noteworthy that all modifications of the S1 substituent did not lead to mammalian cytotoxicity for the highest tested concentration of 200 μM.

Table 2. Anti-T. cruzi Activity and Mammalian Cytotoxicity of Synthetic Analogues with a Variation of S1 Substitution^a

			IC₅₀ (μM) ± SD^b
entry	compound	S1	trypomastigote	amastigote	CC₅₀ (μM) ± SD^c	SI^d
1	1^e	OH	38.6 ± 8.3	86.5 ± 16.2	>200	>2.3
2	2^e	OMe	NA	NA	>200	ND
3	5	OMOM	6.5 ± 4.9	24.4 ± 10.3	>200	>8.2
4	6	OPMB	NA	4.0 ± 1.4	>200	>50
5	7^f	OAllyl	NA	NA	>200	ND
6	8^f	OBn	NA	9.5 ± 1.3	>200	>21.1
7	25	H	NA	10.9 ± 6.5	>200	>18.3
8	benznidazole		17.7 ± 1.9	5.0 ± 1.5	190.6 ± 13.4	38.1

^{^a}

SD: standard deviation; ND: not determined; NA: not active.

^{^b}

IC₅₀: 50% inhibitory concentration.

^{^c}

CC₅₀: 50% cytotoxic concentration.

^{^d}

SI: selectivity index, given by the ratio between CC₅₀ in NCTC cells and IC₅₀ in intracellular amastigotes.

^{^e}

Published in ref (18).

^{^f}

Published in ref (20).

Considering modification of the S2 hydrocarbon side chains (Table 3), we first questioned whether the saturation of either or both alkenes would affect the biological activity, a potentially important consideration from a synthetic perspective where saturation would avoid the problem of alkene isomerization during Ullmann coupling. Pleasingly, a consistent and potent activity was observed against T. cruzi amastigotes irrespective of which side chain was hydrogenated (or indeed both, 5.5–16.6 μM, Entries 1–7). For the phenols 13 and 19, significant mammalian toxicity was observed, although alkylation of the phenol as methyl or PMB ether avoided this problem. In contrast, analogue 11 was the only derivative of this subset aside from 13 and 19 to display activity against the trypomastigote form. We next examined whether deletion of the S2 side chains was tolerated. For activity against amastigotes, this revealed that both side chains are likely required (Entries 8–12), with only analogue 18 displaying appreciable bioactivity (albeit reduced compared to derivatives featuring two side chains, Entries 1–7). It is curious that this deletion led to activity for compound 16, a direct analogue of 2, which in its native form is apparently inactive (Table 1, Entry 2). Finally, the effect of S3 deletion was studied through analogues 23/24 (A-ring) and 14/15 (B-ring). In all cases (Table 4), appreciable activity was observed against the amastigote form of the parasite and also against trypomastigotes for the free phenols, albeit again at a cost of mammalian toxicity. Given the improved efficiency of Ullmann coupling of iodide 41 (Scheme 2), which lacks the A-ring methoxy substituent, this deletion may again offer a synthetic benefit for access to further natural product analogues.

Table 3. Anti-T. cruzi Activity and Mammalian Cytotoxicity of Synthetic Analogues with a Variation of S2 Substitution^a

					IC₅₀ (μM) ± SD^b
entry	compound	S1	S2-A	S2-B	trypomastigote	amastigote	CC₅₀ (μM) ± SD^c	SI^d
1	13	OH	Allyl	n-Pr	7.6 ± 1.9	16.6 ± 1.0	42.0 ± 3.8	2.5
2	19	OH	n-Pr	Allyl	4.6 ± 3.8	10.5 ± 8.3	14.2 ± 0.1	1.3
3	11	OMe	Allyl	n-Pr	21.9 ± 6.1	11.7 ± 7.0	>200	>17.1
4	9^e	OMe	n-Pr	n-Pr	NA	13.3 ± 1.2	>200	>15.0
5	10	OPMB	n-Pr	n-Pr	NA	5.5 ± 3.5	>200	>36.4
6	12	OPMB	Allyl	n-Pr	NA	8.6 ± 2.1	>200	>23.3
7	18	OPMB	n-Pr	Allyl	NA	13.4 ± 5.4	>200	>14.9
8	16	OMe	Allyl	H	20.3 ± 0.4	NA	>200	ND
9	20	OMe	H	Allyl	63.1 ± 6.2	25.7 ± 12.2	>200	>7.8
10	17	OPMB	Allyl	H	NA	NA	>200	ND
11	21	OPMB	H	Allyl	NA	NA	>200	ND
12	22	OAllyl	H	Allyl	NA	NA	>200	ND
13	benznidazole				17.7 ± 1.9	5.0 ± 1.5	190.6 ± 13.4	38.1

^{^a}

SD: standard deviation; ND: not determined; NA: not active.

^{^b}

IC₅₀: 50% inhibitory concentration.

^{^c}

CC₅₀: 50% cytotoxic concentration.

^{^d}

SI: selectivity index, given by the ratio between CC₅₀ in NCTC cells and IC₅₀ in intracellular amastigotes.

^{^e}

Published in ref (20).

Table 4. Anti-T. cruzi Activity and Mammalian Cytotoxicity of Synthetic Analogues with S3 Deletions^a

					IC₅₀ (μM) ± SD^b
entry	compound	S1	S3-A	S3-B	trypomastigote	amastigote	CC₅₀ (μM) ± SD^c	SI^d
1	23	OH	H	OMe	2.5 ± 1.3	7.7 ± 1.3	128.6 ± 5.2	16.7
2	24	OPMB	H	OMe	NA	11.6 ± 8.4	>200	>17.2
3	15	OH	OMe	H	4.6 ± 3.0	22.5 ± 18.8	123.4 ± 9.4	5.5
4	14	OPMB	OMe	H	NA	11.0 ± 2.3	>200	>18.2
5	benznidazole				17.7 ± 1.9	5.0 ± 1.5	190.6 ± 13.4	38.1

^{^a}

SD: standard deviation; ND: not determined; NA: not active.

^{^b}

IC₅₀: 50% inhibitory concentration.

^{^c}

CC₅₀: 50% cytotoxic concentration.

^{^d}

SI: selectivity index, given by the ratio between CC₅₀ in NCTC cells and IC₅₀ in intracellular amastigotes.

The Drugs for Neglected Disease Initiative (DNDi) defines the “hit criteria” for Chagas disease as a compound accessed by a synthetic pathway of up to 8 steps, with an IC₅₀ value against amastigotes lower that 10 μM and a selectivity index of at least 10. (31) Among the 21 analogues studied in this work, five meet these criteria, displaying a potency equivalent to the current therapeutic agent benznidazole, and a further seven display activity of <15 μM. Only those analogues possessing a free phenol exhibited mammalian toxicity. In general, low activity was observed against the extracellular trypomastigotes compared to the intracellular amastigotes, which may suggest that the compounds’ mode of action is implicated in amastigote replication or a possible immunomodulatory effect whereby the compounds activate the macrophage, rather than acting on the parasite directly.

The following trends against the amastigote form of T. cruzi emerge from the SAR study (Figure 2): (1) The presence of both S2 side chains is likely important for activity, although one or both may be saturated. (2) Either of the S3 methoxy groups may be removed without a significant effect on antiparasitic activity, which may be of utility from a synthetic perspective. (3) The S1 substituent may not be crucial (Table 3) but can also accommodate functionalization with various ether groups, which in general reduce toxicity compared to the equivalent phenols (e.g., 13 vs 11 or 12, 19 vs 18, 23 vs 24). In particular, the most potent analogues (6, 8, 10, and 12) feature benzylic ethers at this position, suggesting there is significant scope for further exploration of this substituent vector. In all, this study shows that the dehydrodieugenol framework offers a robust platform for further analogue design, including the synthesis of candidates featuring improved “drug-like” properties.

Figure 2. SAR trends for the dehydrodieugenol scaffold.

In conclusion, a robust synthetic route to the dehydrodieugenol natural products has been developed, which centers on an Ullmann coupling to form the biaryl ether linkage. This approach enabled the preparation of 21 synthetic analogues, most of which are not accessible from the natural products themselves. While further mechanism of action and pharmacokinetic studies as well as additional analogues that encompass more significant variations on the aromatic rings and their side chains will be needed to inform the design process, the study shows that this biaryl ether scaffold has much flexibility and promise for the discovery of bioactive natural-product based antiparasitic agents.

Methods

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Ethics Statement

BALB/c mice were obtained from the animal breeding facility at the Instituto Adolfo Lutz, Brazil. The animals were maintained in sterilized cages under a controlled environment and received water and food ad libitum. All procedures performed were previously approved by the Animal Care and Use Committee from Instituto Adolfo Lutz, Secretary of Health of Sao Paulo State (Project number CEUA 05/2018) in agreement with the Guide for the Care and Use of Laboratory Animals from the National Academy of Sciences.

Parasites and Mammalian Cell Maintenance

Macrophages were collected from the peritoneal cavity of BALB/c mice by washing them with RPMI-1640 medium supplemented with 10% fetal calf serum and were maintained at 37 °C in a 5% CO₂ humidified incubator. Trypomastigotes of T. cruzi (Y strain) were maintained in Rhesus monkey kidney cells (LLC-MK2, ATCC CCL 7) and cultivated in RPMI-1640 medium supplemented with 2% fetal calf serum at 37 °C in a 5% CO₂ humidified incubator. Murine conjunctive cells (NCTC clone 929, ATCC) were maintained in RPMI-1640 supplemented with 10% FBS at 37 °C in a 5% CO₂ humidified incubator. (20)

Antitrypomastigote Assay

LLC-MK2-derived trypomastigotes were seeded (1 × 10⁶ cells/well) in 96-well plates and incubated with the compounds serially diluted 2-fold (up to 100 μM) for 24 h in RPMI 1640 medium at 37 °C in a 5% CO₂ humidified incubator. Subsequently, resazurin (0.011% in PBS) was added for 24 h to check the parasite viability. (30) The optical density was determined in the FilterMax F5 (Molecular Devices) at 570 nm. Benznidazole was used as the standard.

Antiamastigote Assay

Peritoneal macrophages (1 × 10⁵ cells/well), collected from the peritoneal cavity of the BALB/c mice, were seeded in 16-well chamber slides (NUNC, Thermo Fisher Scientific) and infected with trypomastigotes (10:1, parasite/macrophage ratio). After 2 h, the compounds (in concentrations of 30–0.23 μM) were incubated with infected macrophages for 48 h at 37 °C in a 5% CO₂ humidified incubator. The slides were fixed with MeOH, stained with Giemsa, and observed under a light microscope (EVOS M5000, Termo, USA) with digital image equipment. The 50% inhibitory concentration (IC₅₀) values were determined by the infection index. (20) >90% infection of macrophages was established in this assay.

Cytotoxicity against Mammalian Cells

Fibroblast NCTC cells (clone 929) (6 × 10⁴ cells/well) were seeded in 96-well plates and incubated with the compounds (200–1.56 μM) for 48 h at 37 °C in a 5% CO₂ humidified incubator. The 50% cytotoxic concentration (CC₅₀) was determined by the MTT colorimetric assay. (32) The selectivity index (SI) was determined as CC₅₀/IC₅₀ against amastigotes.

Statistical Analysis

IC₅₀ and CC₅₀ values were calculated using a sigmoid dose–response curve in GraphPad Prism 6.0 software (GraphPad Software, San Diego, CA, USA). The assays were repeated at least twice, and the samples were tested in duplicate.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00523.

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Author Information

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Corresponding Authors
- Andre G. Tempone - Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil; http://orcid.org/0000-0003-2559-7344; Email: [email protected]
- Edward A. Anderson - Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom; http://orcid.org/0000-0002-4149-0494; Email: [email protected]
Authors
- Claire E. Sear - Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
- Pauline Pieper - Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
- Maiara Amaral - Faculdade de Medicina, Universidade de São Paulo, São Paulo 05403-000, Brazil; Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil
- Maiara M. Romanelli - Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil
- Thais A. Costa-Silva - Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil
- Marius M. Haugland - Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom; Present Address: M.M.H.: Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Joseph A. Tate - Syngenta Ltd., Jealott’s Hill International Research Centre, Bracknell RG42 6EY, United Kingdom
- João H. G. Lago - Centre of Natural Sciences and Humanities, Federal University of ABC (UFBC), Avenida dos Estados 5001, Santo Andre, São Paulo 09210-580, Brazil
Author Contributions
The manuscript was written through contributions of all authors.
Notes
The authors declare no competing financial interest.

Acknowledgments

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The authors wish to thank Hannah Asiki for assistance with the synthesis of compounds 32 and 35. C.E.S. thanks the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine for a studentship (EP/L015838/1), generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. P.P. thanks the Swiss National Science Foundation for an SNSF Fellowship and the Marie Skłodowska-Curie actions for an Individual Fellowship (GA No. 832700). E.A.A. thanks the Oxford Internal GCRF Research England Fund (Grant No. 0006019) and the EPSRC for additional support (EP/S013172/1). This work was funded by grants and fellowships provided from São Paulo State Research Foundation (FAPESP 2018/10279-6, 2018/25128-3), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Abbreviations

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BINAP	(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)
CCL2	CC chemokine ligand 2
CCR2	CC chemokine receptor 2
CCR5	CC chemokine receptor 5
DMF	N,N-dimethylformamide
MOM	methoxymethyl
NMP	N-methylpyrrolidinone
TMEDA	N,N,N′,N′-tetramethylethylenediamine
PMB	para-methoxybenzyl
TLC	thin layer chromatography
TMHD	2,2,6,6-tetramethyl-3,5-heptanedione

References

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This article references 32 other publications.

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Hollingsworth, T. D., Adams, E. R., Anderson, R. M., Atkins, K., Bartsch, S., Basáñez, M.-G., Behrend, M., Blok, D. J., Chapman, L. A. C., Coffeng, L., Courtenay, O., Crump, R. E., de Vlas, S. J., Dobson, A., Dyson, L., Farkas, H., Galvani, A. P., Gambhir, M., Gurarie, D., Irvine, M. A., Jervis, S., Keeling, M. J., Kelly-Hope, L., King, C., Lee, B. Y., Le Rutte, E. A., Lietman, T. M., Ndeffo-Mbah, M., Medley, G. F., Michael, E., Pandey, A., Peterson, J. K., Pinsent, A., Porco, T. C., Richardus, J. H., Reimer, L., Rock, K. S., Singh, B. K., Stolk, W., Swaminathan, S., Torr, S. J., Townsend, J., Truscott, J., Walker, M., Zoueva, A., and NTD Modelling Consortium (2015) Quantitative analyses and modelling to support achievement of the 2020 goals for nine neglected tropical diseases. Parasites Vectors 8, 630, DOI: 10.1186/s13071-015-1235-1
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Quantitative analyses and modelling to support achievement of the 2020 goals for nine neglected tropical diseases
Hollingsworth T Deirdre; Chapman Lloyd A C; Courtenay Orin; Crump Ron E; Dyson Louise; Farkas Hajnal; Irvine Michael A; Jervis Sarah; Keeling Matt J; Rock Kat S; Adams Emily R; Kelly-Hope Louise; Reimer Lisa; Torr Steve J; Anderson Roy M; Basanez Maria-Gloria; Truscott James; Walker Martin; Atkins Katherine; Medley Graham F; Bartsch Sarah; Lee Bruce Y; Behrend Matthew; Blok David J; Coffeng Luc; de Vlas Sake J; Le Rutte Epke A; Richardus Jan Hendrik; Stolk Wilma; Dobson Andy; Peterson Jennifer K; Galvani Alison P; Ndeffo-Mbah Martial; Pandey Abhishek; Townsend Jeffrey; Gambhir Manoj; Pinsent Amy; Gurarie David; King Charles; Lietman Thomas M; Porco Travis C; Michael Edwin; Singh Brajendra K; Swaminathan Subramanian; Zoueva Alexandra
Parasites & vectors (2015), 8 (), 630 ISSN:.
Quantitative analysis and mathematical models are useful tools in informing strategies to control or eliminate disease. Currently, there is an urgent need to develop these tools to inform policy to achieve the 2020 goals for neglected tropical diseases (NTDs). In this paper we give an overview of a collection of novel model-based analyses which aim to address key questions on the dynamics of transmission and control of nine NTDs: Chagas disease, visceral leishmaniasis, human African trypanosomiasis, leprosy, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. Several common themes resonate throughout these analyses, including: the importance of epidemiological setting on the success of interventions; targeting groups who are at highest risk of infection or re-infection; and reaching populations who are not accessing interventions and may act as a reservoir for infection,. The results also highlight the challenge of maintaining elimination 'as a public health problem' when true elimination is not reached. The models elucidate the factors that may be contributing most to persistence of disease and discuss the requirements for eventually achieving true elimination, if that is possible. Overall this collection presents new analyses to inform current control initiatives. These papers form a base from which further development of the models and more rigorous validation against a variety of datasets can help to give more detailed advice. At the moment, the models' predictions are being considered as the world prepares for a final push towards control or elimination of neglected tropical diseases by 2020.
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De Rycker, M., Baragaña, B., Duce, S. L., and Gilbert, I. H. (2018) Challenges and recent progress in drug discovery for tropical diseases. Nature 559, 498– 506, DOI: 10.1038/s41586-018-0327-4
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Challenges and recent progress in drug discovery for tropical diseases
De Rycker, Manu; Baragana, Beatriz; Duce, Suzanne L.; Gilbert, Ian H.
Nature (London, United Kingdom) (2018), 559 (7715), 498-506CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries. These diseases predominantly affect the world's poorest people. Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments. This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress. While there have been notable successes, there is still a long way to go.
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(Accessed 2020-07-21) Chagas disease (also known as American trypanosomiasis), https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis).
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Sanchez-Valdez, F. J., Padilla, A., Wang, W., Orr, D., and Tarleton, R. L. (2018) Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure. eLife 7, e34039 DOI: 10.7554/eLife.34039
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Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure
Sanchez-Valdez, Fernando J.; Padilla, Angel; Wang, Wei; Orr, Dylan; Tarleton, Rick L.
eLife (2018), 7 (), e34039/1-e34039/20CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
The ability of the Chagas disease agent Trypanosoma cruzi to resist extended in vivo exposure to highly effective trypanocidal compds. prompted us to explore the potential for dormancy and its contribution to failed drug treatments in this infection. We document the development of non-proliferating intracellular amastigotes in vivo and in vitro in the absence of drug treatment. Non-proliferative amastigotes ultimately converted to trypomastigotes and established infections in new host cells. Most significantly, dormant amastigotes were uniquely resistant to extended drug treatment in vivo and in vitro and could re-establish a flourishing infection after as many as 30 days of drug exposure. These results demonstrate a dormancy state in T. cruzi that accounts for the failure of highly cytotoxic compds. to completely resolve the infection. The ability of T. cruzi to establish dormancy throws into question current methods for identifying curative drugs but also suggests alternative therapeutic approaches.
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Silva-Dos-Santos, D., Barreto-De-Albuquerque, J., Guerra, B., Moreira, O. C., Berbert, L. R., Ramos, M. T., Mascarenhas, B. A. S., Britto, C., Morrot, A., Serra Villa-Verde, D. M., Garzoni, L. R., Savino, W., Cotta-De-Almeida, V., and Meis, J. d. (2017) Unraveling Chagas disease transmission through the oral route: Gateways to Trypanosoma cruzi infection and target tissues. PLoS Neglected Trop. Dis. 11, e0005507 DOI: 10.1371/journal.pntd.0005507
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Ribeiro, V., Dias, N., Paiva, T., Hagström-Bex, L., Nitz, N., Pratesi, R., and Hecht, M. (2020) Current trends in the pharmacological management of Chagas disease. Int. J. Parasitol.: Drugs Drug Resist. 12, 7– 17, DOI: 10.1016/j.ijpddr.2019.11.004
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Current trends in the pharmacological management of Chagas disease
Ribeiro Vanessa; Dias Nayra; Paiva Tais; Hagstrom-Bex Luciana; Nitz Nadjar; Pratesi Riccardo; Hecht Mariana
International journal for parasitology. Drugs and drug resistance (2020), 12 (), 7-17 ISSN:.
Chagas disease (CD) is a tropical neglected illness, affecting mainly populations of low socioeconomic status in Latin America. An estimated 6 to 8 million people worldwide are infected with Trypanosoma cruzi, the etiological agent of CD. Despite being one of the main global health problems, this disease continues without effective treatment during the chronic phase of the infection. The limitation of therapeutic strategies has been one of the biggest challenges on the fight against CD. Nifurtimox and benznidazole, developed in the 1970s, are still the only commercial options with established efficacy on CD. However, the efficacy of these drugs have a proven efficacy only during early infection and the benefits in the chronic phase are questionable. Consequently, there is a growing need for new pharmacological alternatives, either by optimization of existing drugs or by the formulation of new compounds. In the present study, a literature review of the currently adopted therapy, its concomitant combination with other drugs, and potential future treatments for CD was performed, considering articles published from 2012. The revised articles were selected according to the protocol of treatment: evaluation of drug association, drug repositioning and research of new drugs. As a result of the present revision, it was possible to conclude that the use of benznidazole in combination with other compounds showed better results when compared with its use as a single therapy. The search of new drugs has been the strategy most used in pursuing more effective forms of treatment for CD. However, studies have still focused on basic research, that is, they are still in a pre-clinical stage, using methodologies based on in vitro or in animal studies.
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Field, 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., and Gilbert, I. H. (2017) Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need. Nat. Rev. Microbiol. 15, 217– 231, DOI: 10.1038/nrmicro.2016.193
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Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need
Field, 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.
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Wang, S., Dong, G., and Sheng, C. (2019) Structural Simplification of Natural Products. Chem. Rev. 119, 4180– 4220, DOI: 10.1021/acs.chemrev.8b00504
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Structural Simplification of Natural Products
Wang, Shengzheng; Dong, Guoqiang; Sheng, Chunquan
Chemical Reviews (Washington, DC, United States) (2019), 119 (6), 4180-4220CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. Natural products (NPs) are important sources of clin. drugs due to their structural diversity and biol. prevalidation. However, the structural complexity of NPs leads to synthetic difficulties, unfavorable pharmacokinetic profiles, and poor drug-likeness. Structural simplification by truncating unnecessary substructures is a powerful strategy for overcoming these limitations and improving the efficiency and success rate of NP-based drug development. Herein, we will provide a comprehensive review of the structural simplification of NPs with a focus on design strategies, case studies, and new technologies. In particular, a no. of successful examples leading to marketed drugs or drug candidates will be discussed in detail to illustrate how structural simplification is applied in lead optimization of NPs.
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Villalta, F. and Rachakonda, G. (2019) Advances in preclinical approaches to Chagas disease drug discovery. Expert Opin. Drug Discovery 14, 1161– 1174, DOI: 10.1080/17460441.2019.1652593
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Advances in preclinical approaches to Chagas disease drug discovery
Villalta, Fernando; Rachakonda, Girish
Expert Opinion on Drug Discovery (2019), 14 (11), 1161-1174CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)
A review. Chagas disease affects 8-10 million people worldwide, mainly in Latin America. The current therapy for Chagas disease is limited to nifurtimox and benznidazole, which are effective in treating only the acute phase of the disease but with severe side effects. Therefore, there is an unmet need for new drugs and for the exploration of innovative approaches which may lead to the discovery of new effective and safe drugs for its treatment. The authors report and discuss recent approaches including structure-based design that have led to the discovery of new promising small mol. candidates for Chagas disease which affect prime targets that intervene in the sterol pathway of T. cruzi. Other trypanosome targets, phenotypic screening, the use of artificial intelligence and the challenges with Chagas disease drug discovery are also discussed. The application of recent scientific innovations to the field of Chagas disease have led to the discovery of new promising drug candidates for Chagas disease. Phenotypic screening brought new hits and opportunities for drug discovery. Artificial intelligence also has the potential to accelerate drug discovery in Chagas disease and further research into this is warranted.
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Bhattacharya, A., Corbeil, A., do Monte-Neto, R. L., and Fernandez-Prada, C. (2020) Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery. Genes 11, 722, DOI: 10.3390/genes11070722
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Of drugs and trypanosomatids: new tools and knowledge to reduce bottlenecks in drug discovery
Bhattacharya, Arijit; Corbeil, Audrey; Monte-Neto, Rubens L. Do; Fernandez-Prada, Christopher
Genes (2020), 11 (7), 722CODEN: GENEG9; ISSN:2073-4425. (MDPI AG)
A review. Leishmaniasis (Leishmania species), sleeping sickness (Trypanosoma brucei), and Chagas disease (Trypanosoma cruzi) are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technol. advances in parasitol., chem., and genomics have unlocked new possibilities for novel drug concepts and compd. screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biol. context, as well as different examples of recently discovered lead compds.
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Newman, D. J. and Cragg, G. M. (2016) Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 79, 629– 661, DOI: 10.1021/acs.jnatprod.5b01055
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Natural Products as Sources of New Drugs from 1981 to 2014
Newman, David J.; Cragg, Gordon M.
Journal of Natural Products (2016), 79 (3), 629-661CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from Jan. 1, 1981, to Dec. 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions and the designation "natural product botanical", or "NB", to cover those botanical "defined mixts." now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small mols. approved, 131, or 75%, are other than "S" (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore it is considered that this area of natural product research should be expanded significantly.
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da Rosa, R., Schenkel, E. P., and Campos Bernardes, L. S. (2020) Semisynthetic and newly designed derivatives based on natural chemical scaffolds: moving beyond natural products to fight Trypanosoma cruzi. Phytochem. Rev. 19, 105– 122, DOI: 10.1007/s11101-020-09659-8
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Semisynthetic and newly designed derivatives based on natural chemical scaffolds: moving beyond natural products to fight Trypanosoma cruzi
da Rosa, Rafael; Schenkel, Eloir Paulo; Campos Bernardes, Lilian Sibelle
Phytochemistry Reviews (2020), 19 (1), 105-122CODEN: PRHEBS; ISSN:1568-7767. (Springer)
A review. Secondary metabolites obtained from natural sources are medicinally relevant mols. About one-third of all FDA-approved drugs are derived from or based on natural products, which suggests that mol. optimization is often required for translation from benchtop to clin. practice. Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease highly prevalent in Latin America. It has a significant impact on socioeconomic indicators and is not easily cured by the two currently available drugs, benznidazole and nifurtimox. Considering the importance of developing new bioactive mols. based on natural products, this article reviews 21 years of literature reports on the semisynthesis and total synthesis of new compds. targeting T. cruzi. From 1997 to 2018, sixty-six articles reporting five hundred and thirty-seven mols. active against different strains and life stages of the parasite were published. Quinones, alkaloids, terpenes, and lignans were the four largest classes of derivs., the majority of which had IC50 values low enough to indicate that natural product derivs. can be an important source of potential new drugs to treat Chagas disease. We highlight important mols. in each secondary metabolite class, discussing factors such as selectivity and the basis for their design. An assessment of drug-likeness parameters was performed, which might prove useful for selecting lead compds. for preclin. drug studies.
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Santos, S. S., de Araújo, R. V., Giarolla, J., Seoud, O. E., and Ferreira, E. I. (2020) Searching for drugs for Chagas disease, leishmaniasis and schistosomiasis: a review. Int. J. Antimicrob. Agents 55, 105906, DOI: 10.1016/j.ijantimicag.2020.105906
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Searching for drugs for Chagas disease, leishmaniasis and schistosomiasis: a review
Santos, Soraya Silva; Vinicius de Araujo, Renan; Giarolla, Jeanine; El Seoud, Omar; Ferreira, Elizabeth Igne
International Journal of Antimicrobial Agents (2020), 55 (4), 105906CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
A review. Chagas disease, leishmaniasis and schistosomiasis are neglected diseases (NDs) and are a considerable global challenge. Despite the huge no. of people infected, NDs do not create interest from pharmaceutical companies because the assocd. revenue is generally low. Most of the research on these diseases has been conducted in academic institutions. The chemotherapeutic armamentarium for NDs is scarce and inefficient and better drugs are needed. Researchers have found some promising potential drug candidates using medicinal chem. and computational approaches. Most of these compds. are synthetic but some are from natural sources or are semi-synthetic. Drug repurposing or repositioning has also been greatly stimulated for NDs. This review considers some potential drug candidates and provides details of their design, discovery and activity.
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Zimmermann, L. A., de Moraes, M. H., da Rosa, R., de Melo, E. B., Paula, F. R., Schenkel, E. P., Steindel, M., and Bernardes, L. S. C. (2018) Synthesis and SAR of new isoxazole-triazole bis-heterocyclic compounds as analogues of natural lignans with antiparasitic activity. Bioorg. Med. Chem. 26, 4850– 4862, DOI: 10.1016/j.bmc.2018.08.025
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Synthesis and SAR of new isoxazole-triazole bis-heterocyclic compounds as analogues of natural lignans with antiparasitic activity
Zimmermann, Lara A.; de Moraes, Milene H.; da Rosa, Rafael; de Melo, Eduardo B.; Paula, Favero R.; Schenkel, Eloir P.; Steindel, Mario; Bernardes, Lilian S. C.
Bioorganic & Medicinal Chemistry (2018), 26 (17), 4850-4862CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
Despite the impressive scientific and technol. advances of recent decades, no effective treatment is currently available for Chagas disease. The authors research group has been studying the design and synthesis of analogs of natural lignans aiming to identify compds. with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivs. and the structure-activity relation study conducted based on results of biol. assays against Trypanosoma cruzi amastigotes. Thirty-seven compds. were active, and eight of them had GI50 values lower than 100 μM (GI50 88.4-12.2 μM). A qual. structure activity relation study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compds. Compd. 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole as the most active in the series (GI50 12.2 μM), showing, in vitro, low toxicity and potency similar to benznidazole (GI50 10.2 μM). These results suggest that this compd. can be a promising scaffold for the design of new trypanocidal compds.
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Fraser, A. L., Menzies, S. K., King, E. F. B., Tulloch, L. B., Gould, E. R., Zacharova, M. K., Smith, T. K., and Florence, G. J. (2018) Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors. ACS Infect. Dis. 4, 560– 567, DOI: 10.1021/acsinfecdis.7b00187
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Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors
Fraser, Andrew L.; Menzies, Stefanie K.; King, Elizabeth F. B.; Tulloch, Lindsay B.; Gould, Eoin R.; Zacharova, Marija K.; Smith, Terry K.; Florence, Gordon J.
ACS Infectious Diseases (2018), 4 (4), 560-567CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the prepn. of a focused library of substituted-tetrahydropyran derivs. and their evaluation as selective chem. tools for trypanosomatid inhibition and the follow-on development of photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compds. maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani. In addn., we demonstrate the utility of the photoaffinity probes for target identification through preliminary cellular localization studies.
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Cheuka, P. M., Mayoka, G., Mutai, P., and Chibale, K. (2017) The Role of Natural Products in Drug Discovery and Development against Neglected Tropical Diseases. Molecules 22, 58, DOI: 10.3390/molecules22010058
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The role of natural products in drug discovery and development against neglected tropical diseases
Cheuka, Peter Mubanga; Mayoka, Godfrey; Mutai, Peggoty; Chibale, Kelly
Molecules (2017), 22 (1), 58/1-58/41CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are also responsible for over 500,000 deaths per yr and are characterized by long-term disability and severe pain. The impact of the combined NTDs closely rivals that of malaria and tuberculosis. Current treatment options are assocd. with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. In this review, we highlight the potential that remains untapped in natural products as drug leads for NTDs. We cover natural products from plant, marine, and microbial sources including natural-product-inspired semi-synthetic derivs. which have been evaluated against the various causative agents of NTDs. Our coverage is limited to four major NTDs which include human African trypanosomiasis (sleeping sickness), leishmaniasis, schistosomiasis and lymphatic filariasis.
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Wells, T. N. C. (2011) Natural products as starting points for future anti-malarial therapies: going back to our roots?. Malar. J. 10, S3, DOI: 10.1186/1475-2875-10-S1-S3
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Natural products as starting points for future anti-malarial therapies: going back to our roots?
Wells, Timothy N. C.
Malaria Journal (2011), 10 (Suppl. 1), S3CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)
A review. Background: The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results: Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Mols. such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chem. and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compds. from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compds.-starting points for new drug discovery programs. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or 'acting in the reversed order', starting with observational clin. studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clin. observational data exist, or can be generated. The first step should be the confirmation and definition of the clin. activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacol. characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited nos. of well-controlled clin. studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clin. data on such products. Conclusions: The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the 'smash and grab' approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacol. and design and reporting of clin. observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chem. and pharmacol. characterization of exts. from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require addnl. support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clin. best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new mol. scaffolds which will form the basis of the next generation of anti-malarial therapies.
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Grecco, S. S., Costa-Silva, T. A., Jerz, G., de Sousa, F. S., Londero, V. S., Galuppo, M. K., Lima, M. L., Neves, B. J., Andrade, C. H., Tempone, A. G., and Lago, J. H. G. (2017) Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages. Chem.-Biol. Interact. 277, 55– 61, DOI: 10.1016/j.cbi.2017.08.017
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Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages
Grecco, Simone S.; Costa-Silva, Thais A.; Jerz, Gerold; de Sousa, Fernanda S.; Londero, Vinicius S.; Galuppo, Mariana K.; Lima, Marta L.; Neves, Bruno J.; Andrade, Carolina H.; Tempone, Andre G.; Lago, Joao Henrique G.
Chemico-Biological Interactions (2017), 277 (), 55-61CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
Chagas disease is a neglected tropical disease, caused by the protozoan parasite Trypanosoma cruzi, which affects more than eight million people in Tropical and Subtropical countries esp. in Latin America. Current treatment is limited to nifurtimox and benznidazole, both with reduced effectiveness and high toxicity. In this work, the n-hexane ext. from leaves of Nectandra leucantha (Lauraceae) displayed in vitro antitrypanosomal activity against T. cruzi. Using several chromatog. steps, four related neolignans were isolated and chem. characterized as dehydrodieugenol B (1), 1-(8-propenyl)-3-[3'-methoxy-1'-(8-propenyl)-phenoxy]-4,5-dimethoxybenzene (2), 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4-hydroxy-5-methoxybenzene (3), and 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4,5-dimethoxybenzene (4). These compds. were tested against intracellular amastigotes and extracellular trypomastigotes of T. cruzi and for mammalian cytotoxicity. Neolignan 4 showed the higher selectivity index (SI) against trypomastigotes (>5) and amastigotes (>13) of T. cruzi. The investigation of the mechanism of action demonstrated that neolignan 4 caused substantial alteration of the plasma membrane permeability, together with mitochondrial dysfunctions in trypomastigote forms. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compds. were non-mutagenic, non-carcinogenic, non-genotoxic, weak hERG blockers, with acceptable vol. of distribution (1.66-3.32 L/kg), and low rodent oral toxicity (LD50 810-2200 mg/kg). Considering some clin. events of cerebral Chagas disease, the compds. also demonstrated favorable properties, such as blood-brain barrier penetration. Unfavorable properties were also predicted as high promiscuity for P 450 isoforms, high plasma protein binding affinity (>91%), and moderate-to-low oral bioavailability. Finally, none of the isolated neolignans was predicted as interference compds. (PAINS). Considering the promising chem. and biol. properties of the isolated neolignans, these compds. could be used as starting points to develop new lead compds. for Chagas disease.
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Costa-Silva, T. A. d., Grecco, S. S., de Sousa, F. S., Lago, J. H. G., Martins, E. G. A., Terrazas, C. A., Varikuti, S., Owens, K. L., Beverley, S. M., Satoskar, A. R., and Tempone, A. G. (2015) Immunomodulatory and Antileishmanial Activity of Phenylpropanoid Dimers Isolated from Nectandra leucantha. J. Nat. Prod. 78, 653– 657, DOI: 10.1021/np500809a
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Ferreira, D. D., Sousa, F. S., Costa-Silva, T. A., Reimão, J. Q., Torrecilhas, A. C., Johns, D. M., Sear, C. E., Honorio, K. M., Lago, J. H. G., Anderson, E. A., and Tempone, A. G. (2019) Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi. Eur. J. Med. Chem. 176, 162– 174, DOI: 10.1016/j.ejmech.2019.05.001
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Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi
Ferreira, Daiane D.; Sousa, Fernanda S.; Costa-Silva, Thais A.; Reimao, Juliana Q.; Torrecilhas, Ana C.; Johns, Deidre M.; Sear, Claire E.; Honorio, Kathia M.; Lago, Joao Henrique G.; Anderson, Edward A.; Tempone, Andre G.
European Journal of Medicinal Chemistry (2019), 176 (), 162-174CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited no. and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivs. was prepd. to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compds. demonstrated activity against trypomastigotes (IC50 values from 8 to 64 μM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 μM). Eighteen derivs. demonstrated no mammalian cytotoxicity up to 200 μM. The phenolic acetate deriv. of natural dehydrodieugenol B (I) was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compd. caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being obsd. Fluorescence assays demonstrated that this deriv. affected neither the permeability nor the elec. potential of the parasitic plasma membrane, an effect also corroborated by SEM studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivs. represents a promising starting point for future Chagas disease drug discovery studies.
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Giri, R., Brusoe, A., Troshin, K., Wang, J. Y., Font, M., and Hartwig, J. F. (2018) Mechanism of the Ullmann Biaryl Ether Synthesis Catalyzed by Complexes of Anionic Ligands: Evidence for the Reaction of Iodoarenes with Ligated Anionic CuI Intermediates. J. Am. Chem. Soc. 140, 793– 806, DOI: 10.1021/jacs.7b11853
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Mechanism of the Ullmann Biaryl Ether Synthesis Catalyzed by Complexes of Anionic Ligands: Evidence for the Reaction of Iodoarenes with Ligated Anionic CuI Intermediates
Giri, Ramesh; Brusoe, Andrew; Troshin, Konstantin; Wang, Justin Y.; Font, Marc; Hartwig, John F.
Journal of the American Chemical Society (2018), 140 (2), 793-806CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A series of exptl. studies, along with DFT calcns., are reported that provide a detailed view into the mechanism of Ullmann coupling of phenols with aryl halides in the presence of catalysts generated from Cu(I) and bidentate, anionic ligands. These studies encompass catalysts contg. anionic ligands formed by deprotonation of 8-hydroxyquinoline, 2-pyridylmethyl tert-Bu ketone, and 2,2,6,6-tetramethylheptane-3,5-dione. Three-coordinate, heteroleptic species [Cu(LX)OAr]- were shown by expt. and DFT calcns. to be the most stable complexes in catalytic systems contg. 8-hydroxyquinoline or 2-pyridylmethyl tert-Bu ketone and to be generated reversibly in the system contg. 2,2,6,6-tetramethylheptane-3,5-dione. These heteroleptic complexes were characterized by a combination of 19F NMR, 1H NMR, and UV-vis spectroscopy, as well as ESI-MS. The heteroleptic complexes generated in situ react with iodoarenes to form biaryl ethers in high yields without evidence for an aryl radical intermediate. Measurements of 13C/12C isotope effects showed that oxidative addn. of the iodoarene occurs irreversibly. This information, in combination with the kinetic data, shows that oxidative addn. occurs to the [Cu(LX)OAr]- complexes and is turnover-limiting. A Hammett anal. of the effect of phenoxide electronic properties on the rate of the reaction of [Cu(LX)OAr]- with iodotoluene also is consistent with oxidative addn. of the iodoarene to an anionic phenoxide complex. Calcns. by DFT suggest that this oxidative addn. is followed by dissocn. of I- and reductive elimination of the biaryl ether from the resulting neutral Cu(III) complex.
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Evano, G., Wang, J., and Nitelet, A. (2017) Metal-mediated C–O bond forming reactions in natural product synthesis. Org. Chem. Front. 4, 2480– 2499, DOI: 10.1039/C7QO00671C
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Metal-mediated C-O bond forming reactions in natural product synthesis
Evano, Gwilherm; Wang, Jianjun; Nitelet, Antoine
Organic Chemistry Frontiers (2017), 4 (12), 2480-2499CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
A review. Metal catalyzed reactions for the formation of C-O bonds have had a dramatic impact in natural product synthesis over the past few decades. Various metals have been reported to efficiently catalyze cross-coupling reactions for the formation of various C(sp2)-O bonds from aryl/alkenyl halides or synthetic equiv. and phenols, aliph. alcs. and water. The implementation of such reactions in natural product synthesis enabled the emergence of new bond disconnections, which notably resulted in remarkably efficient and short synthetic pathways. The use of these reactions for the formation of C-O bonds in natural product synthesis is overviewed in this crit. review, with an emphasis on copper and palladium catalysts which are the most efficient ones to date.
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Sambiagio, C., Marsden, S. P., Blacker, A. J., and McGowan, P. C. (2014) Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 43, 3525– 3550, DOI: 10.1039/C3CS60289C
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Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development
Sambiagio, Carlo; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C.
Chemical Society Reviews (2014), 43 (10), 3525-3550CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. The history and development of copper catalyzed Ullmann type coupling reactions between aryl halides and various classes of nucleophiles, focusing mostly on the different mechanisms proposed through the years was covered. Cu(I) and Cu(III) complexes involved in the Ullmann reaction and N/O selectivity in aminoalc. arylation were discussed. Recent developments in green chem. for these reactions, such as reactions in aq. media and heterogeneous catalysis were also covered.
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Kwak, J.-H., In, J.-K., Lee, M.-S., Choi, E.-H., Lee, H., Hong, J. T., Yun, Y.-P., Lee, S. J., Seo, S.-Y., Suh, Y.-G., and Jung, J.-K. (2008) Concise synthesis of Obovatol: Chemoselective ortho-bromination of phenol and survey of Cu-catalyzed diaryl ether couplings. Arch. Pharmacal Res. 31, 1559– 1563, DOI: 10.1007/s12272-001-2151-9
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Concise synthesis of Obovatol: Chemoselective ortho-bromination of phenol and survey of Cu-catalyzed diaryl ether couplings
Kwak, Jae-Hwan; In, Jin-Kyung; Lee, Mi-Sung; Choi, Eun-Hwa; Lee, Heesoon; Hong, Jin Tae; Yun, Yeo-Pyo; Lee, Soo Jae; Seo, Seung-Yong; Suh, Young-Ger; Jung, Jae-Kyung
Archives of Pharmacal Research (2008), 31 (12), 1559-1563CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)
Concise total synthesis of obovatol (I) was achieved from the com. available eugenol via linear 4 steps in 40% overall yield. The key features of the synthesis involve the chemoselective orthobromination of phenol in the presence of isolated double bond and the efficient Cu-catalyzed Ullmann coupling of two arom. moieties for the diaryl ether skeleton.
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Buck, E., Song, Z. J., Tschaen, D., Dormer, P. G., Volante, R. P., and Reider, P. J. (2002) Ullmann Diaryl Ether Synthesis: Rate Acceleration by 2,2,6,6-Tetramethylheptane-3,5-dione. Org. Lett. 4, 1623– 1626, DOI: 10.1021/ol025839t
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Ullmann Diaryl Ether Synthesis: Rate Acceleration by 2,2,6,6-Tetramethylheptane-3,5-dione
Buck, Elizabeth; Song, Zhiguo Jake; Tschaen, David; Dormer, Peter G.; Volante, R. P.; Reider, Paul J.
Organic Letters (2002), 4 (9), 1623-1626CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
In the copper salt catalyzed ether formation from aryl bromides or iodides and phenols, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD) was found to greatly accelerate the ordinarily difficult reaction, making it occur under more moderate temps. and reaction times. A series of aryl halides and phenols were shown to form ethers in NMP as the solvent, cesium carbonate as the base, and CuCl and TMHD as the catalysts. The reaction was shown to tolerate electron-rich aryl bromides and electron-neutral phenols.
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Ma, D. and Cai, Q. (2003) N, N-Dimethyl Glycine-Promoted Ullmann Coupling Reaction of Phenols and Aryl Halides. Org. Lett. 5, 3799– 3802, DOI: 10.1021/ol0350947
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N,N-Dimethyl Glycine-Promoted Ullmann Coupling Reaction of Phenols and Aryl Halides
Ma, Dawei; Cai, Qian
Organic Letters (2003), 5 (21), 3799-3802CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
Ullmann-type diaryl ether synthesis can be performed at 90 °C using either aryl iodides or aryl bromides as the substrates under the assistance of N,N-dimethylglycine.
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Garnier, T., Danel, M., Magné, V., Pujol, A., Bénéteau, V., Pale, P., and Chassaing, S. (2018) Copper(I)–USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S-, and C-Arylation Reactions: Scope and Application to Total Synthesis. J. Org. Chem. 83, 6408– 6422, DOI: 10.1021/acs.joc.8b00620
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Copper(I)-USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S-, and C-Arylation Reactions: Scope and Application to Total Synthesis
Garnier, Tony; Danel, Mathieu; Magne, Valentin; Pujol, Anthony; Beneteau, Valerie; Pale, Patrick; Chassaing, Stefan
Journal of Organic Chemistry (2018), 83 (12), 6408-6422CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The copper(I)-doped zeolite CuI-USY proved to be a versatile, efficient, and recyclable catalyst for various Ullmann-type coupling reactions. Easy to prep. and cheap, this catalytic material enables the arylation and heteroarylation of diverse O-, N-, S-, and C-nucleophiles under ligand-free conditions while exhibiting large functional group compatibility. The facility of this catalyst to promote C-O bond formation was further demonstrated with the total synthesis of 3-methylobovatol, a naturally occurring diaryl ether of biol. relevance. From a mechanistic viewpoint, two competitive pathways depending on the nature of the nucleophile and consistent with the obtained results have been proposed.
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Kijjoa, A., Pinto, M. M. M., Tantisewie, B., and Herz, W. (1989) A biphenyl type neolignan and a biphenyl ether from Magnolia henryi. Phytochemistry 28, 1284– 1286, DOI: 10.1016/0031-9422(89)80237-7
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A biphenyl type neolignan and a biphenyl ether from Magnolia henryi
Kijjoa, Anake; Pinto, Madalena M. M.; Tantisewie, Bumrung; Herz, Werner
Phytochemistry (1989), 28 (4), 1284-6CODEN: PYTCAS; ISSN:0031-9422.
A new biphenyl type neolignan 5,5'-diallyl-2,2'-dihydroxy-3-methoxybiphenyl (I) and a new related ether 4',5-diallyl-2-hydroxy-3-methoxybiphenyl ether (II) were isolated from the bark of M. henryi and identified by spectral methods. Magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) was also isolated.
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Pilkington, L. I. and Barker, D. (2015) Synthesis of 3-Methylobovatol. Synlett 26, 2425– 2428, DOI: 10.1055/s-0035-1560262
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Synthesis of 3-Methylobovatol
Pilkington, Lisa I.; Barker, David
Synlett (2015), 26 (17), 2425-2428CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
Biphenyl lignans are rare compds. that exhibit a broad range of biol. activities. The first total synthesis of natural biphenyl ether lignan, 3-methylobovatol, has been achieved in four steps. This synthesis allows for modification of the C-2 phenol and in doing so, will facilitate various structure-activity relationship studies into these bioactive compds.
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Martins, L. F., Mesquita, J. T., Pinto, E. G., Costa-Silva, T. A., Borborema, S. E. T., Galisteo Junior, A. J., Neves, B. J., Andrade, C. H., Shuhaib, Z. A., Bennett, E. L., Black, G. P., Harper, P. M., Evans, D. M., Fituri, H. S., Leyland, J. P., Martin, C., Roberts, T. D., Thornhill, A. J., Vale, S. A., Howard-Jones, A., Thomas, D. A., Williams, H. L., Overman, L. E., Berlinck, R. G. S., Murphy, P. J., and Tempone, A. G. (2016) Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes. J. Nat. Prod. 79, 2202– 2210, DOI: 10.1021/acs.jnatprod.6b00256
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Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes
Martins, Ligia F.; Mesquita, Juliana T.; Pinto, Erika G.; Costa-Silva, Thais A.; Borborema, Samanta E. T.; Galisteo Junior, Andres J.; Neves, Bruno J.; Andrade, Carolina H.; Shuhaib, Zainab Al; Bennett, Elliot L.; Black, Gregory P.; Harper, Philip M.; Evans, Daniel M.; Fituri, Hisham S.; Leyland, John P.; Martin, Claire; Roberts, Terence D.; Thornhill, Andrew J.; Vale, Stephen A.; Howard-Jones, Andrew; Thomas, Dafydd A.; Williams, Harri L.; Overman, Larry E.; Berlinck, Roberto G. S.; Murphy, Patrick J.; Tempone, Andre G.
Journal of Natural Products (2016), 79 (9), 2202-2210CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
Synthetic analogs of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines (I) and (II) presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of (I) and (II) was investigated in host cells and in parasites. Both compds. induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines (I) and (II) on macrophages. The same compds. also promoted anti-inflammatory activity in L. infantum-infected macrophages cocultived with splenocytes, reducing the prodn. of cytokines MCP-1 and IFN-γ. Guanidines (I) and (II) affect the bioenergetic metab. of Leishmania, with selective elimination of parasites via a host-independent mechanism.
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Katsuno, K., Burrows, J. N., Duncan, K., van Huijsduijnen, R. H., Kaneko, T., Kita, K., Mowbray, C. E., Schmatz, D., Warner, P., and Slingsby, B. T. (2015) Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discovery 14, 751– 758, DOI: 10.1038/nrd4683
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Hit and lead criteria in drug discovery for infectious diseases of the developing world
Katsuno, 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.
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Tada, H., Shiho, O., Kuroshima, K.-i., Koyama, M., and Tsukamoto, K. (1986) An improved colorimetric assay for interleukin 2. J. Immunol. Methods 93, 157– 165, DOI: 10.1016/0022-1759(86)90183-3
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An improved colorimetric assay for interleukin 2
Tada, Hiroko; Shiho, Osamu; Kuroshima, Kenichi; Koyama, Masaru; Tsukamoto, Kyozo
Journal of Immunological Methods (1986), 93 (2), 157-65CODEN: JIMMBG; ISSN:0022-1759.
Mosmann's method for measuring the no. of viable cells with a tetrazolium salt, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-di-phenyltetrazolium bromide (MTT), was modified to make it possible to measure a large no. of interleukin 2 (IL-2) samples at one time with less labor and more accuracy. Each step of the method was examd. in detail and modified (the modified MTT method). An IL-2-dependent mouse natural killer cell line, NKC3, was used as an indicator cell line. The incubation period before adding MTT was reduced to 24 h. A soln. of 10% SDS-0.01 N HCl was used to dissolve the MTT formazan produced. The authors compared the value obtained by the modified MTT method and the conventional [3H]thymidine method, and confirmed that the ests. of IL-2 content were almost equal. The variation of IL-2 content measured by both methods was within 5% in terms of the std. error.
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Abstract
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Figure 1
Figure 1. Structures of the dehydrodieugenol natural products and planned SAR/synthesis strategy.
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Scheme 1
Scheme 1. Synthesis of Natural Products 1 and 2 and Analogues 5–10^a
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^aReagents and conditions: (a) MOMCl (1.5 equiv), i-Pr₂EtN, CH₂Cl₂; (b) s-BuLi (1.5 equiv), TMEDA, THF, 0 °C to rt; I₂ (1.5 equiv); (c) CuCl (50 mol %), TMHD (50 mol %), Cs₂CO₃ (2 equiv), dioxane/NMP (2:1), 80 °C; (d) 2 M HCl/MeOH (1:10); (e) PMBCl (1.2 equiv), K₂CO₃(2.5 equiv), DMF, 100 °C; (f) MeI (1.4 equiv), K₂CO₃ (4 equiv), DMF; (g) 1 M HCl/EtOH (1:2.5), 80 °C; (h) H₂, Pd/C (30 mol %), EtOH.
Scheme 2
Scheme 2. Synthesis of Analogues 11–25^a
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^aReagents and conditions: (a) CuCl (50 mol %), TMHD (50 mol %), Cs₂CO₃ (2 equiv), dioxane/NMP (2:1), 80 °C; (b) 2 M HCl/MeOH (1:10); (c) 1 M HCl/EtOH (1:2.5), 80 °C; (d) coupled using CuI (10 mol %), N,N-dimethylglycine hydrochloride (30 mol %), K₂CO₃ (2 equiv), DMSO, 80 °C; (26) (e) PMBCl (1.2 equiv), K₂CO₃ (2.5 equiv), DMF, 100 °C; (f) Pd₂(dba)₃ (1 mol %), BINAP (1 mol %), AllylMgCl (2.5 equiv), dioxane.
Figure 2
Figure 2. SAR trends for the dehydrodieugenol scaffold.
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References
This article references 32 other publications.
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  A review. Natural products (NPs) are important sources of clin. drugs due to their structural diversity and biol. prevalidation. However, the structural complexity of NPs leads to synthetic difficulties, unfavorable pharmacokinetic profiles, and poor drug-likeness. Structural simplification by truncating unnecessary substructures is a powerful strategy for overcoming these limitations and improving the efficiency and success rate of NP-based drug development. Herein, we will provide a comprehensive review of the structural simplification of NPs with a focus on design strategies, case studies, and new technologies. In particular, a no. of successful examples leading to marketed drugs or drug candidates will be discussed in detail to illustrate how structural simplification is applied in lead optimization of NPs.
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  A review. Chagas disease affects 8-10 million people worldwide, mainly in Latin America. The current therapy for Chagas disease is limited to nifurtimox and benznidazole, which are effective in treating only the acute phase of the disease but with severe side effects. Therefore, there is an unmet need for new drugs and for the exploration of innovative approaches which may lead to the discovery of new effective and safe drugs for its treatment. The authors report and discuss recent approaches including structure-based design that have led to the discovery of new promising small mol. candidates for Chagas disease which affect prime targets that intervene in the sterol pathway of T. cruzi. Other trypanosome targets, phenotypic screening, the use of artificial intelligence and the challenges with Chagas disease drug discovery are also discussed. The application of recent scientific innovations to the field of Chagas disease have led to the discovery of new promising drug candidates for Chagas disease. Phenotypic screening brought new hits and opportunities for drug discovery. Artificial intelligence also has the potential to accelerate drug discovery in Chagas disease and further research into this is warranted.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFKku7rO&md5=530169e16a2fc0e5f372854baebd9b9e
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  A review. Leishmaniasis (Leishmania species), sleeping sickness (Trypanosoma brucei), and Chagas disease (Trypanosoma cruzi) are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technol. advances in parasitol., chem., and genomics have unlocked new possibilities for novel drug concepts and compd. screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biol. context, as well as different examples of recently discovered lead compds.
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  Natural Products as Sources of New Drugs from 1981 to 2014
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  This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from Jan. 1, 1981, to Dec. 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions and the designation "natural product botanical", or "NB", to cover those botanical "defined mixts." now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small mols. approved, 131, or 75%, are other than "S" (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore it is considered that this area of natural product research should be expanded significantly.
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12. 12
  da Rosa, R., Schenkel, E. P., and Campos Bernardes, L. S. (2020) Semisynthetic and newly designed derivatives based on natural chemical scaffolds: moving beyond natural products to fight Trypanosoma cruzi. Phytochem. Rev. 19, 105– 122, DOI: 10.1007/s11101-020-09659-8
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  Semisynthetic and newly designed derivatives based on natural chemical scaffolds: moving beyond natural products to fight Trypanosoma cruzi
  da Rosa, Rafael; Schenkel, Eloir Paulo; Campos Bernardes, Lilian Sibelle
  Phytochemistry Reviews (2020), 19 (1), 105-122CODEN: PRHEBS; ISSN:1568-7767. (Springer)
  A review. Secondary metabolites obtained from natural sources are medicinally relevant mols. About one-third of all FDA-approved drugs are derived from or based on natural products, which suggests that mol. optimization is often required for translation from benchtop to clin. practice. Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease highly prevalent in Latin America. It has a significant impact on socioeconomic indicators and is not easily cured by the two currently available drugs, benznidazole and nifurtimox. Considering the importance of developing new bioactive mols. based on natural products, this article reviews 21 years of literature reports on the semisynthesis and total synthesis of new compds. targeting T. cruzi. From 1997 to 2018, sixty-six articles reporting five hundred and thirty-seven mols. active against different strains and life stages of the parasite were published. Quinones, alkaloids, terpenes, and lignans were the four largest classes of derivs., the majority of which had IC50 values low enough to indicate that natural product derivs. can be an important source of potential new drugs to treat Chagas disease. We highlight important mols. in each secondary metabolite class, discussing factors such as selectivity and the basis for their design. An assessment of drug-likeness parameters was performed, which might prove useful for selecting lead compds. for preclin. drug studies.
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13. 13
  Santos, S. S., de Araújo, R. V., Giarolla, J., Seoud, O. E., and Ferreira, E. I. (2020) Searching for drugs for Chagas disease, leishmaniasis and schistosomiasis: a review. Int. J. Antimicrob. Agents 55, 105906, DOI: 10.1016/j.ijantimicag.2020.105906
  13
  Searching for drugs for Chagas disease, leishmaniasis and schistosomiasis: a review
  Santos, Soraya Silva; Vinicius de Araujo, Renan; Giarolla, Jeanine; El Seoud, Omar; Ferreira, Elizabeth Igne
  International Journal of Antimicrobial Agents (2020), 55 (4), 105906CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
  A review. Chagas disease, leishmaniasis and schistosomiasis are neglected diseases (NDs) and are a considerable global challenge. Despite the huge no. of people infected, NDs do not create interest from pharmaceutical companies because the assocd. revenue is generally low. Most of the research on these diseases has been conducted in academic institutions. The chemotherapeutic armamentarium for NDs is scarce and inefficient and better drugs are needed. Researchers have found some promising potential drug candidates using medicinal chem. and computational approaches. Most of these compds. are synthetic but some are from natural sources or are semi-synthetic. Drug repurposing or repositioning has also been greatly stimulated for NDs. This review considers some potential drug candidates and provides details of their design, discovery and activity.
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14. 14
  Zimmermann, L. A., de Moraes, M. H., da Rosa, R., de Melo, E. B., Paula, F. R., Schenkel, E. P., Steindel, M., and Bernardes, L. S. C. (2018) Synthesis and SAR of new isoxazole-triazole bis-heterocyclic compounds as analogues of natural lignans with antiparasitic activity. Bioorg. Med. Chem. 26, 4850– 4862, DOI: 10.1016/j.bmc.2018.08.025
  14
  Synthesis and SAR of new isoxazole-triazole bis-heterocyclic compounds as analogues of natural lignans with antiparasitic activity
  Zimmermann, Lara A.; de Moraes, Milene H.; da Rosa, Rafael; de Melo, Eduardo B.; Paula, Favero R.; Schenkel, Eloir P.; Steindel, Mario; Bernardes, Lilian S. C.
  Bioorganic & Medicinal Chemistry (2018), 26 (17), 4850-4862CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  Despite the impressive scientific and technol. advances of recent decades, no effective treatment is currently available for Chagas disease. The authors research group has been studying the design and synthesis of analogs of natural lignans aiming to identify compds. with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivs. and the structure-activity relation study conducted based on results of biol. assays against Trypanosoma cruzi amastigotes. Thirty-seven compds. were active, and eight of them had GI50 values lower than 100 μM (GI50 88.4-12.2 μM). A qual. structure activity relation study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compds. Compd. 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole as the most active in the series (GI50 12.2 μM), showing, in vitro, low toxicity and potency similar to benznidazole (GI50 10.2 μM). These results suggest that this compd. can be a promising scaffold for the design of new trypanocidal compds.
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15. 15
  Fraser, A. L., Menzies, S. K., King, E. F. B., Tulloch, L. B., Gould, E. R., Zacharova, M. K., Smith, T. K., and Florence, G. J. (2018) Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors. ACS Infect. Dis. 4, 560– 567, DOI: 10.1021/acsinfecdis.7b00187
  15
  Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors
  Fraser, Andrew L.; Menzies, Stefanie K.; King, Elizabeth F. B.; Tulloch, Lindsay B.; Gould, Eoin R.; Zacharova, Marija K.; Smith, Terry K.; Florence, Gordon J.
  ACS Infectious Diseases (2018), 4 (4), 560-567CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the prepn. of a focused library of substituted-tetrahydropyran derivs. and their evaluation as selective chem. tools for trypanosomatid inhibition and the follow-on development of photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compds. maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani. In addn., we demonstrate the utility of the photoaffinity probes for target identification through preliminary cellular localization studies.
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16. 16
  Cheuka, P. M., Mayoka, G., Mutai, P., and Chibale, K. (2017) The Role of Natural Products in Drug Discovery and Development against Neglected Tropical Diseases. Molecules 22, 58, DOI: 10.3390/molecules22010058
  16
  The role of natural products in drug discovery and development against neglected tropical diseases
  Cheuka, Peter Mubanga; Mayoka, Godfrey; Mutai, Peggoty; Chibale, Kelly
  Molecules (2017), 22 (1), 58/1-58/41CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are also responsible for over 500,000 deaths per yr and are characterized by long-term disability and severe pain. The impact of the combined NTDs closely rivals that of malaria and tuberculosis. Current treatment options are assocd. with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. In this review, we highlight the potential that remains untapped in natural products as drug leads for NTDs. We cover natural products from plant, marine, and microbial sources including natural-product-inspired semi-synthetic derivs. which have been evaluated against the various causative agents of NTDs. Our coverage is limited to four major NTDs which include human African trypanosomiasis (sleeping sickness), leishmaniasis, schistosomiasis and lymphatic filariasis.
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17. 17
  Wells, T. N. C. (2011) Natural products as starting points for future anti-malarial therapies: going back to our roots?. Malar. J. 10, S3, DOI: 10.1186/1475-2875-10-S1-S3
  17
  Natural products as starting points for future anti-malarial therapies: going back to our roots?
  Wells, Timothy N. C.
  Malaria Journal (2011), 10 (Suppl. 1), S3CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)
  A review. Background: The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results: Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Mols. such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chem. and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compds. from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compds.-starting points for new drug discovery programs. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or 'acting in the reversed order', starting with observational clin. studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clin. observational data exist, or can be generated. The first step should be the confirmation and definition of the clin. activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacol. characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited nos. of well-controlled clin. studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clin. data on such products. Conclusions: The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the 'smash and grab' approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacol. and design and reporting of clin. observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chem. and pharmacol. characterization of exts. from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require addnl. support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clin. best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new mol. scaffolds which will form the basis of the next generation of anti-malarial therapies.
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18. 18
  Grecco, S. S., Costa-Silva, T. A., Jerz, G., de Sousa, F. S., Londero, V. S., Galuppo, M. K., Lima, M. L., Neves, B. J., Andrade, C. H., Tempone, A. G., and Lago, J. H. G. (2017) Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages. Chem.-Biol. Interact. 277, 55– 61, DOI: 10.1016/j.cbi.2017.08.017
  18
  Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages
  Grecco, Simone S.; Costa-Silva, Thais A.; Jerz, Gerold; de Sousa, Fernanda S.; Londero, Vinicius S.; Galuppo, Mariana K.; Lima, Marta L.; Neves, Bruno J.; Andrade, Carolina H.; Tempone, Andre G.; Lago, Joao Henrique G.
  Chemico-Biological Interactions (2017), 277 (), 55-61CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
  Chagas disease is a neglected tropical disease, caused by the protozoan parasite Trypanosoma cruzi, which affects more than eight million people in Tropical and Subtropical countries esp. in Latin America. Current treatment is limited to nifurtimox and benznidazole, both with reduced effectiveness and high toxicity. In this work, the n-hexane ext. from leaves of Nectandra leucantha (Lauraceae) displayed in vitro antitrypanosomal activity against T. cruzi. Using several chromatog. steps, four related neolignans were isolated and chem. characterized as dehydrodieugenol B (1), 1-(8-propenyl)-3-[3'-methoxy-1'-(8-propenyl)-phenoxy]-4,5-dimethoxybenzene (2), 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4-hydroxy-5-methoxybenzene (3), and 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4,5-dimethoxybenzene (4). These compds. were tested against intracellular amastigotes and extracellular trypomastigotes of T. cruzi and for mammalian cytotoxicity. Neolignan 4 showed the higher selectivity index (SI) against trypomastigotes (>5) and amastigotes (>13) of T. cruzi. The investigation of the mechanism of action demonstrated that neolignan 4 caused substantial alteration of the plasma membrane permeability, together with mitochondrial dysfunctions in trypomastigote forms. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compds. were non-mutagenic, non-carcinogenic, non-genotoxic, weak hERG blockers, with acceptable vol. of distribution (1.66-3.32 L/kg), and low rodent oral toxicity (LD50 810-2200 mg/kg). Considering some clin. events of cerebral Chagas disease, the compds. also demonstrated favorable properties, such as blood-brain barrier penetration. Unfavorable properties were also predicted as high promiscuity for P 450 isoforms, high plasma protein binding affinity (>91%), and moderate-to-low oral bioavailability. Finally, none of the isolated neolignans was predicted as interference compds. (PAINS). Considering the promising chem. and biol. properties of the isolated neolignans, these compds. could be used as starting points to develop new lead compds. for Chagas disease.
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19. 19
  Costa-Silva, T. A. d., Grecco, S. S., de Sousa, F. S., Lago, J. H. G., Martins, E. G. A., Terrazas, C. A., Varikuti, S., Owens, K. L., Beverley, S. M., Satoskar, A. R., and Tempone, A. G. (2015) Immunomodulatory and Antileishmanial Activity of Phenylpropanoid Dimers Isolated from Nectandra leucantha. J. Nat. Prod. 78, 653– 657, DOI: 10.1021/np500809a
  There is no corresponding record for this reference.
20. 20
  Ferreira, D. D., Sousa, F. S., Costa-Silva, T. A., Reimão, J. Q., Torrecilhas, A. C., Johns, D. M., Sear, C. E., Honorio, K. M., Lago, J. H. G., Anderson, E. A., and Tempone, A. G. (2019) Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi. Eur. J. Med. Chem. 176, 162– 174, DOI: 10.1016/j.ejmech.2019.05.001
  20
  Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi
  Ferreira, Daiane D.; Sousa, Fernanda S.; Costa-Silva, Thais A.; Reimao, Juliana Q.; Torrecilhas, Ana C.; Johns, Deidre M.; Sear, Claire E.; Honorio, Kathia M.; Lago, Joao Henrique G.; Anderson, Edward A.; Tempone, Andre G.
  European Journal of Medicinal Chemistry (2019), 176 (), 162-174CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
  Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited no. and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivs. was prepd. to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compds. demonstrated activity against trypomastigotes (IC50 values from 8 to 64 μM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 μM). Eighteen derivs. demonstrated no mammalian cytotoxicity up to 200 μM. The phenolic acetate deriv. of natural dehydrodieugenol B (I) was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compd. caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being obsd. Fluorescence assays demonstrated that this deriv. affected neither the permeability nor the elec. potential of the parasitic plasma membrane, an effect also corroborated by SEM studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivs. represents a promising starting point for future Chagas disease drug discovery studies.
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21. 21
  Giri, R., Brusoe, A., Troshin, K., Wang, J. Y., Font, M., and Hartwig, J. F. (2018) Mechanism of the Ullmann Biaryl Ether Synthesis Catalyzed by Complexes of Anionic Ligands: Evidence for the Reaction of Iodoarenes with Ligated Anionic CuI Intermediates. J. Am. Chem. Soc. 140, 793– 806, DOI: 10.1021/jacs.7b11853
  21
  Mechanism of the Ullmann Biaryl Ether Synthesis Catalyzed by Complexes of Anionic Ligands: Evidence for the Reaction of Iodoarenes with Ligated Anionic CuI Intermediates
  Giri, Ramesh; Brusoe, Andrew; Troshin, Konstantin; Wang, Justin Y.; Font, Marc; Hartwig, John F.
  Journal of the American Chemical Society (2018), 140 (2), 793-806CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A series of exptl. studies, along with DFT calcns., are reported that provide a detailed view into the mechanism of Ullmann coupling of phenols with aryl halides in the presence of catalysts generated from Cu(I) and bidentate, anionic ligands. These studies encompass catalysts contg. anionic ligands formed by deprotonation of 8-hydroxyquinoline, 2-pyridylmethyl tert-Bu ketone, and 2,2,6,6-tetramethylheptane-3,5-dione. Three-coordinate, heteroleptic species [Cu(LX)OAr]- were shown by expt. and DFT calcns. to be the most stable complexes in catalytic systems contg. 8-hydroxyquinoline or 2-pyridylmethyl tert-Bu ketone and to be generated reversibly in the system contg. 2,2,6,6-tetramethylheptane-3,5-dione. These heteroleptic complexes were characterized by a combination of 19F NMR, 1H NMR, and UV-vis spectroscopy, as well as ESI-MS. The heteroleptic complexes generated in situ react with iodoarenes to form biaryl ethers in high yields without evidence for an aryl radical intermediate. Measurements of 13C/12C isotope effects showed that oxidative addn. of the iodoarene occurs irreversibly. This information, in combination with the kinetic data, shows that oxidative addn. occurs to the [Cu(LX)OAr]- complexes and is turnover-limiting. A Hammett anal. of the effect of phenoxide electronic properties on the rate of the reaction of [Cu(LX)OAr]- with iodotoluene also is consistent with oxidative addn. of the iodoarene to an anionic phenoxide complex. Calcns. by DFT suggest that this oxidative addn. is followed by dissocn. of I- and reductive elimination of the biaryl ether from the resulting neutral Cu(III) complex.
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22. 22
  Evano, G., Wang, J., and Nitelet, A. (2017) Metal-mediated C–O bond forming reactions in natural product synthesis. Org. Chem. Front. 4, 2480– 2499, DOI: 10.1039/C7QO00671C
  22
  Metal-mediated C-O bond forming reactions in natural product synthesis
  Evano, Gwilherm; Wang, Jianjun; Nitelet, Antoine
  Organic Chemistry Frontiers (2017), 4 (12), 2480-2499CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
  A review. Metal catalyzed reactions for the formation of C-O bonds have had a dramatic impact in natural product synthesis over the past few decades. Various metals have been reported to efficiently catalyze cross-coupling reactions for the formation of various C(sp2)-O bonds from aryl/alkenyl halides or synthetic equiv. and phenols, aliph. alcs. and water. The implementation of such reactions in natural product synthesis enabled the emergence of new bond disconnections, which notably resulted in remarkably efficient and short synthetic pathways. The use of these reactions for the formation of C-O bonds in natural product synthesis is overviewed in this crit. review, with an emphasis on copper and palladium catalysts which are the most efficient ones to date.
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23. 23
  Sambiagio, C., Marsden, S. P., Blacker, A. J., and McGowan, P. C. (2014) Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 43, 3525– 3550, DOI: 10.1039/C3CS60289C
  23
  Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development
  Sambiagio, Carlo; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C.
  Chemical Society Reviews (2014), 43 (10), 3525-3550CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. The history and development of copper catalyzed Ullmann type coupling reactions between aryl halides and various classes of nucleophiles, focusing mostly on the different mechanisms proposed through the years was covered. Cu(I) and Cu(III) complexes involved in the Ullmann reaction and N/O selectivity in aminoalc. arylation were discussed. Recent developments in green chem. for these reactions, such as reactions in aq. media and heterogeneous catalysis were also covered.
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24. 24
  Kwak, J.-H., In, J.-K., Lee, M.-S., Choi, E.-H., Lee, H., Hong, J. T., Yun, Y.-P., Lee, S. J., Seo, S.-Y., Suh, Y.-G., and Jung, J.-K. (2008) Concise synthesis of Obovatol: Chemoselective ortho-bromination of phenol and survey of Cu-catalyzed diaryl ether couplings. Arch. Pharmacal Res. 31, 1559– 1563, DOI: 10.1007/s12272-001-2151-9
  24
  Concise synthesis of Obovatol: Chemoselective ortho-bromination of phenol and survey of Cu-catalyzed diaryl ether couplings
  Kwak, Jae-Hwan; In, Jin-Kyung; Lee, Mi-Sung; Choi, Eun-Hwa; Lee, Heesoon; Hong, Jin Tae; Yun, Yeo-Pyo; Lee, Soo Jae; Seo, Seung-Yong; Suh, Young-Ger; Jung, Jae-Kyung
  Archives of Pharmacal Research (2008), 31 (12), 1559-1563CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)
  Concise total synthesis of obovatol (I) was achieved from the com. available eugenol via linear 4 steps in 40% overall yield. The key features of the synthesis involve the chemoselective orthobromination of phenol in the presence of isolated double bond and the efficient Cu-catalyzed Ullmann coupling of two arom. moieties for the diaryl ether skeleton.
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25. 25
  Buck, E., Song, Z. J., Tschaen, D., Dormer, P. G., Volante, R. P., and Reider, P. J. (2002) Ullmann Diaryl Ether Synthesis: Rate Acceleration by 2,2,6,6-Tetramethylheptane-3,5-dione. Org. Lett. 4, 1623– 1626, DOI: 10.1021/ol025839t
  25
  Ullmann Diaryl Ether Synthesis: Rate Acceleration by 2,2,6,6-Tetramethylheptane-3,5-dione
  Buck, Elizabeth; Song, Zhiguo Jake; Tschaen, David; Dormer, Peter G.; Volante, R. P.; Reider, Paul J.
  Organic Letters (2002), 4 (9), 1623-1626CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  In the copper salt catalyzed ether formation from aryl bromides or iodides and phenols, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD) was found to greatly accelerate the ordinarily difficult reaction, making it occur under more moderate temps. and reaction times. A series of aryl halides and phenols were shown to form ethers in NMP as the solvent, cesium carbonate as the base, and CuCl and TMHD as the catalysts. The reaction was shown to tolerate electron-rich aryl bromides and electron-neutral phenols.
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26. 26
  Ma, D. and Cai, Q. (2003) N, N-Dimethyl Glycine-Promoted Ullmann Coupling Reaction of Phenols and Aryl Halides. Org. Lett. 5, 3799– 3802, DOI: 10.1021/ol0350947
  26
  N,N-Dimethyl Glycine-Promoted Ullmann Coupling Reaction of Phenols and Aryl Halides
  Ma, Dawei; Cai, Qian
  Organic Letters (2003), 5 (21), 3799-3802CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  Ullmann-type diaryl ether synthesis can be performed at 90 °C using either aryl iodides or aryl bromides as the substrates under the assistance of N,N-dimethylglycine.
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27. 27
  Garnier, T., Danel, M., Magné, V., Pujol, A., Bénéteau, V., Pale, P., and Chassaing, S. (2018) Copper(I)–USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S-, and C-Arylation Reactions: Scope and Application to Total Synthesis. J. Org. Chem. 83, 6408– 6422, DOI: 10.1021/acs.joc.8b00620
  27
  Copper(I)-USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S-, and C-Arylation Reactions: Scope and Application to Total Synthesis
  Garnier, Tony; Danel, Mathieu; Magne, Valentin; Pujol, Anthony; Beneteau, Valerie; Pale, Patrick; Chassaing, Stefan
  Journal of Organic Chemistry (2018), 83 (12), 6408-6422CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The copper(I)-doped zeolite CuI-USY proved to be a versatile, efficient, and recyclable catalyst for various Ullmann-type coupling reactions. Easy to prep. and cheap, this catalytic material enables the arylation and heteroarylation of diverse O-, N-, S-, and C-nucleophiles under ligand-free conditions while exhibiting large functional group compatibility. The facility of this catalyst to promote C-O bond formation was further demonstrated with the total synthesis of 3-methylobovatol, a naturally occurring diaryl ether of biol. relevance. From a mechanistic viewpoint, two competitive pathways depending on the nature of the nucleophile and consistent with the obtained results have been proposed.
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28. 28
  Kijjoa, A., Pinto, M. M. M., Tantisewie, B., and Herz, W. (1989) A biphenyl type neolignan and a biphenyl ether from Magnolia henryi. Phytochemistry 28, 1284– 1286, DOI: 10.1016/0031-9422(89)80237-7
  28
  A biphenyl type neolignan and a biphenyl ether from Magnolia henryi
  Kijjoa, Anake; Pinto, Madalena M. M.; Tantisewie, Bumrung; Herz, Werner
  Phytochemistry (1989), 28 (4), 1284-6CODEN: PYTCAS; ISSN:0031-9422.
  A new biphenyl type neolignan 5,5'-diallyl-2,2'-dihydroxy-3-methoxybiphenyl (I) and a new related ether 4',5-diallyl-2-hydroxy-3-methoxybiphenyl ether (II) were isolated from the bark of M. henryi and identified by spectral methods. Magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) was also isolated.
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29. 29
  Pilkington, L. I. and Barker, D. (2015) Synthesis of 3-Methylobovatol. Synlett 26, 2425– 2428, DOI: 10.1055/s-0035-1560262
  29
  Synthesis of 3-Methylobovatol
  Pilkington, Lisa I.; Barker, David
  Synlett (2015), 26 (17), 2425-2428CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
  Biphenyl lignans are rare compds. that exhibit a broad range of biol. activities. The first total synthesis of natural biphenyl ether lignan, 3-methylobovatol, has been achieved in four steps. This synthesis allows for modification of the C-2 phenol and in doing so, will facilitate various structure-activity relationship studies into these bioactive compds.
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30. 30
  Martins, L. F., Mesquita, J. T., Pinto, E. G., Costa-Silva, T. A., Borborema, S. E. T., Galisteo Junior, A. J., Neves, B. J., Andrade, C. H., Shuhaib, Z. A., Bennett, E. L., Black, G. P., Harper, P. M., Evans, D. M., Fituri, H. S., Leyland, J. P., Martin, C., Roberts, T. D., Thornhill, A. J., Vale, S. A., Howard-Jones, A., Thomas, D. A., Williams, H. L., Overman, L. E., Berlinck, R. G. S., Murphy, P. J., and Tempone, A. G. (2016) Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes. J. Nat. Prod. 79, 2202– 2210, DOI: 10.1021/acs.jnatprod.6b00256
  30
  Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes
  Martins, Ligia F.; Mesquita, Juliana T.; Pinto, Erika G.; Costa-Silva, Thais A.; Borborema, Samanta E. T.; Galisteo Junior, Andres J.; Neves, Bruno J.; Andrade, Carolina H.; Shuhaib, Zainab Al; Bennett, Elliot L.; Black, Gregory P.; Harper, Philip M.; Evans, Daniel M.; Fituri, Hisham S.; Leyland, John P.; Martin, Claire; Roberts, Terence D.; Thornhill, Andrew J.; Vale, Stephen A.; Howard-Jones, Andrew; Thomas, Dafydd A.; Williams, Harri L.; Overman, Larry E.; Berlinck, Roberto G. S.; Murphy, Patrick J.; Tempone, Andre G.
  Journal of Natural Products (2016), 79 (9), 2202-2210CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
  Synthetic analogs of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines (I) and (II) presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of (I) and (II) was investigated in host cells and in parasites. Both compds. induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines (I) and (II) on macrophages. The same compds. also promoted anti-inflammatory activity in L. infantum-infected macrophages cocultived with splenocytes, reducing the prodn. of cytokines MCP-1 and IFN-γ. Guanidines (I) and (II) affect the bioenergetic metab. of Leishmania, with selective elimination of parasites via a host-independent mechanism.
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31. 31
  Katsuno, K., Burrows, J. N., Duncan, K., van Huijsduijnen, R. H., Kaneko, T., Kita, K., Mowbray, C. E., Schmatz, D., Warner, P., and Slingsby, B. T. (2015) Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discovery 14, 751– 758, DOI: 10.1038/nrd4683
  31
  Hit and lead criteria in drug discovery for infectious diseases of the developing world
  Katsuno, 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.
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32. 32
  Tada, H., Shiho, O., Kuroshima, K.-i., Koyama, M., and Tsukamoto, K. (1986) An improved colorimetric assay for interleukin 2. J. Immunol. Methods 93, 157– 165, DOI: 10.1016/0022-1759(86)90183-3
  32
  An improved colorimetric assay for interleukin 2
  Tada, Hiroko; Shiho, Osamu; Kuroshima, Kenichi; Koyama, Masaru; Tsukamoto, Kyozo
  Journal of Immunological Methods (1986), 93 (2), 157-65CODEN: JIMMBG; ISSN:0022-1759.
  Mosmann's method for measuring the no. of viable cells with a tetrazolium salt, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-di-phenyltetrazolium bromide (MTT), was modified to make it possible to measure a large no. of interleukin 2 (IL-2) samples at one time with less labor and more accuracy. Each step of the method was examd. in detail and modified (the modified MTT method). An IL-2-dependent mouse natural killer cell line, NKC3, was used as an indicator cell line. The incubation period before adding MTT was reduced to 24 h. A soln. of 10% SDS-0.01 N HCl was used to dissolve the MTT formazan produced. The authors compared the value obtained by the modified MTT method and the conventional [3H]thymidine method, and confirmed that the ests. of IL-2 content were almost equal. The variation of IL-2 content measured by both methods was within 5% in terms of the std. error.
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Synthesis and Structure–Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruziClick to copy article linkArticle link copied!

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Parasites and Mammalian Cell Maintenance

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Antiamastigote Assay

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Synthesis and Structure–Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi
Click to copy article linkArticle link copied!