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Synthesis and In Vivo Profiling of Desymmetrized Antimalarial Trioxolanes with Diverse Carbamate Side Chains
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Synthesis and In Vivo Profiling of Desymmetrized Antimalarial Trioxolanes with Diverse Carbamate Side Chains
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  • Matthew T. Klope
    Matthew T. Klope
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
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  • Juan A. Tapia Cardona
    Juan A. Tapia Cardona
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
    Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, United States
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  • Jun Chen
    Jun Chen
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
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  • Ryan L. Gonciarz
    Ryan L. Gonciarz
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
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  • Ke Cheng
    Ke Cheng
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
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    Orcidhttps://orcid.org/0000-0001-5057-3120
  • Priyadarshini Jaishankar
    Priyadarshini Jaishankar
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
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  • Julie Kim
    Julie Kim
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
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  • Jenny Legac
    Jenny Legac
    Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, United States
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  • Philip J. Rosenthal
    Philip J. Rosenthal
    Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, United States
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  • Adam R. Renslo*
    Adam R. Renslo
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
    *Email: [email protected]; Phone: 415-514-9698; Fax: 415-514-4507.
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    Orcidhttps://orcid.org/0000-0002-1240-2846
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ACS Medicinal Chemistry Letters

Cite this: ACS Med. Chem. Lett. 2024, XXXX, XXX, XXX-XXX
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https://doi.org/10.1021/acsmedchemlett.4c00365
Published September 5, 2024

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Abstract

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The recent withdrawal of artefenomel from clinical development leaves no endoperoxide-class agents in the antimalarial pipeline. Synthetic endoperoxides with a desymmetrized structure have demonstrated promising physiochemical and in vivo properties. Here we expand on our initial investigation of trans-3″ carbamate substitution with a diverse array of amine-, alcohol-, and sulfinyl-terminated analogues prepared in (S,S) and (R,R) configurations. In general, this chemotype combines low-nM antiplasmodial activity with excellent aqueous solubility but widely varying human liver microsome (HLM) stability. We evaluated 20 novel analogues in the P. berghei mouse malaria model, identifying new analogues such as RLA-4767 (9a) and RLA-5489 (9d), with HLM stability and pharmacokinetic profiles superior to analogues from our initial report (e.g., RLA-4776, 8a). These new leads approach or equal the efficacy of artefenomel after two daily oral doses of 10 mg/kg, thus revealing a promising chemotype with the potential to deliver development candidates.

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Despite notable progress in the preclinical arena, malaria remains a cause of significant mortality, particularly in sub-Saharan Africa. (1) Artemisinin-based combination therapy, the standard treatment for uncomplicated malaria, and intravenous artesunate, the standard for severe malaria, are threatened by the increasing prevalence of artemisinin partial resistance (ART-R), which has recently emerged in eastern Africa. (2,3) Among synthetic endoperoxide-class agents evaluated over the past two decades, (4) the adamantyl-1,2,4-trioxolane pharmacophore identified by Vennerstrom and co-workers (5,6) has produced the only clinical candidates: arterolane (OZ277) (7) which is approved as combination therapy in certain regions, and artefenomel (OZ439), (8) which exhibits a superior exposure profile and predicted efficacy in ART-R (Figure 1). (9,10) Arterolane, used in combination with piperaquine in some countries, has theoretical efficacy concerns, and has had rather limited clinical impact. (11) The long clinical development of artefenomel was recently discontinued, after failing to reach clinical pharmacokinetic and pharmacodynamic benchmarks developed around an admirable, if challenging, (12) goal of achieving single-exposure efficacy. As well, food effects, (13) and complex solution-phase behavior (14) produced formulation challenges that contributed to a difficult clinical path for artefenomel. Accordingly, there are currently no endoperoxide agents in the clinical pipeline.

Figure 1

Figure 1. Structure of dihydroartemisinin, arterolane, and the closely related trans-3″ carbamate chemotype explored herein and in our preliminary report. (15)

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Herein we report the further evaluation of desymmetrized trioxolane analogues related to arterolane but based on trans-3″ substitution with heteroaliphatic carbamate side chains (Figure 1). We hypothesized that 3″ substitution with trans stereochemistry should offer similarly stability of the endoperoxide bridge as with traditional cis-4″ substitution found in arterolane and artefenomel (Figure 2). Indeed, in our prior studies, we showed that trans-3″ regioisomers of arterolane (16) and artefenomel (17) exhibited similar low-nM antiplasmodial activity and promising in vivo efficacy in the P. berghei model of malaria. A move from amide to carbamate side chains produced analogues that were considerably more efficacious than arterolane. (15) Subsequently, O’Neill and co-workers described (18) desymmetrized analogues of the tetraoxane E209 with enhanced solubilities, further supporting this approach toward identifying molecules with differentiated properties. We now expand on our initial survey of this chemotype, describing more than 40 new analogues prepared in enantiopure forms and evaluated in key in vitro ADME and in vivo PK/PD studies.

Figure 2

Figure 2. Conformational dynamics of trioxolane antimalarials determine their antiplasmodial effects, with the minor, peroxide-exposed conformer (top right) undergoing Fenton-like reactivity with ferrous iron sources in the parasite, leading to a pharmacodynamic effect. Shown at bottom are the 1,3-diaxial interactions that disfavor the iron-reactive conformer in artefenomel (left) and in the trans-R3 carbamate chemotype explored herein (right).

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We aimed to expand on our initial study of trans-3″ carbamates, exploring both enantiomeric forms for all new analogues, and preparing (S,S) forms of those analogues previously prepared only in the (R,R) forms. (15) Thus, (S,S)-trans-3″ analogues were synthesized in an enantiocontrolled fashion, starting with (R)-Taniaphos-mediated asymmetric borylation of cyclohexenone to prepare intermediate 2 bearing the S configuration (Scheme 1). Oxidation of the C–B bond and protection of the resulting alcohol as a tert-butyldiphenylsilyl (TBDPS) ether afforded ketone 4. This material undergoes diastereocontrolled Griesbaum co-ozonolysis with adamantan-2-one O-methyloxime, to afford the desired trans intermediate 5 in a 12:1 diastereomeric ratio (dr) as determined by 1H NMR analysis. Subsequent deprotection of 5 and conversion to the p-nitrophenylcarbonate 7 allowed for late-stage diversification into the desired (S,S)-trans-3″-carbamate analogues 9a-dd. An analogous approach, but using the antipode of the Taniaphos ligand, was used to prepare (R,R)-trans-3″-carbamates 8a-dd.

Scheme 1

Scheme 1. Representative Enantiocontrolled Synthesis of (R,R)-trans-3″ Analogues 9a–dd▼
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▼Reagents and conditions: (a) B2pin2, t-BuONa, CuCl. (R)-Taniaphos, MeOH rt 24 h (b) NaBO3·4H2O, THF/H2O (3:1) rt 2.5 h (c) t-BuPh2SiCl, imidazole, THF 0 °C to rt 16.5 h (d) adamantan-2-one O-methyloxime, O3, CCl4 0 °C 3.5 h (e) TBAF, THF 0 °C to rt 3 h (f) 4-NO2PhOC(O)Cl, i-Pr2EtN, DMAP, CH2Cl2 0 °C to rt 18.5 h (g) R1(R2)NH, Et3N, CH2Cl2. An analogous route was used to prepare analogues (R,R)-trans-3″ analogues 8a–dd, using (S)-Taniaphos in the first step.

In our preliminary report, (15) carbamate analogues 8a, 8b, 8c, 8d, and 8i were all found to be more efficacious than the arterolane control when administered as a once daily 2 mg/kg oral dose for 4 days (Chart 1). With a single higher dose of 40 mg/kg, analogues such as 8c, 8j, 8k, and 8n cured 20–60% of animals at day 30, as compared to 100% cures for single-dose artefenomel at this dosage. Importantly, all of the carbamate analogues evaluated showed good aqueous solubility, and many (e.g., 8a/b, 9a/b, 9c) exhibited excellent stability in human liver microsome (HLM) preparations. From this auspicious starting point, we sought to explore a more diverse array of carbamate side chains and to evaluate all of the analogues in both enantiomeric forms (Chart 1).

Chart 1

Chart 1. In Vitro Activity of 8a-8dd and 9a-9dd against P. falciparum (EC50 ± SEM)a
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aReported EC50 values are the means of at least three determinations.

Since only three analogues with (S, S) stereochemistry had been prepared in our initial study, we began by synthesizing the (S, S) forms of previously reported (R, R) analogues and evaluating these compounds for their antiplasmodial effects against W2 strain P. falciparum (Chart 1, 9d–n). Similar to the (R, R) forms 8d–n, the (S, S) stereoisomers demonstrated potent antiplasmodial effect, with EC50 values of the enantiomer pairs generally within 2-fold of each other. Noting the potent antiparasitic effect and favorable solubility of analogues bearing terminal primary amines, we next explored additional (R, R) and (S, S) analogues bearing 2-substituted ethylenediamine substitutions (8o–8r, 9o–9r) and found that these analogues as well retained potent, low-nM antiparasitic activity. Replacing the terminal amino function with hydroxyl, as in the change from aminooxetanes 8r/9r to hydroxyoxetanes 8s and 9s resulted in a ∼ 10-fold decrease in potency, suggesting a role for basic amines in promoting cellular uptake or retention, although the potent morpholine analogues 8f and 9f proved an exception to the wider trend.
In a recent report on the SAR of antimalarial benzoxaboroles, (19) a dramatic and favorable effect was noted for analogues with azetidine-bearing side chains, in many cases improving in vivo efficacy dramatically. Since the benzoxaborole warhead is known to be essential for antiplasmodial activity in this class and was retained across the analogues studied, we inferred that the improved in vivo efficacy of azetidinyl analogues most likely stemmed from improved uptake, reduced efflux, and/or favorable modulation of other ADME properties arising from the azetidine side chains. With a hypothesis that similar favorable effects might be transferrable to the trioxolane pharmacophore, we synthesized trans-3″ carbamates with various alkyl-substituted azetidine alcohols (8u–y, 9u–y) as well as sulfoxide-, sulfone-, and sulfoximine-substituted azetidines (8z-8bb, 9z-9bb), and also two alicyclic sulfoximine analogues (8cc-8dd, 9cc-9dd). Indeed, we observed low-nM antiparasitic activity across all of the substituted azetidine analogues, which notably are neutral, lacking the basic amine functions present in the earlier potent carbamate analogues. By contrast, the alicyclic sulfoximines 8cc/dd and 9cc/dd, were less potent overall and showed the largest difference in potency between stereoisomeric pairs.
A majority of the new analogues was evaluated for in vitro human liver microsome (HLM) stability and kinetic solubility in pH 7.4 PBS (Table 2). As expected, the presence of a primary basic amine, or sulfoxide or sulfoximine in the side chain generally resulted in high kinetic solubilities in excess of 100 μM. With regard to HLM stability, we previously observed excellent clearance values for the enantiomer pairs 8a/9a and 8b/9b, whereas 8c was much more rapidly metabolized than 9c, which showed HLM clearance (CL) values similar to 8a/9a/8b/9b. Additional enantiomer pairs evaluated here included the full set of 8n-dd/9n-dd (Table 2). The amine-bearing enantiomer pairs 8n–r/9n–r showed moderate to high clearance, with only 8r/9r showing a significant stereoisomer effect. The lowest clearance values of the new carbamate analogues were for 9g (piperidinyl) and 9m (aminoazetidinyl), both of which had HLM CL < 11.6 μL/min/mg. Unfortunately, and despite their potent antiparasitic effects, the large subset of substituted azetidinyl carbamates 8u-bb and 9u-bb was very rapidly metabolized in the HLM preparations, suggesting a particular metabolic liability of this ring system in the context of the trioxolane 3″-carbamate chemotype. Similarly, the alicyclic sulfoximine analogues 8cc/dd and 9cc/dd also exhibited rapid HLM clearance.
Table 1. In Vitro ADME Data for Selected Analogues and Controls
 HLM CLint (μL/min/mg)Solubility PBS (μM) HLM CLint (μL/min/mg)Solubility PBS (μM) HLM CLint (μL/min/mg)Solubility PBS (μM)
OZ277<7a504b8n45.81679w68318.2
OZ43963.7a0.181b9n58.7-8v48058.7
8aa12.8-8o41.7-9v63841.5
9aa<11.51749o37.41438x39215.9
8ba14.3-8p37.41429x65715.1
9ba21.41649p24.91628y23424.8
8ca1231458q29.91629y21110.8
9ca11.81189q25.313.48z516138
9d23.11448r23.41229z750184
8ea39.41449r13587.78aa52666.7
9e1201678s76.2-9aa85181.1
9g<11.6-9s3331128bb234268
9h-1098t43.774.99bb431142
9i28.2-9t52.71298cc243128
9j69.61128u-71.49cc319129
9k92.71179u-1378dd43579.3
9m<11.61018w57916.19dd450234
a

data from our preliminary report. (15)

b

data from ref. (20) HLM CLint is human liver microsome intrinsic clearance.

Table 2. Oral Efficacy of trans-R3 Analogues and Controls in P. berghei-Infected Female Swiss Webster Mice
Experiment 1DaysaExperiment 3DaysaExperiment 4 (cont.)Daysa
OZ4391d × 20 mg/kg30OZ4391d × 20 mg/kg309r2d × 10 mg/kg9
8a128c1d × 50 mg/kg128u7
8c142d × 10 mg/kg308y9
  2d × 4 mg/kg11  
Experiment 2DaysaExperiment 4DaysaExperiment 5Daysa
OZ4391d × 20 mg/kg30  OZ2772d × 10 mg/kg14
9a10OZ2772d × 10 mg/kg149d30
8c119a308q11
9c98c128r8
9g79c118s6
9m59o119s6
9o118p138t12
8r79q149u4
      9dd6
a

maximal survival benefit as indicated by days postinfection for longest-surviving mouse in each group (n = 5). Vehicle-treated mice survive 4–5 days postinfection. Mice with no parasitemia at day 30 were judged to be cured. Kaplan–Meier curves are provided for the five experiments as Figure S1 (Supporting Information).

Next, we used the P. berghei mouse model of malaria to assess the oral efficacy of selected new carbamate analogues, using arterolane (OZ277) or artefenomel (OZ439) as positive controls (Table 2). Briefly, female Swiss-Webster mice were infected intraperitoneally with P. berghei-infected murine erythrocytes, following which mice were treated via oral gavage with 100 μL of formulated test compound or vehicle according to the dosing paradigm indicated (Table 2). Cohorts were organized with five animals per treatment group, Giemsa-stained blood smears were taken over time to monitor parasitemia, and animals were considered cured if parasitemia could not be detected at day 30. All regimens were well-tolerated, with no overt signs of toxicity for any of the analogues studied.
In our previous report, we explored both repeat and single-exposure regimens, finding that the most efficacious carbamates could afford cures in some animals with a single 40 mg/kg dose. For comparison, artefenomel was reported (8) to produce cures at half this dose. Since artefenomel represents a benchmark for single-exposure efficacy in the P. berghei model, we chose to evaluate new carbamates at a single 20 mg/kg dose, comparing survival benefits to those afforded by artefenomel at the same dose. In the first in vivo experiment conducted using this 1 × 20 mg/kg protocol, we found that previously described analogues 8a and 8c extended survival up to 12 and 14 days, respectively, compared to 5 days for vehicle control, and 30 days for artefenomel (Table 2 Supplemental Figure S1). A half-dozen new analogues evaluated in experiment 2 showed less significant survival benefits, although 9o was as effective as 8c, the latter among the best analogues from the original study.
We next explored various two-dose regimens that we expected should show a broader range of survival benefit and thereby allow more meaningful rank-odering of new analogues. Using analogue 8c as test article for a dose-ranging study, we compared regimens of 10 mg/kg once daily for 2 days (producing 3/5 cures at day 30) and 4 mg/kg once daily for 2 days (survival benefit to 11 days, but no cures). This experiment thus nominated the 10 mg/kg × 2d regimen as a new benchmark for studying the efficacy of carbamate analogues.
Using the new once daily for 2 days regimen, we found in experiment 4 that 9a produced cures in 3/5 mice, consistent with the favorable efficacy of its enantiomer 8a in our previous report. It was interesting that 8c (also included in experiment 4) produced no cures, in contrast to the 3/5 cures produced in experiment 3. We attribute this to biological variation and the possibility that animals in experiment 4 received a larger inoculum. In any event, the superior efficacy of 9a vs 8c in experiment 4 was gratifying. Of the remaining analogues explored in experiment 4, none produced cures, although structurally similar analogues 9q and 8p exhibited the most favorable effects on survival, with end points extended to 14 and 13 days, respectively (Supplemental Figure S1)
In experiment 5, we evaluated eight additional analogues, and were excited to find that (S,S) enantiomer 9d, an analogue of 9a lacking the gem-dimethyl side-chain substitution, produced cures in all five mice and thus represents the most efficacious analogue identified in the current study (Figure S1, Supporting Information). In stark contrast, analogues 8r, 8s, 9s, 9u, and 9dd performed poorly, providing little additional benefit over vehicle treated animals. Thus, the 10 mg/kg × 2d regimen readily distinguished analogues with curative efficacy such as 9a and 9d from those exhibiting more modest survival benefit (e.g., 8c, 8p, 9q) and further, from those with little to no efficacy (8r–s, 9s, 9u).
In a final in vivo study (experiment 6, Figure 3), we compared 9a with analogue 9p (enantiomer of analogue 8p), and three carbamates bearing different cyclic ring systems–the piperidine 9g, aminoazetidine 9m, and 1,4-diaminocyclohexane 9i. The results of this study largely confirmed the emerging structure-efficacy trends for the series. Thus, analogue 9p (13 days survival and 1 cure) showed efficacy that was very similar to that of its enantiomer 8p. The analogue 9i, bearing a terminal primary amine, also performed well, and identically to 9p. The least efficacious analogue was piperidine 9g, which lacks the basic amine function found in most of the efficacious analogues. Most disappointing in this light was the aminoazetidine 9m, which despite bearing basic amine functionality and showing potent in vitro activity, performed only marginally better than 9g and the vehicle control.

Figure 3

Figure 3. Results of in vivo experiment 6, showing the survival of mice treated with test compound or artefenomel control with 2 × 10 mg/kg oral doses. Mice surviving at day 30 were judged to be cured.

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In our earlier report (15) on trans-3″ carbamates, we identified 8a, 8c, and 8d as the most promising with respect to in vivo efficacy, all three proving superior to arterolane in terms of cures, following a 2 mg/kg × 4d regimen. In terms of reduced frequency dosing, compound 8c was most extensively studied and notably produced cures (8/10 animals in two separate studies) with a single 40 mg/kg dose. To these leads we can now add (S,S) analogues 9a, 9d, 9i, and 9p as additional examples of this chemotype exhibiting promising in vivo efficacy with reduced dosing frequencies.
To better understand PK/PD relationships in this chemotype, we performed mouse PK studies of 8a, 9a, and 9d with oral and IV administration at 10 and 3 mg/kg, respectively (Table 3 and Table S1). We found that (S,S) analogue 9a showed reduced clearance and ∼50% higher AUC than its (R,R) enantiomer 8a, while the volume of distribution and bioavailability were similar at ∼2.5 L/kg and ∼39%, respectively (Table 3). Analogue 9d exhibited lower clearance than either 8a or 9a, the highest AUC, and similar volumes of distribution and oral bioavailability. The reported (7) half-life (1.4 h) and bioavailability (35%) of arterolane in rat is thus comparable to that for 8a/9a/9d in mouse. Consistent with the superior efficacy of 9d over arterolane in our studies, it was previously reported (7) that three daily 10 mg/kg doses of arterolane produced a 67% cure rate in the P. berghei model. This compares with the fully curative efficacy achieved herein with just two 10 mg/kg daily oral doses of 9d (experiments 4 and 5, Table 1 and Figure S1).
Table 3. In Vitro Human Microsome Clearance and Selected PK Parameters for Compounds 8a, 9a, and 9d
 in vitro ADMEin vivo PK (IV dose 3 mg/kg)in vivo PK (PO dose 10 mg/kg)
compoundHLM (μL/min/mg)CL (L/h/kg)Vss (L/kg)T1/2 (hr)AUClast (ng/mL*hr)F (%)
8a12.86.512.792.0955539.3
9a<11.54.622.501.4481838.9
9d23.13.962.331.66103843.1
Herein we described the stereocontrolled synthesis and in vitro and in vivo evaluation of novel trans-3″ substituted 1,2,4-trioxolane carbamates, focusing on analogues with small to medium-size rings and bearing primary amine, alcohol, or sulfinyl functionality. We found that acyclic, primary amine-bearing carbamates exhibited the most promising efficacy in a murine malaria model and also the best metabolic stability in human liver microsomes. Exemplar trans-3″ carbamate 9d produced complete cures in the P. berghei model after two daily 10 mg/kg oral doses, demonstrating efficacy superiority to arterolane under this regimen and equivalent to artefenomel at 1 day × 20 mg/kg. Although some improvements over arterolane in PK and PD profiles can be realized in trans-3″ carbamates like 8a/9a/9d, their PK profiles are more similar to those of arterolane than artefenomel. Accordingly, we judge that a single-exposure cure may be an unrealistic objective for this chemotype. On the other hand, 9d exhibited efficacy equivalent to 20 mg/kg × 1d artefenomel under the 10 mg/kg × 2d regimen, while exhibiting superior HLM stability and dramatically improved solubility. While useful for in vivo screening, the P. berghei model is limited in its ability to predict efficacy and dose to treat human malaria. The humanized SCID mouse model of P. falciparum (21) represents the current preclinical benchmark for evaluating the efficacies of antimalarial drug candidates. The trans-3″ chemotype and optimized analogues such as 9d identified here are promising leads appropriate for evaluation in this model and as leads for the discovery of next generation antimalarial trioxolanes.

Experimental Procedures

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EC50 of Experimental Compounds against Cultured P. falciparum Parasites

Caution! P. falciparum is a Biosafety Level-2 (BSL-2) human pathogen and was handled by using BSL-2 procedures. Erythrocytic cultures of P. falciparum strain W2 (BEI Resources) were maintained using standard methods at 2% hematocrit in RPMI 1640 medium (Invitrogen) supplemented with 0.5% AlbuMAX II (Gibco Life Technologies), 0.1 mM hypoxanthine, 30 μg/mL gentamicin, 24 mM NaHCO3, and 25 mM HEPES pH 7.4 at 37 °C in an atmosphere of 5% O2, 5% CO2, and 90% N2. Infected cultures were exposed to 12 drug concentrations (3-fold serial dilution from 10 μM −0.06 nM) or an equal volume of DMSO with tips changed between each serial dilution to minimize potential carryover of lipophilic compounds. Test plates were incubated at 37 °C under the above atmosphere for 72 h, following which erythrocytes were pelleted and fixed in 2% formaldehyde in PBS (pH 7.4) at room temperature overnight. 2% Formaldehyde PBS was removed, and parasites were resuspended in permeabilization media (100 mM NH4Cl, 0.1% Triton-X, PBS pH 7.4) with freshly added 25 nM YOYO-1 fluorescent dye. Plates were incubated at 4 °C for a minimum of 24 h. Parasitemia was determined from dot plots of 5 × 104 cells acquired on a FACSCalibur flow cytometer using CELLQUEST software (Becton Dickinson), using initial gating values determined from unstained uninfected erythrocyte and stained uninfected erythrocyte controls. IC50s were determined using GraphPad Prism software with 3 experimental replicates per compound.

P. berghei Mouse Malaria Model

Female Swiss Webster mice (∼20 g body weight) were infected intraperitoneally with 106 P. berghei-infected erythrocytes collected from a previously infected mouse. Beginning 1 h after inoculation, the mice were treated once daily by oral gavage for 1–2 days as indicated with 100 μL of solution of test compound formulated in 10% DMSO: 50% PEG400:40% of a 20% HP-β-CD solution in water. There were five mice in each test arm. Infections were monitored by daily microscopic evaluation of Giemsa-stained blood smears starting on day seven. Parasitemia was determined by counting the number of infected erythrocytes per 1000 erythrocytes. Body weight was measured over the course of the treatment. Mice were euthanized when parasitemia exceeded 50% or when a weight loss of more than 15% occurred. Parasitemia, animal survival, and morbidity were closely monitored for 30 days postinfection, when experiments were terminated.

Pharmacokinetic Studies

Pharmacokinetic studies with IV (3 mg/kg) and PO (10 mg/kg) dosing was performed in male CD1 mice (n = 3 per group) with a formulation 10% DMSO: 50% PEG400:40% of a 20% HP-β-CD solution in water. Microsampling (40 mL) via facial vein was performed at 0, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h into K2EDTA tubes. The blood samples were collected and centrifuged to obtain plasma (8000 rpm, 5 min) within 15 min post sampling. Nine blood samples were collected from each mouse; three samples were collected for each time point. Data was processed by Phoenix WinNonlin (version 8.3); samples below limit of quantitation were excluded in the PK parameters and mean concentration calculation.

Animal Welfare

No alternative to the use of laboratory animals is available for in vivo efficacy assessments. Animals were housed and fed according to NIH and USDA regulations in the Animal Care Facility at San Francisco General Hospital. Trained animal care technicians provide routine care, and veterinary staff is readily available. Euthanasia was performed when malaria parasitemias topped 50%, a level that does not appear to be accompanied by distress but predicts progression to lethal disease. Euthanasia was accomplished with CO2 followed by cervical dislocation. These methods are in accordance with the recommendations of the Panel on Euthanasia of the American Veterinary Medical Association. Our studies have been approved by the UCSF Committee on Animal Research.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00365.

  • Kaplan–Meier survival curves, pharmacokinetic parameters, synthetic procedures (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Matthew T. Klope - Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
    • Juan A. Tapia Cardona - Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States;  Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, United States
    • Jun Chen - Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
    • Ryan L. Gonciarz - Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
    • Ke Cheng - Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States;  Orcidhttps://orcid.org/0000-0001-5057-3120
    • Priyadarshini Jaishankar - Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
    • Julie Kim - Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States
    • Jenny Legac - Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, United States
    • Philip J. Rosenthal - Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, United States
  • Author Contributions

    M.K., P.J.R., and A.R.R. conceived of experiments. M.K, J.C., R.L.G, K.C., P.J., and J.K. synthesized compounds. M.K, J.A.T., and J.L performed in vitro antiplasmodial assays and the mouse infection model. M.K. and A.R.R. drafted the manuscript and all authors reviewed and/or edited the manuscript.

  • Notes
    The authors declare the following competing financial interest(s): A.R.R. holds equity in Tatara Therapeutics, Inc. which seeks to develop iron-activated therapeutics for cancer and infectious disease.

Acknowledgments

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A.R.R. acknowledges funding from the US National Institutes of Health, R01 Grant AI105106.

Abbreviations

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(ART-R)

artemisinin partial resistance

(PK)

pharmacokinetic

(PD)

pharmacodynamic

(HLM)

human liver microsome

(ADME)

absorption, distribution, metabolism and excretion

References

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This article references 21 other publications.

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    The structure and stereochem. of the cyclohexane substituents of analogs of arterolane (OZ277) had little effect on potency against Plasmodium falciparum in vitro. Weak base functional groups were not required for high antimalarial potency, but they were essential for high antimalarial efficacy in P. berghei-infected mice. Five new ozonides with antimalarial efficacy and ADME profiles superior or equal to that of arterolane were identified.
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    Dong, Y.; Wang, X.; Kamaraj, S.; Bulbule, V. J.; Chiu, F. C. K.; Chollet, J.; Dhanasekaran, M.; Hein, C. D.; Papastogiannidis, P.; Morizzi, J.; Shackleford, D. M.; Barker, H.; Ryan, E.; Scheurer, C.; Tang, Y.; Zhao, Q.; Zhou, L.; White, K. L.; Urwyler, H.; Charman, W. N.; Matile, H.; Wittlin, S.; Charman, S. A.; Vennerstrom, J. L. Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439). J. Med. Chem. 2017, 60, 2654– 2668,  DOI: 10.1021/acs.jmedchem.6b01586
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    Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)
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    Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addn. of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, addnl. functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addn. of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often assocd. with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.
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    Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C. K.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Santo Tomas, J.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N. Identification of an Antimalarial Synthetic Trioxolane Drug Development Candidate. Nature 2004, 430, 900– 904,  DOI: 10.1038/nature02779
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    The discovery of artemisinin more than 30 yr ago provided a completely new antimalarial structural prototype; i.e., a mol. with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by hem, released as a result of Hb digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centered free radicals, leading to alkylation of hem and proteins (enzymes), one of which-the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)-may be crit. to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indexes and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chem. (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (noncompliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here the authors describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.
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    Charman, S. A.; Arbe-Barnes, S.; Bathurst, I. C.; Brun, R.; Campbell, M.; Charman, W. N.; Chiu, F. C. K.; Chollet, J.; Craft, J. C.; Creek, D. J.; Dong, Y.; Matile, H.; Maurer, M.; Morizzi, J.; Nguyen, T.; Papastogiannidis, P.; Scheurer, C.; Shackleford, D. M.; Sriraghavan, K.; Stinge-lin, L.; Tang, Y.; Urwyler, H.; Wang, X.; White, K. L.; Wittlin, S.; Zhou, L.; Vennerstrom, J. L. Synthetic Ozonide Drug Candidate OZ439 Offers New Hope for a Single-Dose Cure of Uncomplicated Malaria. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 4400– 4405,  DOI: 10.1073/pnas.1015762108
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    Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clin. trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase Ila trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clin. drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with ICs0 values comparable to those for the clin. used artemisinin derivs. Unlike all other synthetic peroxides and semisynthetic artemisinin derivs., OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-contg. antimalarial agents, such as the artemisinin derivs. and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concn. vs. time profile in three preclin. species. The outstanding efficacy and prolonged blood concns. of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.
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    Straimer, J.; Gnädig, N. F.; Stokes, B. H.; Ehrenberger, M.; Crane, A. A.; Fidock, D. A. Plasmodium Falciparum K13 Mutations Differentially Impact Ozonide Susceptibility and Parasite Fitness In Vitro. MBio 2017, 8, e00172-17,  DOI: 10.1128/mBio.00172-17
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    Ozonide Antimalarial Activity in the Context of Artemisinin-Resistant Malaria
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    Trends in Parasitology (2019), 35 (7), 529-543CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)
    A review. The ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations assocd. with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is assocd. with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ∼1 h). Importantly, some ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivs. Here, it describe recent progress made towards understanding ozonide antimalarial activity and discuss ozonide utility within the context of artemisinin resistance.
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    Kim, H. S.; Hammill, J. T.; Guy, R. K. Seeking the Elusive Long-Acting Ozonide: Discovery of Artefenomel (OZ439). J. Med. Chem. 2017, 60, 2651– 2653,  DOI: 10.1021/acs.jmedchem.7b00299
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    Seeking the Elusive Long-Acting Ozonide: Discovery of Artefenomel (OZ439)
    Kim, Ho Shin; Hammill, Jared T.; Guy, R. Kiplin
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    The majority of frontline therapies for the treatment of malaria are combination drugs contg. artemisinin (or its semisynthetic analogs), known as artemisinin combination therapies (ACTs). While generally efficacious, ACTs and the first generation fully synthetic ozonide, arterolane (OZ277, 1), suffer from rapid clearance requiring 3-day dosing regimens. Extensive structure-activity studies led to the discovery of a second-generation ozonide, artefenomel (OZ439, 2), which has overcome this limitation, maintaining the rapid onset of action and potent activity of the artemisinin derivs. while exhibiting greatly improved pharmacokinetics, low projected cost of goods, prophylactic activity, and the potential for a single dose cure.
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    Salim, M.; Khan, J.; Ramirez, G.; Clulow, A. J.; Hawley, A.; Ramachandruni, H.; Boyd, B. J. Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations. Mol. Pharmaceutics 2018, 15, 3535– 3544,  DOI: 10.1021/acs.molpharmaceut.8b00541
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    Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations
    Salim, Malinda; Khan, Jamal; Ramirez, Gisela; Clulow, Andrew J.; Hawley, Adrian; Ramachandruni, Hanu; Boyd, Ben J.
    Molecular Pharmaceutics (2018), 15 (8), 3535-3544CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Milk has been used as a vehicle for the delivery of antimalarial drugs during clin. trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of cryst. drug in suspension during in vitro intestinal lipolysis of milk contg. OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissoln. of the free base form 1 and recrystn. of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addn. of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although cryst. ppts. of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant redn. in cryst. OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.
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    Clulow, A. J.; Salim, M.; Hawley, A.; Gilbert, E. P.; Boyd, B. J. The Curious Case of the OZ439 Mesylate Salt: An Amphiphilic Antimalarial Drug with Diverse Solution and Solid State Structures. Mol. Pharmaceutics 2018, 15, 2027– 2035,  DOI: 10.1021/acs.molpharmaceut.8b00173
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    The curious case of the OZ439 mesylate salt: An amphiphilic antimalarial drug with diverse solution and solid state structures
    Clulow, Andrew J.; Salim, Malinda; Hawley, Adrian; Gilbert, Elliot P.; Boyd, Ben J.
    Molecular Pharmaceutics (2018), 15 (5), 2027-2035CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Efforts to develop orally administered drugs tend to place an exceptional focus on aq. soly. as this is an essential criterion for their absorption in the gastrointestinal tract. In this work we examine the solid state behavior and soly. of OZ439, a promising single-dose cure for malaria being developed as the highly water-sol. mesylate salt. The aq. phase behavior of the OZ439 mesylate salt was detd. using a combination of small angle neutron and X-ray scattering (SANS and SAXS, resp.). It was found that this salt has low soly. at low concns. with the drug largely pptd. in free base aggregates. However, with increasing concn. these cryst. aggregates were obsd. to dissoc. into cationic micelles and lamellar phases, effectively increasing the dissolved drug concn. It was also found that the dissolved OZ439 spontaneously pptd. in the presence of biol. relevant anions, which we attribute to the high lattice energies of most of the salt forms of the drug. These findings show that aq. soly. is not always what it seems in the context of amphiphilic drug mols. and highlights that its use as the principal metric in selecting drug candidates for development can be perilous.
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    Blank, B. R.; Gonciarz, R. L.; Talukder, P.; Gut, J.; Legac, J.; Rosenthal, P. J.; Renslo, A. R. Antimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy. ACS Infect. Dis. 2020, 6, 1827– 1835,  DOI: 10.1021/acsinfecdis.0c00064
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    Antimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy
    Blank, Brian R.; Gonciarz, Ryan L.; Talukder, Poulami; Gut, Jiri; Legac, Jennifer; Rosenthal, Philip J.; Renslo, Adam R.
    ACS Infectious Diseases (2020), 6 (7), 1827-1835CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
    The emergence of artemisinin resistance, combined with certain suboptimal properties of ozonide agents arterolane and artefenomel, has necessitated the search for new drug candidates in the endoperoxide class. Our group has focused on trioxolane analogs with substitution patterns not previously explored. Here, we describe the enantioselective synthesis of analogs bearing a trans-3'' carbamate side chain and find these to be superior, both in vitro and in vivo, to the previously reported amides. We identified multiple analogs that surpass the oral efficacy of arterolane in the Plasmodium berghei model while exhibiting drug-like properties (logD, soly., metabolic stability) similar or superior to next-generation clin. candidates like E209 and OZ609. While the preclin. assessment of new analogs is still underway, current data suggest the potential of this chemotype as a likely source of future drug candidates from the endoperoxide class.
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    Blank, B. R.; Gut, J.; Rosenthal, P. J.; Renslo, A. R. Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane. J. Med. Chem. 2017, 60, 6400– 6407,  DOI: 10.1021/acs.jmedchem.7b00699
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    Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane
    Blank, Brian R.; Gut, Jiri; Rosenthal, Philip J.; Renslo, Adam R.
    Journal of Medicinal Chemistry (2017), 60 (14), 6400-6407CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane, namely I and II [R = NHCH2C(Me)2NH2, NHCH2CONH2, piperidino, 4-aminopiperidino, etc.]. Conformational anal. suggested that trans-3''-substituted trioxolanes would exhibit Fe(II) reactivity and antiparasitic activity similar to that achieved with canonical cis-4'' substitution. The chiral 3'' analogs were prepd. as single stereoisomers and evaluated alongside their 4'' congeners against cultured malaria parasites and in a murine malaria model. As predicted, the trans-3'' analogs exhibited in vitro antiplasmodial activity remarkably similar to that of their cis-4'' comparators. In contrast, efficacy in the Plasmodium berghei mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3'' analogs, e.g., I (R = 4-aminopiperidino), outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials.
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    Blank, B. R.; Gut, J.; Rosenthal, P. J.; Renslo, A. R. Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials. ACS Med. Chem. Lett. 2023, 14, 493– 498,  DOI: 10.1021/acsmedchemlett.3c00039
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    Woodley, C. M.; Nixon, G. L.; Basilico, N.; Parapini, S.; Hong, W. D.; Ward, S. A.; Biagini, G. A.; Leung, S. C.; Taramelli, D.; Onuma, K.; Hasebe, T.; O’Neill, P. M. Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205. ACS Med. Chem. Lett. 2021, 12, 1077– 1085,  DOI: 10.1021/acsmedchemlett.1c00031
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    Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205
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    ACS Medicinal Chemistry Letters (2021), 12 (7), 1077-1085CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    Methodol. for the synthesis of nonlinear analogs of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced mol. symmetry on in vitro antimalarial activity and physicochem. properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF soly. for three of the four analogs studied. Pharmacokinetic studies in rats comparing a selected nonlinear analog and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% vs. 41%). These findings provide support for further in vivo efficacy studies in preclin. animal species.
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    Charman, S. A.; Andreu, A.; Barker, H.; Blundell, S.; Campbell, A.; Campbell, M.; Chen, G.; Chiu, F. C. K.; Crighton, E.; Katneni, K.; Morizzi, J.; Patil, R.; Pham, T.; Ryan, E.; Saunders, J.; Shackleford, D. M.; White, K. L.; Almond, L.; Dickins, M.; Smith, D. A.; Moehrle, J. J.; Burrows, J. N.; Abla, N. An in Vitro Toolbox to Accelerate Anti-Malarial Drug Discovery and Development. Malar. J. 2020, 19, 1,  DOI: 10.1186/s12936-019-3075-5
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    An in vitro toolbox to accelerate anti-malarial drug discovery and development
    Charman, Susan A.; Andreu, Alice; Barker, Helena; Blundell, Scott; Campbell, Anna; Campbell, Michael; Chen, Gong; Chiu, Francis C. K.; Crighton, Elly; Katneni, Kasiram; Morizzi, Julia; Patil, Rahul; Pham, Thao; Ryan, Eileen; Saunders, Jessica; Shackleford, David M.; White, Karen L.; Almond, Lisa; Dickins, Maurice; Smith, Dennis A.; Moehrle, Joerg J.; Burrows, Jeremy N.; Abla, Nada
    Malaria Journal (2020), 19 (1), 1CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)
    Modeling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochem. properties, permeability, binding, intrinsic clearance and cytochrome P 450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochem. properties in relation to changing target product and candidate profiles. Ionization consts. were detd. by potentiometric titrn. and partition coeffs. were measured using a shake-flask method. Soly. was assessed in biorelevant media and permeability coeffs. and efflux ratios were detd. using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equil. dialysis. Metabolic stability and cytochrome P 450 inhibition were assessed using human liver microsomes. Sample anal. was conducted by LC-MS/MS. Both soly. and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compds. were somewhat more lipophilic than legacy drugs. For many compds., permeability and protein binding were challenging to assess and both required the use of exptl. conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compds. exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P 450 enzymes was minimal for most compds. This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodol. issues common to many of the more lipophilic compds. and highlighted areas which require more work to customize exptl. conditions for compds. being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single lab. allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
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    Jiménez-Díaz, M. B.; Mulet, T.; Viera, S.; Gómez, V.; Garuti, H.; Ibáñez, J.; Alvarez-Doval, A.; Shultz, L. D.; Martínez, A.; Gargallo-Viola, D.; Angulo-Barturen, I. Improved Murine Model of Malaria Using Plasmodium Falciparum Competent Strains and Non-Myelodepleted NOD-Scid IL2Rgammanull Mice Engrafted with Human Erythrocytes. Antimicrob. Agents Chemother. 2009, 53, 4533– 4536,  DOI: 10.1128/AAC.00519-09
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    Antimicrobial Agents and Chemotherapy (2009), 53 (10), 4533-4536CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    Murine models of Plasmodium falciparum malaria may become crucial tools in drug discovery. Here we show that non-myelodepleted NOD-scid IL2Rγnull mice engrafted with human erythrocytes support an infectious burden up to tenfold higher than that supported by engrafted NOD-scid β2microglobulinnull mice. The new model was validated for drug discovery and was used to assess the therapeutic efficacy of 4-pyridones, selective inhibitors of P. falciparum cytochrome bc1.
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  • Abstract

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    Figure 1

    Figure 1. Structure of dihydroartemisinin, arterolane, and the closely related trans-3″ carbamate chemotype explored herein and in our preliminary report. (15)

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    Figure 2

    Figure 2. Conformational dynamics of trioxolane antimalarials determine their antiplasmodial effects, with the minor, peroxide-exposed conformer (top right) undergoing Fenton-like reactivity with ferrous iron sources in the parasite, leading to a pharmacodynamic effect. Shown at bottom are the 1,3-diaxial interactions that disfavor the iron-reactive conformer in artefenomel (left) and in the trans-R3 carbamate chemotype explored herein (right).

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    Scheme 1

    Scheme 1. Representative Enantiocontrolled Synthesis of (R,R)-trans-3″ Analogues 9a–dd▼
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    ▼Reagents and conditions: (a) B2pin2, t-BuONa, CuCl. (R)-Taniaphos, MeOH rt 24 h (b) NaBO3·4H2O, THF/H2O (3:1) rt 2.5 h (c) t-BuPh2SiCl, imidazole, THF 0 °C to rt 16.5 h (d) adamantan-2-one O-methyloxime, O3, CCl4 0 °C 3.5 h (e) TBAF, THF 0 °C to rt 3 h (f) 4-NO2PhOC(O)Cl, i-Pr2EtN, DMAP, CH2Cl2 0 °C to rt 18.5 h (g) R1(R2)NH, Et3N, CH2Cl2. An analogous route was used to prepare analogues (R,R)-trans-3″ analogues 8a–dd, using (S)-Taniaphos in the first step.

    Chart 1

    Chart 1. In Vitro Activity of 8a-8dd and 9a-9dd against P. falciparum (EC50 ± SEM)a
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    aReported EC50 values are the means of at least three determinations.

    Figure 3

    Figure 3. Results of in vivo experiment 6, showing the survival of mice treated with test compound or artefenomel control with 2 × 10 mg/kg oral doses. Mice surviving at day 30 were judged to be cured.

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  • References

    This article references 21 other publications.

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      Woodley, C. M.; Amado, P. S. M.; Cristiano, M. L. S.; O'Neill, P. M. Artemisinin Inspired Synthetic Endoperoxide Drug Candidates: Design, Synthesis, and Mechanism of Action Studies. Med. Res. Rev. 2021, 41, 3062– 3095,  DOI: 10.1002/med.21849
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      Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studies
      Woodley, Christopher M.; Amado, Patricia S. M.; Cristiano, Maria L. S.; O'Neill, Paul M.
      Medicinal Research Reviews (2021), 41 (6), 3062-3095CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)
      A review. Artemisinin combination therapies (ACTs) have been used as the first-line treatments against Plasmodium falciparum malaria for decades. Recent advances in chem. proteomics have shed light on the complex mechanism of action of semi-synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme-mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide-based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2-dioxanes, 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes. Two of these classes, the 1,2,4-trioxolanes (arterolane and artefenomel) and the 1,2,4,5-tetraoxanes (N205 and E209) based antimalarials, have been explored extensively and are still in active development. In contrast, the most recent publication pertaining to the development of the 1,2-dioxane, Arteflene, and 1,2,4-trioxanes fenozan-50F, DU1301, and PA1103/SAR116242 was published in 2008. This review summarizes the synthesis, biol. and clin. evaluation, and mechanistic studies of the most developed synthetic endoperoxide antimalarials, providing an update on those classes still in active development.
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      Dong, Y.; Wittlin, S.; Sriraghavan, K.; Chollet, J.; Charman, S. A.; Charman, W. N.; Scheurer, C.; Urwyler, H.; Santo Tomas, J.; Snyder, C.; Creek, D. J.; Morizzi, J.; Koltun, M.; Matile, H.; Wang, X.; Padmanilayam, M.; Tang, Y.; Dorn, A.; Brun, R.; Vennerstrom, J. L. The Structure-Activity Relationship of the Antimalarial Ozonide Arterolane (OZ277). J. Med. Chem. 2010, 53, 481– 491,  DOI: 10.1021/jm901473s
      5
      The Structure-Activity Relationship of the Antimalarial Ozonide Arterolane (OZ277)
      Dong, Yuxiang; Wittlin, Sergio; Sriraghavan, Kamaraj; Chollet, Jacques; Charman, Susan A.; Charman, William N.; Scheurer, Christian; Urwyler, Heinrich; Santo Tomas, Josefina; Snyder, Christopher; Creek, Darren J.; Morizzi, Julia; Koltun, Maria; Matile, Hugues; Wang, Xiaofang; Padmanilayam, Maniyan; Tang, Yuanqing; Dorn, Arnulf; Brun, Reto; Vennerstrom, Jonathan L.
      Journal of Medicinal Chemistry (2010), 53 (1), 481-491CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The structure and stereochem. of the cyclohexane substituents of analogs of arterolane (OZ277) had little effect on potency against Plasmodium falciparum in vitro. Weak base functional groups were not required for high antimalarial potency, but they were essential for high antimalarial efficacy in P. berghei-infected mice. Five new ozonides with antimalarial efficacy and ADME profiles superior or equal to that of arterolane were identified.
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    6. 6
      Dong, Y.; Wang, X.; Kamaraj, S.; Bulbule, V. J.; Chiu, F. C. K.; Chollet, J.; Dhanasekaran, M.; Hein, C. D.; Papastogiannidis, P.; Morizzi, J.; Shackleford, D. M.; Barker, H.; Ryan, E.; Scheurer, C.; Tang, Y.; Zhao, Q.; Zhou, L.; White, K. L.; Urwyler, H.; Charman, W. N.; Matile, H.; Wittlin, S.; Charman, S. A.; Vennerstrom, J. L. Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439). J. Med. Chem. 2017, 60, 2654– 2668,  DOI: 10.1021/acs.jmedchem.6b01586
      6
      Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)
      Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J.; Chiu, Francis C. K.; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D.; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M.; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L.; Urwyler, Heinrich; Charman, William N.; Matile, Hugues; Wittlin, Sergio; Charman, Susan A.; Vennerstrom, Jonathan L.
      Journal of Medicinal Chemistry (2017), 60 (7), 2654-2668CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addn. of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, addnl. functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addn. of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often assocd. with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.
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    7. 7
      Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C. K.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Santo Tomas, J.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N. Identification of an Antimalarial Synthetic Trioxolane Drug Development Candidate. Nature 2004, 430, 900– 904,  DOI: 10.1038/nature02779
      7
      Identification of an antimalarial synthetic trioxolane drug development candidate
      Vennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf; Hunziker, Daniel; Matile, Hugues; McIntosh, Kylie; Padmanilayam, Maniyan; Santo Tomas, Josefina; Scheurer, Christian; Scorneaux, Bernard; Tang, Yuanqing; Urwyler, Heinrich; Wittlin, Sergio; Charman, William N.
      Nature (London, United Kingdom) (2004), 430 (7002), 900-904CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The discovery of artemisinin more than 30 yr ago provided a completely new antimalarial structural prototype; i.e., a mol. with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by hem, released as a result of Hb digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centered free radicals, leading to alkylation of hem and proteins (enzymes), one of which-the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)-may be crit. to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indexes and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chem. (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (noncompliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here the authors describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.
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    8. 8
      Charman, S. A.; Arbe-Barnes, S.; Bathurst, I. C.; Brun, R.; Campbell, M.; Charman, W. N.; Chiu, F. C. K.; Chollet, J.; Craft, J. C.; Creek, D. J.; Dong, Y.; Matile, H.; Maurer, M.; Morizzi, J.; Nguyen, T.; Papastogiannidis, P.; Scheurer, C.; Shackleford, D. M.; Sriraghavan, K.; Stinge-lin, L.; Tang, Y.; Urwyler, H.; Wang, X.; White, K. L.; Wittlin, S.; Zhou, L.; Vennerstrom, J. L. Synthetic Ozonide Drug Candidate OZ439 Offers New Hope for a Single-Dose Cure of Uncomplicated Malaria. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 4400– 4405,  DOI: 10.1073/pnas.1015762108
      8
      Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria
      Charman, Susan A.; Arbe-Barnes, Sarah; Bathurst, Ian C.; Brun, Reto; Campbell, Michael; Charman, William N.; Chiu, Francis C. K.; Chollet, Jacques; Craft, J. Carl; Creek, Darren J.; Dong, Yuxiang; Matile, Hugues; Maurer, Melanie; Morizzi, Julia; Nguyen, Tien; Papastogiannidis, Petros; Scheurer, Christian; Shackleford, David M.; Sriraghavan, Kamaraj; Stingelin, Lukas; Tang, Yuanqing; Urwyler, Heinrich; Wang, Xiaofang; White, Karen L.; Wittlin, Sergio; Zhou, Lin; Vennerstrom, Jonathan L.
      Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (11), 4400-4405, S4400/1-S4400/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clin. trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase Ila trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clin. drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with ICs0 values comparable to those for the clin. used artemisinin derivs. Unlike all other synthetic peroxides and semisynthetic artemisinin derivs., OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-contg. antimalarial agents, such as the artemisinin derivs. and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concn. vs. time profile in three preclin. species. The outstanding efficacy and prolonged blood concns. of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.
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    9. 9
      Straimer, J.; Gnädig, N. F.; Stokes, B. H.; Ehrenberger, M.; Crane, A. A.; Fidock, D. A. Plasmodium Falciparum K13 Mutations Differentially Impact Ozonide Susceptibility and Parasite Fitness In Vitro. MBio 2017, 8, e00172-17,  DOI: 10.1128/mBio.00172-17
      There is no corresponding record for this reference.
    10. 10
      Giannangelo, C.; Fowkes, F. J. I.; Simpson, J. A.; Charman, S. A.; Creek, D. J. Ozonide Antimalarial Activity in the Context of Artemisinin-Resistant Malaria. Trends Parasitol. 2019, 35, 529– 543,  DOI: 10.1016/j.pt.2019.05.002
      10
      Ozonide Antimalarial Activity in the Context of Artemisinin-Resistant Malaria
      Giannangelo, Carlo; Fowkes, Freya J. I.; Simpson, Julie A.; Charman, Susan A.; Creek, Darren J.
      Trends in Parasitology (2019), 35 (7), 529-543CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)
      A review. The ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations assocd. with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is assocd. with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ∼1 h). Importantly, some ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivs. Here, it describe recent progress made towards understanding ozonide antimalarial activity and discuss ozonide utility within the context of artemisinin resistance.
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    11. 11
      Kim, H. S.; Hammill, J. T.; Guy, R. K. Seeking the Elusive Long-Acting Ozonide: Discovery of Artefenomel (OZ439). J. Med. Chem. 2017, 60, 2651– 2653,  DOI: 10.1021/acs.jmedchem.7b00299
      11
      Seeking the Elusive Long-Acting Ozonide: Discovery of Artefenomel (OZ439)
      Kim, Ho Shin; Hammill, Jared T.; Guy, R. Kiplin
      Journal of Medicinal Chemistry (2017), 60 (7), 2651-2653CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The majority of frontline therapies for the treatment of malaria are combination drugs contg. artemisinin (or its semisynthetic analogs), known as artemisinin combination therapies (ACTs). While generally efficacious, ACTs and the first generation fully synthetic ozonide, arterolane (OZ277, 1), suffer from rapid clearance requiring 3-day dosing regimens. Extensive structure-activity studies led to the discovery of a second-generation ozonide, artefenomel (OZ439, 2), which has overcome this limitation, maintaining the rapid onset of action and potent activity of the artemisinin derivs. while exhibiting greatly improved pharmacokinetics, low projected cost of goods, prophylactic activity, and the potential for a single dose cure.
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    12. 12
      White, N. J.; Nosten, F. H. SERCAP: Is the Perfect the Enemy of the Good?. Malar. J. 2021, 20, 281,  DOI: 10.1186/s12936-021-03821-z
      There is no corresponding record for this reference.
    13. 13
      Salim, M.; Khan, J.; Ramirez, G.; Clulow, A. J.; Hawley, A.; Ramachandruni, H.; Boyd, B. J. Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations. Mol. Pharmaceutics 2018, 15, 3535– 3544,  DOI: 10.1021/acs.molpharmaceut.8b00541
      13
      Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations
      Salim, Malinda; Khan, Jamal; Ramirez, Gisela; Clulow, Andrew J.; Hawley, Adrian; Ramachandruni, Hanu; Boyd, Ben J.
      Molecular Pharmaceutics (2018), 15 (8), 3535-3544CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Milk has been used as a vehicle for the delivery of antimalarial drugs during clin. trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of cryst. drug in suspension during in vitro intestinal lipolysis of milk contg. OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissoln. of the free base form 1 and recrystn. of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addn. of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although cryst. ppts. of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant redn. in cryst. OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.
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    14. 14
      Clulow, A. J.; Salim, M.; Hawley, A.; Gilbert, E. P.; Boyd, B. J. The Curious Case of the OZ439 Mesylate Salt: An Amphiphilic Antimalarial Drug with Diverse Solution and Solid State Structures. Mol. Pharmaceutics 2018, 15, 2027– 2035,  DOI: 10.1021/acs.molpharmaceut.8b00173
      14
      The curious case of the OZ439 mesylate salt: An amphiphilic antimalarial drug with diverse solution and solid state structures
      Clulow, Andrew J.; Salim, Malinda; Hawley, Adrian; Gilbert, Elliot P.; Boyd, Ben J.
      Molecular Pharmaceutics (2018), 15 (5), 2027-2035CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Efforts to develop orally administered drugs tend to place an exceptional focus on aq. soly. as this is an essential criterion for their absorption in the gastrointestinal tract. In this work we examine the solid state behavior and soly. of OZ439, a promising single-dose cure for malaria being developed as the highly water-sol. mesylate salt. The aq. phase behavior of the OZ439 mesylate salt was detd. using a combination of small angle neutron and X-ray scattering (SANS and SAXS, resp.). It was found that this salt has low soly. at low concns. with the drug largely pptd. in free base aggregates. However, with increasing concn. these cryst. aggregates were obsd. to dissoc. into cationic micelles and lamellar phases, effectively increasing the dissolved drug concn. It was also found that the dissolved OZ439 spontaneously pptd. in the presence of biol. relevant anions, which we attribute to the high lattice energies of most of the salt forms of the drug. These findings show that aq. soly. is not always what it seems in the context of amphiphilic drug mols. and highlights that its use as the principal metric in selecting drug candidates for development can be perilous.
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    15. 15
      Blank, B. R.; Gonciarz, R. L.; Talukder, P.; Gut, J.; Legac, J.; Rosenthal, P. J.; Renslo, A. R. Antimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy. ACS Infect. Dis. 2020, 6, 1827– 1835,  DOI: 10.1021/acsinfecdis.0c00064
      15
      Antimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy
      Blank, Brian R.; Gonciarz, Ryan L.; Talukder, Poulami; Gut, Jiri; Legac, Jennifer; Rosenthal, Philip J.; Renslo, Adam R.
      ACS Infectious Diseases (2020), 6 (7), 1827-1835CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      The emergence of artemisinin resistance, combined with certain suboptimal properties of ozonide agents arterolane and artefenomel, has necessitated the search for new drug candidates in the endoperoxide class. Our group has focused on trioxolane analogs with substitution patterns not previously explored. Here, we describe the enantioselective synthesis of analogs bearing a trans-3'' carbamate side chain and find these to be superior, both in vitro and in vivo, to the previously reported amides. We identified multiple analogs that surpass the oral efficacy of arterolane in the Plasmodium berghei model while exhibiting drug-like properties (logD, soly., metabolic stability) similar or superior to next-generation clin. candidates like E209 and OZ609. While the preclin. assessment of new analogs is still underway, current data suggest the potential of this chemotype as a likely source of future drug candidates from the endoperoxide class.
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    16. 16
      Blank, B. R.; Gut, J.; Rosenthal, P. J.; Renslo, A. R. Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane. J. Med. Chem. 2017, 60, 6400– 6407,  DOI: 10.1021/acs.jmedchem.7b00699
      16
      Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane
      Blank, Brian R.; Gut, Jiri; Rosenthal, Philip J.; Renslo, Adam R.
      Journal of Medicinal Chemistry (2017), 60 (14), 6400-6407CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane, namely I and II [R = NHCH2C(Me)2NH2, NHCH2CONH2, piperidino, 4-aminopiperidino, etc.]. Conformational anal. suggested that trans-3''-substituted trioxolanes would exhibit Fe(II) reactivity and antiparasitic activity similar to that achieved with canonical cis-4'' substitution. The chiral 3'' analogs were prepd. as single stereoisomers and evaluated alongside their 4'' congeners against cultured malaria parasites and in a murine malaria model. As predicted, the trans-3'' analogs exhibited in vitro antiplasmodial activity remarkably similar to that of their cis-4'' comparators. In contrast, efficacy in the Plasmodium berghei mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3'' analogs, e.g., I (R = 4-aminopiperidino), outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials.
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    17. 17
      Blank, B. R.; Gut, J.; Rosenthal, P. J.; Renslo, A. R. Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials. ACS Med. Chem. Lett. 2023, 14, 493– 498,  DOI: 10.1021/acsmedchemlett.3c00039
      There is no corresponding record for this reference.
    18. 18
      Woodley, C. M.; Nixon, G. L.; Basilico, N.; Parapini, S.; Hong, W. D.; Ward, S. A.; Biagini, G. A.; Leung, S. C.; Taramelli, D.; Onuma, K.; Hasebe, T.; O’Neill, P. M. Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205. ACS Med. Chem. Lett. 2021, 12, 1077– 1085,  DOI: 10.1021/acsmedchemlett.1c00031
      18
      Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205
      Woodley, Christopher M.; Nixon, Gemma L.; Basilico, Nicoletta; Parapini, Silvia; Hong, Weiqian David; Ward, Stephen A.; Biagini, Giancarlo A.; Leung, Suet C.; Taramelli, Donatella; Onuma, Keiko; Hasebe, Takashi; O'Neill, Paul M.
      ACS Medicinal Chemistry Letters (2021), 12 (7), 1077-1085CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      Methodol. for the synthesis of nonlinear analogs of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced mol. symmetry on in vitro antimalarial activity and physicochem. properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF soly. for three of the four analogs studied. Pharmacokinetic studies in rats comparing a selected nonlinear analog and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% vs. 41%). These findings provide support for further in vivo efficacy studies in preclin. animal species.
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    19. 19
      Zhang, Y.-K.; Plattner, J. J.; Easom, E. E.; Jacobs, R. T.; Guo, D.; Freund, Y. R.; Berry, P.; Ciaravino, V.; Erve, J. C. L.; Rosenthal, P. J.; Campo, B.; Gamo, F.-J.; Sanz, L. M.; Cao, J. Ben-zoxaborole Antimalarial Agents. Part 5. Lead Optimization of Novel Amide Pyrazinyloxy Benzox-aboroles and Identification of a Preclinical Candidate. J. Med. Chem. 2017, 60, 5889– 5908,  DOI: 10.1021/acs.jmedchem.7b00621
      There is no corresponding record for this reference.
    20. 20
      Charman, S. A.; Andreu, A.; Barker, H.; Blundell, S.; Campbell, A.; Campbell, M.; Chen, G.; Chiu, F. C. K.; Crighton, E.; Katneni, K.; Morizzi, J.; Patil, R.; Pham, T.; Ryan, E.; Saunders, J.; Shackleford, D. M.; White, K. L.; Almond, L.; Dickins, M.; Smith, D. A.; Moehrle, J. J.; Burrows, J. N.; Abla, N. An in Vitro Toolbox to Accelerate Anti-Malarial Drug Discovery and Development. Malar. J. 2020, 19, 1,  DOI: 10.1186/s12936-019-3075-5
      20
      An in vitro toolbox to accelerate anti-malarial drug discovery and development
      Charman, Susan A.; Andreu, Alice; Barker, Helena; Blundell, Scott; Campbell, Anna; Campbell, Michael; Chen, Gong; Chiu, Francis C. K.; Crighton, Elly; Katneni, Kasiram; Morizzi, Julia; Patil, Rahul; Pham, Thao; Ryan, Eileen; Saunders, Jessica; Shackleford, David M.; White, Karen L.; Almond, Lisa; Dickins, Maurice; Smith, Dennis A.; Moehrle, Joerg J.; Burrows, Jeremy N.; Abla, Nada
      Malaria Journal (2020), 19 (1), 1CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)
      Modeling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochem. properties, permeability, binding, intrinsic clearance and cytochrome P 450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochem. properties in relation to changing target product and candidate profiles. Ionization consts. were detd. by potentiometric titrn. and partition coeffs. were measured using a shake-flask method. Soly. was assessed in biorelevant media and permeability coeffs. and efflux ratios were detd. using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equil. dialysis. Metabolic stability and cytochrome P 450 inhibition were assessed using human liver microsomes. Sample anal. was conducted by LC-MS/MS. Both soly. and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compds. were somewhat more lipophilic than legacy drugs. For many compds., permeability and protein binding were challenging to assess and both required the use of exptl. conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compds. exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P 450 enzymes was minimal for most compds. This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodol. issues common to many of the more lipophilic compds. and highlighted areas which require more work to customize exptl. conditions for compds. being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single lab. allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
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    21. 21
      Jiménez-Díaz, M. B.; Mulet, T.; Viera, S.; Gómez, V.; Garuti, H.; Ibáñez, J.; Alvarez-Doval, A.; Shultz, L. D.; Martínez, A.; Gargallo-Viola, D.; Angulo-Barturen, I. Improved Murine Model of Malaria Using Plasmodium Falciparum Competent Strains and Non-Myelodepleted NOD-Scid IL2Rgammanull Mice Engrafted with Human Erythrocytes. Antimicrob. Agents Chemother. 2009, 53, 4533– 4536,  DOI: 10.1128/AAC.00519-09
      21
      Improved murine model of malaria using Plasmodium falciparum competent strains and non-myelodepleted NOD-scid IL2Rγnull mice engrafted with human erythrocytes
      Jimenez-Diaz, Maria Belen; Mulet, Teresa; Viera, Sara; Gomez, Vanessa; Garuti, Helen; Ibanez, Javier; Alvarez-Doval, Angela; Shultz, Leonard D.; Martinez, Antonio; Gargallo-Viola, Domingo; Angulo-Barturen, Inigo
      Antimicrobial Agents and Chemotherapy (2009), 53 (10), 4533-4536CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      Murine models of Plasmodium falciparum malaria may become crucial tools in drug discovery. Here we show that non-myelodepleted NOD-scid IL2Rγnull mice engrafted with human erythrocytes support an infectious burden up to tenfold higher than that supported by engrafted NOD-scid β2microglobulinnull mice. The new model was validated for drug discovery and was used to assess the therapeutic efficacy of 4-pyridones, selective inhibitors of P. falciparum cytochrome bc1.
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