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Antimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy.

ABSTRACT: 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 analogues with substitution patterns not previously explored. Here, we describe the enantioselective synthesis of analogues 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 analogues that surpass the oral efficacy of arterolane in the Plasmodium berghei model while exhibiting drug-like properties (logD, solubility, metabolic stability) similar or superior to next-generation clinical candidates like E209 and OZ609. While the preclinical assessment of new analogues is still underway, current data suggest the potential of this chemotype as a likely source of future drug candidates from the endoperoxide class.

SUBMITTER: Blank BR

PROVIDER: S-EPMC7363035 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectivesCircadian rhythms contribute to treatment efficacy in several non-communicable diseases. However, chronotherapy (administering drugs at a particular time-of-day) against infectious diseases has been overlooked. Yet, the daily rhythms of both hosts and disease-causing agents can impact the efficacy of drug treatment. We use the rodent malaria parasite Plasmodium chabaudi, to test whether the daily rhythms of hosts, parasites and their interactions affect sensitivity to the key antimalarial, artemisinin.MethodologyAsexual malaria parasites develop rhythmically in the host's blood, in a manner timed to coordinate with host daily rhythms. Our experiments coupled or decoupled the timing of parasite and host rhythms, and we administered artemisinin at different times of day to coincide with when parasites were either at an early (ring) or later (trophozoite) developmental stage. We quantified the impacts of parasite developmental stage, and alignment of parasite and host rhythms, on drug sensitivity.ResultsWe find that rings were less sensitive to artemisinin than trophozoites, and this difference was exacerbated when parasite and host rhythms were misaligned, with little direct contribution of host time-of-day on its own. Furthermore, the blood concentration of haem at the point of treatment correlated positively with artemisinin efficacy but only when parasite and host rhythms were aligned.Conclusions and implicationsParasite rhythms influence drug sensitivity in vivo. The hitherto unknown modulation by alignment between parasite and host daily rhythms suggests that disrupting the timing of parasite development could be a novel chronotherapeutic approach.Lay summaryWe reveal that chronotherapy (providing medicines at a particular time-of-day) could improve treatment for malaria infections. Specifically, parasites' developmental stage at the time of treatment and the coordination of timing between parasite and host both affect how well antimalarial drug treatment works.

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Antimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy.

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