Abstract
The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration–response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.
Highlights
The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can act prophylactically
This study provides a multi-point high-throughput route for successfully identifying novel antimalarial chemotypes via triaging and clustering asexual blood stage (ABS) hit compounds based on chemotype and activity, secondary screening with liver stage cultures and in vitro pharmacological profiling, and elucidation of mechanism of action via resistance selection experiments
Quantitative high‐throughput screening of over 450,000 compounds tested against P. falciparum asexual blood stage parasites and selection of 994 validated antiplasmodial com‐
Summary
The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can act prophylactically. Quinine (QN), active against ABS parasites, was used extensively until supply shortages and the emergence of drug-resistant parasites spurred the development of novel agents, resulting in chloroquine (CQ), mefloquine (MFQ), sulfadoxine-pyrimethamine (SP), and primaquine (PMQ)[4] These initially proved to be highly effective, with CQ, a 4-aminoquinoline, becoming the mainstay antimalarial for decades. Artemisinin-based combination therapies (ACTs), which combine a fast-acting derivative of the endoperoxide artemisinin (ART) with an antimalarial partner drug, have been used as first-line treatment for ABS infection across virtually all malaria-endemic regions This approach has helped achieve a major reduction in the global disease burden, with annual malaria deaths reducing from approximately one million cases to 400,000 over the period 2000 to 2 0151. Additional strategies are required to further reduce the impact of malaria across the endemic, inter-tropical regions of the globe
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