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Identifying New Chemical Entities that Treat and Prevent Relapsing Vivax and Drug-Resistant Falciparum Malaria in U.S. Military Personnel

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Technical Report

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Trustees of Columbia University in the City of New York New York United States

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Our project aims to identify antimalarial compounds that are active against blood and liver stage of Plasmodium parasites andthat have selectivity and pharmacological profiles that allow them to proceed as candidates for preclinical development aimedat developing new drugs to safely prevent or treat malaria in US Military personnel. The work has gone extremely well. Wehave now completed high-throughput screens against cultured Plasmodium falciparum asexual blood stages of 350,000compounds from the National Center for Advancing Translational Sciences NCATS chemical library. From this we performedvalidation assays with 4,300 compounds and then tested 999 for activity against P. berghei liver stage parasites. 151compounds were found to have submicromolar activity against blood and liver stage parasites and these were assayedagainst mammalian cells and also tested for pharmacological properties metabolic stability, membrane permeability andcompound solubility. From this extensive work, we now have six chemotypes that we have prioritized for medicinal chemistryand large compound analog studies are underway. We also have several back-up chemical series. We are now testing forcompounds that have improved potency and developing structure-activity relationships. Our intent in the coming year is toadvance hit series and identify compounds that will serve as leads for further preclinical work.

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