Identifying New Chemical Entities that Treat and Prevent Relapsing vivax and Drug-Resistant falciparum Malaria in US Military Personnel
Technical Report,30 Sep 2018,29 Sep 2019
Columbia University 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 and that have selectivity and pharmacological profiles that allow them to proceed as candidates for preclinical development aimed at developing new drugs to safely prevent or treat malaria in US Military personnel. We have made substantial progress with this project. We have now completed high-throughput screens against cultured Plasmodium falciparum asexual blood stages of 460,000 compounds from the National Center for Advancing Translational Sciences NCATS chemical library. From this we performed multiple validation assays with 4,300 compounds and tested 994 for activity against P. berghei liver stage parasites.151 compounds were found to have submicromolar activity against blood and liver stage parasites and these were assayed against mammalian cells and also tested for pharmacological properties. From this extensive work, we now have six chemotypes that we have prioritized for medicinal chemistry and large compound analog studies are underway. We also have several back-up chemical series. We have extensive structure-activity relationship data for several compound series, and have identified improved compounds. We have also identified several drug targets including BC1 and DHODH. compounds that have improved potency and developing structure-activity relationships including one series that has desirable pharmacological properties of solubility, potency, stability and membrane permeability. Our intent in the coming year is to identify compounds that will serve as leads for further preclinical work.
- Medicine and Medical Research