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Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases.

Lushun WangMonica J BohmerJinhua WangFlore NardellaJaeson CallaMariana Laureano de SouzaKyra A SchindlerLukas MontejoNimisha MittalFrances RocamoraMayland TreatJordan T CharltonPatrick K TumwebazePhilip J RosenthalRoland A CooperRatna ChakrabartiElizabeth A WinzelerDebopam ChakrabartiNathanael S Gray
Published in: Journal of medicinal chemistry (2024)
While progress has been made in the effort to eradicate malaria, the disease remains a significant threat to global health. Acquired resistance to frontline treatments is emerging in Africa, urging a need for the development of novel antimalarial agents. Repurposing human kinase inhibitors provides a potential expedited route given the availability of a diverse array of kinase-targeting drugs that are approved or in clinical trials. Phenotypic screening of a library of type II human kinase inhibitors identified compound 1 as a lead antimalarial, which was initially developed to target human ephrin type A receptor 2 (EphA2). Here, we report a structure-activity relationship study and lead optimization of compound 1 , which led to compound 33, with improved antimalarial activity and selectivity.
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