Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases
Lushun Wang, Monica J. Bohmer, Jinhua Wang, Flore Nardella, Jaeson Calla, Mariana Laureano de Souza, Kyra A. Schindler, Lukas Montejo, Nimisha Mittal, Frances Rocamora, Mayland Treat, Jordan Charlton, Patrick K. Tumwebaze, Philip Jon Rosenthal, Roland A. Cooper, Ratna Chakrabarti, Elizabeth A. Winzeler, Debopam Chakrabarti, Nathanael S. Gray · 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.