Novel Inhibitors of Plasmodium Phosphatidylinositol 4-kinase IIIβ with Low Propensity for Resistance: Life Cycle Stage Activity and In Vivo Efficacy in a Humanized Mouse Malaria Infection Model.

Anticancer ATP-competitive inhibitors are a promising source of new starting points for antimalarial drug discovery. Herein, we present a novel antimalarial chemotype based on the anticancer human ataxia-telangiectasia-mutated (ATM) kinase inhibitor AZD0156. This class inhibits phosphatidylinositol 4-kinase IIIβ (PI4K) in the human malaria parasite Plasmodium, demonstrating remarkable activities against all stages of the Plasmodium falciparum life cycle. The current series exhibited a lower propensity for resistance and toxicity compared to previous Plasmodium PI4K inhibitors. The lead compound 18 was efficacious in a humanized NOD-scid IL-2Rγnull mouse model of P. falciparum malaria, with an ED90 value of 4.6 mg kg-1.