Exploration of 4(1H)-pyridones as a novel family of potent antimalarial inhibitors of the plasmodial cytochrome bc1.

A novel family of antimalarials based on the 4(1H)-pyridone scaffold is described. The compounds display potent antimalarial activity against Plasmodium falciparum in vitro and in vivo. Like atovaquone, 4(1H)-pyridones exert their antimalarial action by inhibiting selectively the electron-transport chain in P. falciparum at the cytochrome bc1 level (complex III). However, despite the similar mechanism of action, no cross-resistance with atovaquone has been found, suggesting that the binding mode of 4(1H)-pyridones might be different from that of atovaquone. The medicinal chemistry program, focused on improving potency and physicochemical properties, ultimately led to the discovery of GSK932121, which was progressed efficiently into first time in human studies. However, progression of GSK932121 was terminated when new toxicology results were obtained in the rat with a soluble phosphate prodrug of the candidate, indicating a potentially narrow therapeutic index.