Design, synthesis, and biological evaluation of multiple targeting antimalarials.

Malaria still threatens global health seriously today. While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors, multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance. Here, we performed a structure-based drug design on mitochondrial respiratory chain of and identified an extremely potent molecule, RYL-581, which binds to multiple protein binding sites of simultaneously (allosteric site of type II NADH dehydrogenase, Q and Q sites of cytochrome ). Antimalarials with such multiple targeting mechanism of action have never been reported before. RYL-581 kills various drug-resistant strains and shows good solubility as well as activity. This structure-based strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future, especially for drug discovery on membrane-associated targets.