Designing antimalarials with multiple targeting mechanisms of action

Malaria remains a serious global health threat. 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.

The authors of this article performed a structure-based drug design on the mitochondrial respiratory chain of protein binding sites of P. falciparum simultaneously (allosteric site of type II cytochromebc₁). Antimalarials with such multiple targeting mechanisms of action have not been reported previously.

RYL-581 kills various drug-resistant strains invitro and shows good solubility as well as in vivo activity. This structure-based strategy for designing RYL-581 from starting compound may be helpful for other future medicinal chemistry research, particularly for drug discovery on membrane-associated targets.