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.

Journal reference:

Yang, Y., et al. (2021) Design, synthesis, and biological evaluation of multiple targeting antimalarials. Acta Pharmaceutica Sinica B.


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