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

ABSTRACT: 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 Plasmodium falciparum and identified an extremely potent molecule, RYL-581, which binds to multiple protein binding sites of P. falciparum simultaneously (allosteric site of type II NADH dehydrogenase, Q_o and Q_i sites of cytochrome bc ₁). Antimalarials with such multiple targeting mechanism of action have never been reported before. RYL-581 kills various drug-resistant strains in vitro</

SUBMITTER: Yang Y 

PROVIDER: S-EPMC8463279 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature