1. Design, synthesis, and biological evaluation of multiple targeting antimalarials.
- Author
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Yang, Yiqing, Tang, Tongke, Li, Xiaolu, Michel, Thomas, Ling, Liqin, Huang, Zhenghui, Mulaka, Maruthi, Wu, Yue, Gao, Hongying, Wang, Liguo, Zhou, Jing, Meunier, Brigitte, Ke, Hangjun, Jiang, Lubin, and Rao, Yu
- Subjects
ANTIMALARIALS ,NADH dehydrogenase ,PROTEIN binding ,PHARMACEUTICAL chemistry ,CARRIER proteins ,DEHYDROGENASES ,CYTOCHROME oxidase - 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 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 medicinal chemistry projects in the future, especially for drug discovery on membrane-associated targets. A highly potent antimalarial compound, RYL-581, has a potential multi-targeting mechanism of action by simultaneously binding to three pockets (allosteric site of Pf NDH2, Q o and Q i sites of Pf bc 1). [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2021
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