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 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, Qo and Qi sites of cytochrome bc1). Antimalarials with such multiple targeting mechanism of action have not been reported previously. 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 future medicinal chemistry research, particularly for drug discovery on membrane-associated targets.
Article reference: Yiqing Yang, Tongke Tang, Xiaolu Li, Thomas Michele, Liqin Ling, Zhenghui Huang, Maruthi Mulaka, Yue Wu, Hongying Gao Liguo Wang, Jing Zhou, Brigitte Meuniere, Hangjun Ke, Lubin Jiang, Yu Rao, Design, synthesis, and biological evaluation of multiple targeting antimalarials, Acta Pharmaceutica Sinica B, 2021, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2021.05.008
Keywords: Drug design; Multiple targeting compounds; Antimalarial inhibitors; Mechanism of action; Membrane proteins
