Department of Biochemistry and Molecular Biology, University of Buea, P.O. Box 63, Buea, Cameroon.
Centre Pasteur du Cameroon, Yaoundé, Cameroon.
Sci Rep. 2020 Oct 21;10(1):17932. doi: 10.1038/s41598-020-74824-0.
Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In the present study, we describe the in vitro activities and mode of action of 3',4'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones, a novel class of spirofused tetrahydroisoquinoline-oxindole hybrids, as novel antimalarial agents. Whole cell phenotypic screening of these compounds identified (14b), subsequently named (±)-moxiquindole, as the most potent compound in the current series with equipotent antiplasmodial activity against both chloroquine sensitive and multidrug resistant parasite strains with good selectivity. The compound was active against all asexual stages of the parasite including inhibition of merozoite egress. Additionally, (±)-moxiquindole exhibited significant inhibitory effects on hemoglobin degradation, and disrupted vacuolar lipid dynamics. Taken together, our data confirm the antiplasmodial activity of (±)-moxiquindole, and identify 3'4'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones as a novel class of antimalarial agents with multiple modes of action.
优势骨架的分子杂交可能产生具有优越生物活性和延迟耐药性的新型抗疟化学型。在本研究中，我们描述了 3'，4'-二氢-2'H-螺[吲哚-3,1'-异喹啉]-2-酮类的体外活性和作用模式，这是一类新型螺环四氢异喹啉-氧吲哚杂合体，作为新型抗疟药物。对这些化合物进行全细胞表型筛选，鉴定出（14b），随后命名为（±）-莫西喹哚，是当前系列中最有效的化合物，对氯喹敏感和多药耐药虫株具有同等的抗疟活性，且选择性良好。该化合物对寄生虫的所有无性期均具有活性，包括抑制裂殖体逸出。此外，（±）-莫西喹哚还表现出对血红蛋白降解的显著抑制作用，并破坏液泡脂质动态。总之，我们的数据证实了（±）-莫西喹哚的抗疟活性，并确定 3'4'-二氢-2'H-螺[吲哚-3,1'-异喹啉]-2-酮类是一类具有多种作用模式的新型抗疟药物。
