Next Generation Health, Council for Scientific and Industrial Research, Pretoria 0001, South Africa.
Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Services, Wits Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Johannesburg 2000, South Africa.
ACS Infect Dis. 2024 Sep 13;10(9):3358-3367. doi: 10.1021/acsinfecdis.4c00461. Epub 2024 Aug 14.
Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.
为了将抗结核临床候选药物 SQ109 重新定位为抗疟药物，我们研究了其类似物的结构-活性关系，以评估其对人类疟原虫致病性无性血期寄生虫和可传播的有性阶段配子体的活性。我们发现，对于无性和有性阶段，都可以达到 100-300 nM 的等效活性（IC），大多数化合物对多药耐药株仍保持活性。这种多阶段的活性特征依赖于金刚烷头部赋予的高亲脂性，而抗疟原虫活性则严重依赖于二胺连接物。领先的化合物对来自南非不同地区的临床分离株表现出一致的活性。此外，我们还验证了该系列化合物能够阻止向蚊子传播，这标志着这些化合物具有多阶段抗疟原虫活性的新型化学类型。
