Department of Chemistry, University of Central Florida, Orlando, Florida 32816, United States.
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, United States.
J Med Chem. 2020 Oct 22;63(20):11756-11785. doi: 10.1021/acs.jmedchem.0c00858. Epub 2020 Oct 6.
There is an urgent need to develop new efficacious antimalarials to address the emerging drug-resistant clinical cases. Our previous phenotypic screening identified styrylquinoline as a promising antimalarial compound. To optimize , we herein report a detailed structure-activity relationship study of 2-arylvinylquinolines, leading to the discovery of potent, low nanomolar antiplasmodial compounds against a CQ-resistant Dd2 strain, with excellent selectivity profiles (resistance index < 1 and selectivity index > 200). Several metabolically stable 2-arylvinylquinolines are identified as fast-acting agents that kill asexual blood-stage parasites at the trophozoite phase, and the most promising compound also demonstrates transmission blocking potential. Additionally, the monophosphate salt of exhibits excellent antimalarial efficacy in the murine model without noticeable toxicity. Thus, the 2-arylvinylquinolines represent a promising class of antimalarial drug leads.
迫切需要开发新的有效抗疟药物来应对新出现的耐药临床病例。我们之前的表型筛选发现苯乙烯基喹啉是一种很有前途的抗疟化合物。为了进行优化，我们在此报告了 2-芳基乙烯基喹啉的详细构效关系研究，发现了对 CQ 耐药的 Dd2 株具有强大的、低纳摩尔抗疟活性的化合物，具有优异的选择性特征（耐药指数<1 和选择性指数>200）。几种代谢稳定的 2-芳基乙烯基喹啉被鉴定为快速作用剂，可在滋养体阶段杀死无性血期寄生虫，最有前途的化合物也显示出阻断传播的潜力。此外， 的单磷酸盐盐在没有明显毒性的情况下在小鼠模型中表现出优异的抗疟疗效。因此，2-芳基乙烯基喹啉类化合物代表了一类很有前途的抗疟药物先导化合物。
