Synthesis, Structure–Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines

Abstract

There is an urgent need to develop new efficacious antimalarials to address the emerging drug-resistant clinical cases. Our previous phenotypic screening identified styrylquinoline <b>UCF501</b> as a promising antimalarial compound. To optimize <b>UCF501</b>, we herein report a detailed structure-activity relationship study of 2-arylvinylquinolines, leading to the discovery of potent, low nanomolar antiplasmodial compounds against a <i>Plasmodium falciparum</i> 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 <b>24</b> also demonstrates transmission blocking potential. Additionally, the monophosphate salt of <b>24</b> exhibits excellent <i>in vivo</i> antimalarial efficacy in the murine model without noticeable toxicity. Thus, the 2-arylvinylquinolines represent a promising class of antimalarial drug leads.