The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum

作者：Savannah Watson, Mariëtte van der Watt, Anjo Theron, Janette Reader, Sizwe Tshabalala, Erica Erlank, Lizette L. Koekemoer, Mariska Naude, Μarianna Stampolaki, Feyisola Adewole, Katie Sadowska, Pilar Pérez‐Lozano, Andreea L. Turcu, Santiago Vázquez, Ji-Hee Ko, Ben Mazurek, Davinder Singh, Satish R. Malwal, Mathew Njoroge, Kelly Chibale, Oluseye K. Onajole, Antonios Kolocouris, Eric Oldfield, Lyn‐Marié Birkholtz · 发表于：ACS Infectious Diseases · 年份：2024 · DOI：10.1021/acsinfecdis.4c00461 · 被引用次数：9 · 研究领域：Malaria Research and Control、Computational Drug Discovery Methods、Invertebrate Immune Response Mechanisms

High Resolution Image Download MS PowerPoint Slide 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 Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC 50 ) 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.