ACS infectious diseases · 2024
The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Watson Savannah J, van der Watt Mariëtte E, Theron Anjo, Reader Janette, Tshabalala Sizwe, Erlank Erica, Koekemoer Lizette L, Naude Mariska, Stampolaki Marianna, Adewole Feyisola, Sadowska Katie, Pérez-Lozano Pilar, Turcu Andreea L, Vázquez Santiago, Ko Jihee, Mazurek Ben, Singh Davinder, Malwal Satish R, Njoroge Mathew, Chibale Kelly, Onajole Oluseye K, Kolocouris Antonios, Oldfield Eric, Birkholtz Lyn-Marié
Аннотация
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 (IC50) 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.