The Tuberculosis\nDrug Candidate SQ109 and Its Analogs\nHave Multistage Activity against Plasmodium falciparum

Toward\nrepositioning the antitubercular clinical candidate\nSQ109\nas an antimalarial, analogs were investigated for structure–activity\nrelationships for activity against asexual blood stages of the human\nmalaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes.\nWe show that equipotent activity (IC<sub>50</sub>) in the 100–300\nnM range could be attained for both asexual and sexual stages, with\nthe activity of most compounds retained against a multidrug-resistant\nstrain. The multistage activity profile relies on high lipophilicity\nascribed to the adamantane headgroup, and antiplasmodial activity\nis critically dependent on the diamine linker. Frontrunner compounds\nshowed conserved activity against genetically diverse southern African\nclinical isolates. We additionally validated that this series could\nblock transmission to mosquitoes, marking these compounds as novel\nchemotypes with multistage antiplasmodial activity.