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.
