Proceedings of 10th Brazilian Symposium on Medicinal Chemistry

Malaria is one of the most prevalent infectious disease caused by parasites from Plasmodium genus. In this work, we investigated the antiplasmodial and cytotoxic activity of chalcogen-phosphoranes derivatives against sensitive (3D7 strain) and resistant (Dd2, TM90C6B, 3D7R_MMV848, Dd2R_DSM265) P. falciparum strains. Briefly, seleno-phosphoranes showed greater IC50 values (4.2 to >10 µM) when compared with the thio-phosphoranes analogs (0.7 to 1.9 µM). Electron-withdrawing substituents lead to analogs with enhanced antiplasmodial potency compared with electron-donating substituents. The most potent derivative had sulfur and bromide as substituent. This compound was evaluated against resistant strains of P. falciparum (e.g., Dd2, TM90C6B, 3D7R_MMV848, Dd2R_DSM265) and showed no cross-resistance with the gold-standard antimalarials. Hence, thio-phosphoranes showed reasonable potency against sensitive and resistant strains (RI <3) as well as an attractive selectivity index (>20) when tested against HepG2 and HEK293 cells. Our findings indicated that the phosphoranes derivatives are attractive hits for an antimalarial drug discovery program.