Discovery of potent thiosemicarbazone inhibitors of rhodesain and cruzain.

Abstract Herein we report the synthesis and evaluation of a series of thiosemicarbazones as potential inhibitors of cysteine proteases relevant to parasitic diseases. Derivatives of thiosemicarbazone 1 were discovered to be potent inhibitors of cruzain and rhodesain, crucial proteases in the life cycles of Trypanosoma cruzi and T. brucei rhodesiense , the organisms causing Chagas’ disease and sleeping sickness. However, the entire series had only modest potency against falcipain-2, an essential protease for Plasmodium falciparum , the organism causing malaria. Among the active inhibitors, several potently inhibited proliferation of cultures of T. brucei . However, only modest activity was observed in inhibition of proliferation of T. cruzi or P. falciparum .