Discovery of potent thiosemicarbazone inhibitors of rhodesain and cruzain.
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.
Fujii
Naoaki
N
Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94143, USA.
Mallari
Jeremy P
JP
Hansell
Elizabeth J
EJ
Mackey
Z
Z
Doyle
Patricia
P
Zhou
Y M
YM
Gut
Jiri
J
Rosenthal
Philip J
PJ
McKerrow
James H
JH
Guy
R Kiplin
RK
D003546:Cysteine Endopeptidases / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D013882:Thiosemicarbazones; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; C446033:rhodesain