Discovery of potent thiosemicarbazone inhibitors of rhodesain and cruzain

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 1; pp. 121 - 123
• Main Authors: Fujii, Naoaki, Mallari, Jeremy P., Hansell, Elizabeth J., Mackey, Z., Doyle, Patricia, Zhou, Y.M., Gut, Jiri, Rosenthal, Philip J., McKerrow, James H., Guy, R. Kiplin
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 03-01-2005; Elsevier
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Chagas; Cysteine Endopeptidases - drug effects; Enzyme Inhibitors - pharmacology; Malaria; Medical sciences; Pharmacology. Drug treatments; Protease inhibitor; Protozoan Proteins - antagonists & inhibitors; Sleeping sickness; Thiosemicarbazone; Thiosemicarbazones - pharmacology; Sleeping sickness; Thiosemicarbazone; Malaria; Chagas; Protease inhibitor; Kinetoplastida; Protozoa; Apicomplexa; Enzyme; Cysteine endopeptidases; Enzyme inhibitor; Trypanosoma cruzi; Peptidases; Antiprotozoal agent; Life cycle; Plasmodium falciparum; Structure activity relation; Hydrolases; Parasiticide; Inhibition; Chemical synthesis; Trypanosoma brucei
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.10.023

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.
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.