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