Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB.
Human African trypanosomiasis (HAT) is caused by the protozoan parasite Trypanosoma brucei. The cysteine proteases of T. brucei have been shown to be crucial for parasite replication and represent an attractive point for therapeutic intervention. Herein we describe the synthesis of a series of thiosemicarbazones and their activity against the trypanosomal cathepsins TbcatB and rhodesain, as well as human cathepsins L and B. The activity of these compounds was determined against cultured T. brucei, and specificity was assessed with a panel of four mammalian cell lines.
Mallari
Jeremy P
JP
Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, CA 94143-2280, USA.
Shelat
Anang
A
Kosinski
Aaron
A
Caffrey
Conor R
CR
Connelly
Michele
M
Zhu
Fangyi
F
McKerrow
James H
JH
Guy
R Kiplin
RK
D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology
D015853:Cysteine Proteinase Inhibitors; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C446033:rhodesain; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L