title: Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB.
abstract: 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.
authors.affiliation: Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, CA 94143-2280, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Mallari
authors.forename: Anang
authors.initials: A
authors.lastname: Shelat
authors.forename: Aaron
authors.initials: A
authors.lastname: Kosinski
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.forename: Michele
authors.initials: M
authors.lastname: Connelly
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: 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
chemical_list: 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