title: Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB.
abstract: Human African trypanosomiasis (HAT), a major health concern in sub-Saharan Africa, is caused by the protozoan parasite Trypanosoma brucei. Recent studies have shown that a cathepsin B like protease, TbcatB, is essential to the survival of T. brucei in vitro (Mackey, Z. B.; O'Brien, T. C.; Greenbaum, D. C.; Blank, R. B.; McKerrow, J. H. J. Biol. Chem. 2004, 279, 48426-48433). Herein, we describe the first inhibitors of TbcatB, a series of purine nitriles. The compounds are potent trypanocides, killing the parasite with a high degree of selectivity over a panel of three human cell lines. In addition, a predictive model of trypanocidal activity was developed on the basis of potency against TbcatB and various calculated physical property descriptors.
authors.affiliation: Graduate Program in Chemistry and Chemical Biology and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-2280, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Mallari
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.forename: Terri
authors.initials: T
authors.lastname: Obrien
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.forename: Aaron
authors.initials: A
authors.lastname: Kosinski
authors.forename: Michele
authors.initials: M
authors.lastname: Connelly
authors.forename: Michael
authors.initials: M
authors.lastname: Harbut
authors.forename: Doron
authors.initials: D
authors.lastname: Greenbaum
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*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology
chemical_list: D009570:Nitriles; D011687:Purines; D014344:Trypanocidal Agents; D002401:Cathepsin B