Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB

Jeremy P. Mallari, Anang A. Shelat, Terri Obrien, Conor R. Caffrey, Aaron Kosinski, Michele Connelly, Michael Harbut, Doron Greenbaum, James H. McKerrow, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.

Original languageEnglish
Pages (from-to)545-552
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - Feb 14 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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