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

J Med Chem. 2008 Feb 14;51(3):545-52. doi: 10.1021/jm070760l. Epub 2008 Jan 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsin B / antagonists & inhibitors*
  • Cell Line
  • Cell Line, Tumor
  • Humans
  • Models, Molecular
  • Nitriles / chemical synthesis*
  • Nitriles / pharmacology
  • Nitriles / toxicity
  • Purines / chemical synthesis*
  • Purines / pharmacology
  • Purines / toxicity
  • Static Electricity
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / pharmacology
  • Trypanocidal Agents / toxicity
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / enzymology


  • Nitriles
  • Purines
  • Trypanocidal Agents
  • Cathepsin B