Development of Potent Purine-Derived Nitrile Inhibitors of the Trypanosomal Protease TbcatB

J. Med. Chem., 51 (3), 545–552, 2008. 10.1021/jm070760l
Web Release Date: January 4, 2008

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,^§ and R. Kiplin Guy^*^†^‡

Graduate Program in Chemistry and Chemical Biology and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143-2280, Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis Tennessee 38105, and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19146

Received June 26, 2007

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.

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