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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 14, 2008
• 年：2008
• 卷：51
• 期：3
• 页码：545 - 552
• 全文大小：1831K
• 年卷期：v.51,no.3(February 14, 2008)
• ISSN：1520-4804

文摘

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.