TY - JOUR
T1 - Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB
AU - Mallari, Jeremy P.
AU - Shelat, Anang A.
AU - Obrien, Terri
AU - Caffrey, Conor R.
AU - Kosinski, Aaron
AU - Connelly, Michele
AU - Harbut, Michael
AU - Greenbaum, Doron
AU - McKerrow, James H.
AU - Guy, R. Kiplin
PY - 2008/2/14
Y1 - 2008/2/14
N2 - 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.
AB - 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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U2 - 10.1021/jm070760l
DO - 10.1021/jm070760l
M3 - Article
C2 - 18173229
AN - SCOPUS:39149083105
SN - 0022-2623
VL - 51
SP - 545
EP - 552
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -
