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

doi:10.1021/jm070760l

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 journal › Article › peer-review

59 Scopus citations

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.

Original language	English
Pages (from-to)	545-552
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	3
DOIs	https://doi.org/10.1021/jm070760l
State	Published - Feb 14 2008

Funding

Funders

Funder number

National Institute of Allergy and Infectious F32-AI286447 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI168214 Jason W. Rosch Diseases National Institute of Allergy and Infectious P30 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R00-AI166116 Christopher D. Radka Diseases National Institute of Allergy and Infectious T32-AI106700 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI192221 Jason W. Rosch Diseases National Inst...

P01AI035707

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jm070760l

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@article{06570bcd91d64b9cafe039f151b8e6a7,

title = "Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB",

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.",

author = "Mallari, \{Jeremy P.\} and Shelat, \{Anang A.\} and Terri Obrien and Caffrey, \{Conor R.\} and Aaron Kosinski and Michele Connelly and Michael Harbut and Doron Greenbaum and McKerrow, \{James H.\} and Guy, \{R. Kiplin\}",

year = "2008",

month = feb,

day = "14",

doi = "10.1021/jm070760l",

language = "English",

volume = "51",

pages = "545--552",

number = "3",

}

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.

UR - https://www.scopus.com/pages/publications/39149083105

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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 -

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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