Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1

Zhongsheng Zhang; Kayode K. Ojo; Steven M. Johnson; Eric T. Larson; Penqing He; Jennifer A. Geiger; Alejandro Castellanos-Gonzalez; A. Clinton White; Marilyn Parsons; Ethan A. Merritt; Dustin J. Maly; Christophe L.M.J. Verlinde; Wesley C. Van Voorhis; Erkang Fan

doi:10.1016/j.bmcl.2012.06.050

Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1

Zhongsheng Zhang
, Kayode K. Ojo
, Steven M. Johnson
, Eric T. Larson
, Penqing He
, Jennifer A. Geiger
, Alejandro Castellanos-Gonzalez
, A. Clinton White
, Marilyn Parsons
, Ethan A. Merritt
, Dustin J. Maly
, Christophe L.M.J. Verlinde
, Wesley C. Van Voorhis
, Erkang Fan

Internal Medicine

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazole-based compounds in terms of solubility, selectivity, and potency against CpCDPK1 and TgCDPK1. The best inhibitors show inhibitory potencies below 50 nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.

Original language	English (US)
Pages (from-to)	5264-5267
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2012.06.050
State	Published - Aug 15 2012

Keywords

Calcium-dependent protein kinase-1
Cryptosporidium parvum
Enzyme inhibitor
Selectivity
Toxoplasma gondii

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2012.06.050

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Zhang, Z., Ojo, K. K., Johnson, S. M., Larson, E. T., He, P., Geiger, J. A., Castellanos-Gonzalez, A., White, A. C., Parsons, M., Merritt, E. A., Maly, D. J., Verlinde, C. L. M. J., Van Voorhis, W. C., & Fan, E. (2012). Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1. Bioorganic and Medicinal Chemistry Letters, 22(16), 5264-5267. https://doi.org/10.1016/j.bmcl.2012.06.050

Zhang, Z, Ojo, KK, Johnson, SM, Larson, ET, He, P, Geiger, JA, Castellanos-Gonzalez, A , White, AC, Parsons, M, Merritt, EA, Maly, DJ, Verlinde, CLMJ, Van Voorhis, WC & Fan, E 2012, 'Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 16, pp. 5264-5267. https://doi.org/10.1016/j.bmcl.2012.06.050

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title = "Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1",

abstract = "Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazole-based compounds in terms of solubility, selectivity, and potency against CpCDPK1 and TgCDPK1. The best inhibitors show inhibitory potencies below 50 nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.",

keywords = "Calcium-dependent protein kinase-1, Cryptosporidium parvum, Enzyme inhibitor, Selectivity, Toxoplasma gondii",

author = "Zhongsheng Zhang and Ojo, \{Kayode K.\} and Johnson, \{Steven M.\} and Larson, \{Eric T.\} and Penqing He and Geiger, \{Jennifer A.\} and Alejandro Castellanos-Gonzalez and White, \{A. Clinton\} and Marilyn Parsons and Merritt, \{Ethan A.\} and Maly, \{Dustin J.\} and Verlinde, \{Christophe L.M.J.\} and \{Van Voorhis\}, \{Wesley C.\} and Erkang Fan",

note = "Funding Information: This work is supported by the National Institutes of Health grants R01AI089441 (E.A.M. and W.C.V.V.) and R01GM086858 (D.J.M.). J.A.G. was supported by a training grant from the National Institute of Allergy and Infectious Diseases (Grant T32AI007509). We thank Dr. Suzanne Scheele for technical assistance.",

year = "2012",

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doi = "10.1016/j.bmcl.2012.06.050",

language = "English (US)",

volume = "22",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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AU - Zhang, Zhongsheng

AU - Ojo, Kayode K.

AU - Johnson, Steven M.

AU - Larson, Eric T.

AU - He, Penqing

AU - Geiger, Jennifer A.

AU - Castellanos-Gonzalez, Alejandro

AU - White, A. Clinton

AU - Parsons, Marilyn

AU - Merritt, Ethan A.

AU - Maly, Dustin J.

AU - Verlinde, Christophe L.M.J.

AU - Van Voorhis, Wesley C.

AU - Fan, Erkang

N1 - Funding Information: This work is supported by the National Institutes of Health grants R01AI089441 (E.A.M. and W.C.V.V.) and R01GM086858 (D.J.M.). J.A.G. was supported by a training grant from the National Institute of Allergy and Infectious Diseases (Grant T32AI007509). We thank Dr. Suzanne Scheele for technical assistance.

PY - 2012/8/15

Y1 - 2012/8/15

N2 - Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazole-based compounds in terms of solubility, selectivity, and potency against CpCDPK1 and TgCDPK1. The best inhibitors show inhibitory potencies below 50 nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.

AB - Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazole-based compounds in terms of solubility, selectivity, and potency against CpCDPK1 and TgCDPK1. The best inhibitors show inhibitory potencies below 50 nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.

KW - Calcium-dependent protein kinase-1

KW - Cryptosporidium parvum

KW - Enzyme inhibitor

KW - Selectivity

KW - Toxoplasma gondii

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Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1

Abstract

Keywords

ASJC Scopus subject areas

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