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

Research output: Contribution to journalArticle

34 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 languageEnglish (US)
Pages (from-to)5264-5267
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number16
DOIs
StatePublished - Aug 15 2012
Externally publishedYes

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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  • Cite this

    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