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, 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

33 Citations (Scopus)

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

Fingerprint

Protozoa
Cryptosporidium parvum
Toxoplasma
Solubility
Phosphotransferases
Infection
calcium-dependent protein kinase

Keywords

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

ASJC Scopus subject areas

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

Cite this

Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1. / Zhang, Zhongsheng; Ojo, Kayode K.; Johnson, Steven M.; Larson, Eric T.; He, Penqing; Geiger, Jennifer A.; Castellanos, Alejandro; White, A. Clinton; Parsons, Marilyn; Merritt, Ethan A.; Maly, Dustin J.; Verlinde, Christophe L M J; Van Voorhis, Wesley C.; Fan, Erkang.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 16, 15.08.2012, p. 5264-5267.

Research output: Contribution to journalArticle

Zhang, Z, Ojo, KK, Johnson, SM, Larson, ET, He, P, Geiger, JA, Castellanos, 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
Zhang, Zhongsheng ; Ojo, Kayode K. ; Johnson, Steven M. ; Larson, Eric T. ; He, Penqing ; Geiger, Jennifer A. ; Castellanos, Alejandro ; White, A. Clinton ; Parsons, Marilyn ; Merritt, Ethan A. ; Maly, Dustin J. ; Verlinde, Christophe L M J ; Van Voorhis, Wesley C. ; Fan, Erkang. / Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 16. pp. 5264-5267.
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