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

  • Bioorg Med Chem Lett. 2012 Aug 15;22(16):5264-7. doi: 10.1016/j.bmcl.2012.06.050.
Zhongsheng Zhang  1 ,  Kayode K Ojo ,  Steven M Johnson ,  Eric T Larson ,  Penqing He ,  Jennifer A Geiger ,  Alejandro Castellanos-Gonzalez ,  A Clinton White Jr ,  Marilyn Parsons ,  Ethan A Merritt ,  Dustin J Maly ,  Christophe L M J Verlinde ,  Wesley C Van Voorhis ,  Erkang Fan
Affiliations
  • 1. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
PMID: 22795629 DOI: 10.1016/j.bmcl.2012.06.050
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.