Bioorg Med Chem Lett. 2012 Aug 15;22(16):5264-7. doi: 10.1016/j.bmcl.2012.06.050. Epub 2012 Jun 23.

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

Zhang Z¹, Ojo KK, Johnson SM, Larson ET, He P, Geiger JA, Castellanos-Gonzalez A, White AC Jr, Parsons M, Merritt EA, Maly DJ, Verlinde CL, Van Voorhis WC, Fan E.

Author information

1: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.

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.