Bioorg Med Chem Lett. 2012 Jun 23. [Epub ahead of print]
Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1
Zhang Z, 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.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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 50nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.
PMID: 22795629 [PubMed - as supplied by publisher]