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

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• 作者：Zhongsheng Zhang ; Kayode K. Ojo ; Steven M. Johnson ; Eric T. Larson ; Penqing He ; Jennifer A. Geiger ; Alej ; ro 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
• 关键词：Cryptosporidium parvum ; Toxoplasma gondii ; Calcium-dependent protein kinase-1 ; Enzyme inhibitor ; Selectivity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：15 August, 2012
• 年：2012
• 卷：22
• 期：16
• 页码：5264-5267
• 全文大小：1012 K

文摘

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.