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

被引:41
作者
Zhang, Zhongsheng [2 ]
Ojo, Kayode K. [1 ]
Johnson, Steven M. [3 ]
Larson, Eric T. [2 ]
He, Penqing [1 ]
Geiger, Jennifer A. [4 ]
Castellanos-Gonzalez, Alejandro [5 ]
White, A. Clinton, Jr. [5 ]
Parsons, Marilyn [4 ]
Merritt, Ethan A. [2 ]
Maly, Dustin J. [3 ]
Verlinde, Christophe L. M. J. [2 ]
Van Voorhis, Wesley C. [1 ]
Fan, Erkang [2 ]
机构
[1] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA 98195 USA
[2] Univ Washington, Dept Biochem, Seattle, WA 98195 USA
[3] Univ Washington, Dept Chem, Seattle, WA 98195 USA
[4] Seattle Biomed Res Inst, Seattle, WA 98109 USA
[5] Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, Galveston, TX 77555 USA
基金
美国国家卫生研究院;
关键词
Cryptosporidium parvum; Toxoplasma gondii; Calcium-dependent protein kinase-1; Enzyme inhibitor; Selectivity; DESIGN; POTENT; CDPK1;
D O I
10.1016/j.bmcl.2012.06.050
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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. (c) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5264 / 5267
页数:4
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