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

被引：42

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 16期

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

页码：5264 / 5267

页数：4

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