Discovery and optimization of antibacterial AccC inhibitors

被引：41

作者：

Cheng, Cliff C. ^{[1
]}

Shipps, Gerald W., Jr. ^{[1
]}

Yang, Zhiwei ^{[1
]}

Sun, Binyuan ^{[1
]}

Kawahata, Noriyuki ^{[1
]}

Soucy, Kyle A. ^{[1
]}

Soriano, Aileen ^{[2
]}

Orth, Peter ^{[2
]}

Xiao, Li ^{[2
]}

Mann, Paul ^{[2
]}

Black, Todd ^{[2
]}

机构：

[1] Schering Plough Res Inst, Cambridge, MA 02141 USA

[2] Schering Plough Res Inst, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 23期

关键词：

Biotin carboxylase; AccC; Acetyl coenzyme-A carboxylase; ACCase; BCCP; Biotin carboxyl carrier protein; Structure Based Drug Design (SBDD); ALIS: Automated Ligand Identification System; AS-MS: Affinity-Selection Mass Spectrometry; HS294; E; coli; MIC; CARBOXYLASE; IDENTIFICATION; MUTANTS;

D O I：

10.1016/j.bmcl.2009.10.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The biotin carboxylase (AccC) is part of the multi-component bacterial acetyl coenzyme-A carboxylase (ACCase) and is essential for pathogen survival. We describe herein the affinity optimization of an initial hit to give 2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzo[d]imidazole-5-carboxamide (1), which was identified using our proprietary Automated Ligand Identification System (ALIS).(1) The X-ray co-crystal structure of 1 was solved and revealed several key interactions and opportunities for further optimization in the ATP site of AccC. Structure Based Drug Design (SBDD) and parallel synthetic approaches resulted in a novel series of AccC inhibitors, exemplified by (R)-2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo[4,5-b]pyridine-5-carboxamide (40). This compound is a potent and selective inhibitor of bacterial AccC with an IC(50) of 20 nM and a MIC of 0.8 mu g/mL against a sensitized strain of Escherichia coli (HS294 E. coli). (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：6507 / 6514

页数：8

共 14 条

[1] Method for quantitative protein-ligand affinity measurements in compound mixtures [J].