Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part I: Aminoalkoxypyrimidine carboxamides

被引：16

作者：

Gu, Wenxin ^{[1
]}

Wang, Tiansheng ^{[1
]}

Maltais, Francois ^{[1
]}

Ledford, Brian ^{[1
]}

Kennedy, Joseph ^{[1
]}

Wei, Yunyi ^{[1
]}

Gross, Christian H. ^{[1
]}

Parsons, Jonathan ^{[1
]}

Duncan, Leonard ^{[1
]}

Arends, S. J. Ryan ^{[1
]}

Moody, Cameron ^{[1
]}

Perola, Emanuele ^{[1
]}

Green, Jeremy ^{[1
]}

Charifson, Paul S. ^{[1
]}

机构：

[1] Vertex Pharmaceut Inc, Cambridge, MA 02139 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 11期

关键词：

NAD(+)-DNA ligase; Antibacterial; Aminoalkoxypyrimidine carboxamide; Crystal structures; MIC; ESCHERICHIA-COLI; MYCOBACTERIUM-TUBERCULOSIS; REPAIR; IDENTIFICATION; ADENYLATE; MECHANISM; CRYSTAL; ENZYME;

D O I：

10.1016/j.bmcl.2012.04.037

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 2,6-disubstituted aminoalkoxypyrimidine carboxamides (AAPCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligase was discovered through the use of structure-guided design. Two subsites in the NAD(+)-binding pocket were explored to modulate enzyme inhibitory potency: a hydrophobic selectivity region was explored through a series of 2-alkoxy substituents while the sugar (ribose) binding region of NAD(+) was explored via 6-alkoxy substituents. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3693 / 3698

页数：6

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