Design, synthesis and biological evaluation of potent NAD<sup>+sup>-dependent DNA ligase inhibitors as potential antibacterial agents. Part I: Aminoalkoxypyrimidine carboxamides
- 作者：Wenxin Gu<sup> ; sup><sup>wenxin_gu@vrtx.comsup> ; Tiansheng Wang ; Francois Maltais ; Brian Ledford ; Joseph Kennedy ; Yunyi Wei ; Christian H. Gross ; Jonathan Parsons ; Leonard Duncan ; S.J. Ryan Arends ; Cameron Moody ; Emanuele Perola ; Jeremy Green ; Paul S. Charifson
- 关键词：NAD+-DNA ligase ; Antibacterial ; Aminoalkoxypyrimidine carboxamide ; Crystal structures ; MIC
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：1 June, 2012
- 卷：22
- 期：11
- 页码：3693-3698
- 文件大小：724 K
摘要
A series of 2,6-disubstituted aminoalkoxypyrimidine carboxamides (AAPCs) with potent inhibition of bacterial NAD<sup>+sup>-dependent DNA ligase was discovered through the use of structure-guided design. Two subsites in the NAD<sup>+sup>-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<sup>+sup> was explored via 6-alkoxy substituents.