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

作者：Gu Wenxin^*; Wang Tiansheng; Maltais Francois; Ledford Brian; Kennedy Joseph; Wei Yunyi; Gross Christian H; Parsons Jonathan; Duncan Leonard; Arends S J Ryan; Moody Cameron; Perola Emanuele; Green Jeremy; Charifson Paul S

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(11): 3693-3698.

DOI：10.1016/j.bmcl.2012.04.037

• NAD(+)-DNA ligase
• Antibacterial
• Aminoalkoxypyrimidine carboxamide
• Crystal structures
• MIC

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.

• 出版日期2012-6-1