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Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part I: aminoalkoxypyrimidine carboxamides |
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| Authors: | 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 |
| Institution: | Vertex Pharmaceuticals, Inc., 130 Waverly St., Cambridge, MA 02139, United States. wenxin_gu@vrtx.com |
| Abstract: | 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. |
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