title: Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part I: aminoalkoxypyrimidine carboxamides.
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.
authors.affiliation: Vertex Pharmaceuticals, Inc., 130 Waverly St., Cambridge, MA 02139, United States. wenxin_gu@vrtx.com
authors.forename: Wenxin
authors.initials: W
authors.lastname: Gu
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.forename: Francois
authors.initials: F
authors.lastname: Maltais
authors.forename: Brian
authors.initials: B
authors.lastname: Ledford
authors.forename: Joseph
authors.initials: J
authors.lastname: Kennedy
authors.forename: Yunyi
authors.initials: Y
authors.lastname: Wei
authors.forename: Christian H
authors.initials: CH
authors.lastname: Gross
authors.forename: Jonathan
authors.initials: J
authors.lastname: Parsons
authors.forename: Leonard
authors.initials: L
authors.lastname: Duncan
authors.forename: S J Ryan
authors.initials: SJ
authors.lastname: Arends
authors.forename: Cameron
authors.initials: C
authors.lastname: Moody
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D013293:Enterococcus faecalis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009243:NAD / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D009243:NAD; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C030986:pyrimidine