1. Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part I: Aminoalkoxypyrimidine carboxamides
- Author
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Cameron Stuver Moody, Christian H. Gross, Kennedy Joseph M, Paul S. Charifson, Emanuele Perola, Leonard R. Duncan, Tiansheng Wang, Wenxin Gu, Jeremy Green, Yunyi Wei, S J Ryan Arends, Brian Ledford, Jonathan D. Parsons, and Francois Maltais
- Subjects
DNA Ligases ,Stereochemistry ,Clinical Biochemistry ,Nad dependent ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Crystallography, X-Ray ,Biochemistry ,DNA Ligase ATP ,Structure-Activity Relationship ,chemistry.chemical_compound ,Bacterial Proteins ,Catalytic Domain ,Drug Discovery ,Ribose ,Enterococcus faecalis ,Humans ,Potency ,Structure–activity relationship ,Computer Simulation ,Enzyme Inhibitors ,Binding site ,Molecular Biology ,chemistry.chemical_classification ,DNA ligase ,Binding Sites ,Organic Chemistry ,NAD ,Amides ,Anti-Bacterial Agents ,Pyrimidines ,chemistry ,Drug Design ,Molecular Medicine ,NAD+ kinase ,Selectivity - 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.
- Published
- 2012