Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part 2: 4-amino-pyrido[2,3-d]pyrimidin-5(8H)-ones

Tiansheng Wang; Leonard Duncan; Wenxin Gu; Hardwin O'Dowd; Yunyi Wei; Emanuele Perola; Jonathan Parsons; Christian H Gross; Cameron Stuver Moody; S J Ryan Arends; Paul S Charifson

doi:10.1016/j.bmcl.2012.04.038

Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part 2: 4-amino-pyrido[2,3-d]pyrimidin-5(8H)-ones

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3699-703. doi: 10.1016/j.bmcl.2012.04.038. Epub 2012 Apr 19.

Authors

Tiansheng Wang¹, Leonard Duncan, Wenxin Gu, Hardwin O'Dowd, Yunyi Wei, Emanuele Perola, Jonathan Parsons, Christian H Gross, Cameron Stuver Moody, S J Ryan Arends, Paul S Charifson

Affiliation

¹ Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, United States. [email protected]

PMID: 22560470
DOI: 10.1016/j.bmcl.2012.04.038

Abstract

A series of 4-amino-pyrido[2,3-d]pyrimidin-5(8H)-ones were designed and synthesized as a novel class of inhibitors of NAD(+)-dependent DNA ligase that possess potency against Gram-positive bacteria.

MeSH terms

Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Binding Sites
Catalytic Domain
Computer Simulation
Crystallography, X-Ray
DNA Ligase ATP
DNA Ligases / antagonists & inhibitors*
DNA Ligases / metabolism
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Gram-Negative Bacteria / drug effects
Gram-Positive Bacteria / drug effects
Microbial Sensitivity Tests
NAD / metabolism
Pyrimidinones / chemistry*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Bacterial Proteins
Enzyme Inhibitors
Pyrimidinones
NAD
DNA Ligases
DNA Ligase ATP