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

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3693-8. doi: 10.1016/j.bmcl.2012.04.037. Epub 2012 Apr 17.

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.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology
  • 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*
  • Enterococcus faecalis / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Microbial Sensitivity Tests
  • NAD / metabolism
  • Pyrimidines / chemistry
  • Structure-Activity Relationship

Substances

  • Amides
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Pyrimidines
  • NAD
  • DNA Ligases
  • DNA Ligase ATP
  • pyrimidine