Discovery of bacterial NAD⁺-dependent DNA ligase inhibitors: improvements in clearance of adenosine series

Bioorg Med Chem Lett. 2012 Jan 1;22(1):85-9. doi: 10.1016/j.bmcl.2011.11.071. Epub 2011 Nov 23.

Abstract

Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.

MeSH terms

  • Adenine / chemistry
  • Adenosine / chemistry*
  • Administration, Oral
  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Biological Availability
  • Chromatography, Liquid / methods
  • DNA Ligases / antagonists & inhibitors*
  • DNA Ligases / chemistry
  • Dogs
  • Drug Design
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / pharmacology*
  • Fluorine / chemistry
  • Inhibitory Concentration 50
  • Mass Spectrometry / methods
  • Models, Chemical
  • NAD / chemistry*
  • Rats

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • NAD
  • Fluorine
  • DNA Ligases
  • Adenine
  • Adenosine