Discovery of bacterial NAD+-dependent DNA ligase inhibitors: optimization of antibacterial activity

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4556-60. doi: 10.1016/j.bmcl.2011.05.128. Epub 2011 Jun 12.

Abstract

Optimization of adenosine analog inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. Antibacterial activity against Streptococcus pneumoniae and Staphylococcus aureus was improved by modification of the 2-position substituent on the adenine ring and 3'- and 5'-substituents on the ribose. Compounds with logD values 1.5-2.5 maximized potency and maintained drug-like physical properties.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / chemical synthesis
  • Adenosine / pharmacology
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • Crystallography, X-Ray
  • DNA Ligases / antagonists & inhibitors*
  • DNA Ligases / metabolism
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Microbial Sensitivity Tests
  • NAD / metabolism
  • Protein Structure, Tertiary
  • Staphylococcus aureus / drug effects
  • Streptococcus pneumoniae / drug effects

Substances

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