Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity

Bioorg Med Chem Lett. 2012 Nov 1;22(21):6705-11. doi: 10.1016/j.bmcl.2012.08.094. Epub 2012 Sep 4.

Abstract

A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Crystallography, X-Ray
  • DNA Ligases / antagonists & inhibitors*
  • DNA, Bacterial / antagonists & inhibitors
  • Drug Design*
  • Inhibitory Concentration 50
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Rats
  • Staphylococcal Infections / drug therapy
  • Staphylococcus / drug effects*
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • DNA, Bacterial
  • DNA Ligases