Synthesis and evaluation of new tyrosyl-tRNA synthetase inhibitors as antibacterial agents based on a N2-(arylacetyl)glycinanilide scaffold

Eur J Med Chem. 2015 Sep 18:102:631-8. doi: 10.1016/j.ejmech.2015.08.025. Epub 2015 Aug 14.

Abstract

Tyrosyl-tRNA synthetase (TyrRS), an essential enzyme in bacterial protein biosynthesis, is an attractive therapeutic target for finding novel antibacterial agents, and a series of N2-(arylacetyl)glycinanilides has been herein synthesized and identified as TyrRS inhibitors. These efforts yielded several compounds, with IC50 in the low micromolar range against TyrRS from Staphylococcus aureus. Out of the obtained compounds, 3ap is the most active and exhibits excellent activity against both Gram-positive (S. aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains. In comparison with the parent scaffold 3-arylfuran-2(5H)-one, N2-(arylacetyl)glycinanilide significantly improved the potency against Gram-negative bacterial strains, indicating that this scaffold offers a significant potential for developing new antibacterial drugs.

Keywords: Antibacterial agent; Molecular docking; N2-(arylacetyl)glycinanilide; Structure–activity relationship; TyrRS inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / chemical synthesis
  • Acetanilides / chemistry
  • Acetanilides / pharmacology*
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Benzeneacetamides / chemical synthesis
  • Benzeneacetamides / chemistry
  • Benzeneacetamides / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Gram-Negative Bacteria / drug effects*
  • Gram-Positive Bacteria / drug effects*
  • Gram-Positive Bacteria / enzymology
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship
  • Tyrosine-tRNA Ligase / antagonists & inhibitors*
  • Tyrosine-tRNA Ligase / metabolism

Substances

  • Acetanilides
  • Anti-Bacterial Agents
  • Benzeneacetamides
  • Enzyme Inhibitors
  • N2-((3-chlorophenyl)acetyl)-N-(4-nitrophenyl)glycinamide
  • Tyrosine-tRNA Ligase