Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: design, synthesis and evaluation as antibacterial agent

Bioorg Med Chem. 2014 Jul 15;22(14):3620-8. doi: 10.1016/j.bmc.2014.05.018. Epub 2014 May 20.

Abstract

3-Arylfuran-2(5H)-one, a novel antibacterial pharmacophore targeting tyrosyl-tRNA synthetase (TyrRS), was hybridized with the clinically used fluoroquinolones to give a series of novel multi-target antimicrobial agents. Thus, twenty seven 3-arylfuran-2(5H)-one-fluoroquinolone hybrids were synthesized and evaluated for their antimicrobial activities. Some of the hybrids exhibited merits from both parents, displaying a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria. The most potent compound (11) in antibacterial assay shows MIC50 of 0.11μg/mL against Multiple drug resistant Escherichia coli, being about 51-fold more potent than ciprofloxacin. The enzyme assays reveal that 11 is a potent multi-target inhibitor with IC50 of 1.15±0.07μM against DNA gyrase and 0.12±0.04μM against TyrRS, respectively. Its excellent inhibitory activities against isolated enzymes and intact cells strongly suggest that 11 deserves to further research as a novel antibiotic.

Keywords: 3-Arylfuran-2(5H)-one; DNA gyrase; Fluoroquinolone; Hybrid; Multi-target; TyrRS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Bacteria / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Fluoroquinolones / chemistry
  • Fluoroquinolones / pharmacology*
  • Furans / chemistry
  • Furans / pharmacology*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Fluoroquinolones
  • Furans