Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections

J Med Chem. 1996 Feb 2;39(3):673-9. doi: 10.1021/jm9509556.

Abstract

Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Animals
  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology*
  • Dogs
  • Drug Resistance, Microbial
  • Drug Resistance, Multiple
  • Female
  • Linezolid
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Mice
  • Microbial Sensitivity Tests
  • Oxazoles / chemical synthesis*
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Oxazolidinones*
  • Rats

Substances

  • Acetamides
  • Anti-Infective Agents
  • Oxazoles
  • Oxazolidinones
  • eperezolid
  • Linezolid