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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.

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.
AuthorsS J Brickner, D K Hutchinson, M R Barbachyn, P R Manninen, D A Ulanowicz, S A Garmon, K C Grega, S K Hendges, D S Toops, C W Ford, G E Zurenko
JournalJournal of medicinal chemistry (J Med Chem) Vol. 39 Issue 3 Pg. 673-9 (Feb 02 1996) ISSN: 0022-2623 [Print] United States
PMID8576909 (Publication Type: Journal Article)
Chemical References
  • Acetamides
  • Anti-Infective Agents
  • Oxazoles
  • Oxazolidinones
  • eperezolid
  • Linezolid
Topics
  • Acetamides (chemical synthesis, chemistry, pharmacology)
  • Animals
  • Anti-Infective Agents (chemical synthesis, chemistry, pharmacology)
  • Dogs
  • Drug Resistance, Microbial
  • Drug Resistance, Multiple
  • Female
  • Linezolid
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Mice
  • Microbial Sensitivity Tests
  • Oxazoles (chemical synthesis, chemistry, pharmacology)
  • Oxazolidinones
  • Rats

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