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.
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Authors | S 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 |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 39
Issue 3
Pg. 673-9
(Feb 02 1996)
ISSN: 0022-2623 [Print] United States |
PMID | 8576909
(Publication Type: Journal Article)
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Chemical References |
- Acetamides
- Anti-Infective Agents
- Oxazoles
- Oxazolidinones
- eperezolid
- Linezolid
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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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