Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity

J Med Chem. 1996 Feb 2;39(3):680-5. doi: 10.1021/jm950956y.


During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's < or = 0.125 micrograms/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 micrograms/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 micrograms/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmaco-kinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / pharmacokinetics
  • Acetamides / pharmacology*
  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Microbial Sensitivity Tests
  • Mycobacterium avium / drug effects*
  • Mycobacterium tuberculosis / drug effects*
  • Oxazoles / chemical synthesis*
  • Oxazoles / pharmacokinetics
  • Oxazoles / pharmacology*
  • Rats


  • Acetamides
  • Anti-Bacterial Agents
  • Oxazoles
  • U 100480