IDENTIFICATION OF A NOVEL OXAZOLIDINONE (U-100480) WITH POTENT ANTIMYCOBACTERIAL ACTIVITY

During the course of our investigations in the oxazolidinone antibacte rial 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 desig n, synthesis, and evaluation of the in vitro antimycobacterial activit y of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (min imum inhibitory concentrations or MIC's less than or equal to 0.125 mu g/mL). Oxazolidinones 6 and 8 exhibit MIC(90) values of 0.50 mu g/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 myco bacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Myc obacterium avium complex (MIC's = 0.5-4 mu g/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium simil ar to that of clinical comparators isoniazid and azithromycin, respect ively. Consideration of these factors, along with a favorable pharmaco kinetic and chronic toxicity profile in rats, suggests that 6 (U-10048 0) is a promising antimycobacterial agent.