| Autor: |
Barbachyn, M. R., Hutchinson, D. K., Brickner, S. J., Cynamon, M. H., Kilburn, J. O., Klemens, S. P., Glickman, S. E., Grega, K. C., Hendges, S. K., Toops, D. S., Ford, C. W., Zurenko, G. E. |
| Zdroj: |
Journal of Medicinal Chemistry; February 2, 1996, Vol. 39 Issue: 3 p680-685, 6p |
| Abstrakt: |
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 ≤0.125 μg/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 μg/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 μg/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 pharmacokinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent. |
| Databáze: |
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