title: Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity.
abstract: 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.
authors.affiliation: Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Barbachyn
authors.forename: D K
authors.initials: DK
authors.lastname: Hutchinson
authors.forename: S J
authors.initials: SJ
authors.lastname: Brickner
authors.forename: M H
authors.initials: MH
authors.lastname: Cynamon
authors.forename: J O
authors.initials: JO
authors.lastname: Kilburn
authors.forename: S P
authors.initials: SP
authors.lastname: Klemens
authors.forename: S E
authors.initials: SE
authors.lastname: Glickman
authors.forename: K C
authors.initials: KC
authors.lastname: Grega
authors.forename: S K
authors.initials: SK
authors.lastname: Hendges
authors.forename: D S
authors.initials: DS
authors.lastname: Toops
authors.forename: C W
authors.initials: CW
authors.lastname: Ford
authors.forename: G E
authors.initials: GE
authors.lastname: Zurenko
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D010080:Oxazoles; C098012:U 100480