title: Piperazinyl oxazolidinone antibacterial agents containing a pyridine, diazene, or triazene heteroaromatic ring.
abstract: Oxazolidinones are a novel class of synthetic antibacterial agents active against gram-positive organisms including methicillin-resistant Staphylococcus aureus as well as selected anaerobic organisms. Important representatives of this class include the morpholine derivative linezolid 2, which is currently in phase III clinical trials, and the piperazine derivative eperezolid 3. As part of an investigation of the structure-activity relationships of structurally related oxazolidinones, we have prepared and evaluated the antibacterial properties of a series of piperazinyl oxazolidinones in which the distal nitrogen of the piperazinyl ring is substituted with a six-membered heteroaromatic ring. Compounds having MIC values </= 2 microg/mL vs selected gram-positive pathogens were discovered among each of the pyridine, pyridazine, and pyrimidine structural classes. Among these the cyanopyridine 17, the pyridazines 25 and 26, and the pyrimidine 31 exhibited in vivo potency vs S. aureus comparable to that of linezolid.
authors.affiliation: Discovery Research, Pharmacia & Upjohn, 7000 Portage Road, Kalamazoo, Michigan 49001, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Tucker
authors.forename: D A
authors.initials: DA
authors.lastname: Allwine
authors.forename: K C
authors.initials: KC
authors.lastname: Grega
authors.forename: M R
authors.initials: MR
authors.lastname: Barbachyn
authors.forename: J L
authors.initials: JL
authors.lastname: Klock
authors.forename: J L
authors.initials: JL
authors.lastname: Adamski
authors.forename: S J
authors.initials: SJ
authors.lastname: Brickner
authors.forename: D K
authors.initials: DK
authors.lastname: Hutchinson
authors.forename: C W
authors.initials: CW
authors.lastname: Ford
authors.forename: G E
authors.initials: GE
authors.lastname: Zurenko
authors.forename: R A
authors.initials: RA
authors.lastname: Conradi
authors.forename: P S
authors.initials: PS
authors.lastname: Burton
authors.forename: R M
authors.initials: RM
authors.lastname: Jensen
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018938:Caco-2 Cells; D013293:Enterococcus faecalis / Q000187:drug effects; D006801:Humans; D000069349:Linezolid; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D023303:Oxazolidinones; D010539:Permeability; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D014226:Triazenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D010080:Oxazoles; D023303:Oxazolidinones; D010879:Piperazines; D011725:Pyridines; D014226:Triazenes; C098011:eperezolid; D000069349:Linezolid