title: Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogens.
abstract: A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.
authors.affiliation: Combinatorial and Medicinal Chemistry, Pharmacia Corporation, 7000 Portage Road, Kalamazoo, Michigan 49001, USA. michael.r.barbachyn@pharmacia.com
authors.forename: Michael R
authors.initials: MR
authors.lastname: Barbachyn
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Cleek
authors.forename: Lester A
authors.initials: LA
authors.lastname: Dolak
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Garmon
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
authors.forename: Eric P
authors.initials: EP
authors.lastname: Seest
authors.forename: Richard C
authors.initials: RC
authors.lastname: Thomas
authors.forename: Dana S
authors.initials: DS
authors.lastname: Toops
authors.forename: William
authors.initials: W
authors.lastname: Watt
authors.forename: Donn G
authors.initials: DG
authors.lastname: Wishka
authors.forename: Charles W
authors.initials: CW
authors.lastname: Ford
authors.forename: Gary E
authors.initials: GE
authors.lastname: Zurenko
authors.forename: Judith C
authors.initials: JC
authors.lastname: Hamel
authors.forename: Ronda D
authors.initials: RD
authors.lastname: Schaadt
authors.forename: Douglas
authors.initials: D
authors.lastname: Stapert
authors.forename: Betty H
authors.initials: BH
authors.lastname: Yagi
authors.forename: Wade J
authors.initials: WJ
authors.lastname: Adams
authors.forename: Janice M
authors.initials: JM
authors.lastname: Friis
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Slatter
authors.forename: James P
authors.initials: JP
authors.lastname: Sams
authors.forename: Nancee L
authors.initials: NL
authors.lastname: Oien
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Zaya
authors.forename: Larry C
authors.initials: LC
authors.lastname: Wienkers
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wynalda
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000401:mortality; D013211:Staphylococcus aureus; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001555:Benzene Derivatives; D065607:Cytochrome P-450 Enzyme Inhibitors; D007555:Isoxazoles; C470758:N-((3-(3,5-difluoro-4-(4-(hydroxyacetyl)-1-piperazinyl)phenyl)-4,5-dihydro-5-isoxazolyl)methyl)acetamide; D010879:Piperazines; D003577:Cytochrome P-450 Enzyme System