title: Carbon-carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria.
abstract: In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs <or=0.5-1 microg/mL and moderate Gram-negative activity with MICs=2-8 microg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED(50)=1.9 mg/kg. Beta-substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10alpha. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue (34) exhibited an exceptional in vitro activity with MICs of <or= 0.06-0.25 microg/mL against Gram-positive pathogens and with MICs of 1 microg/mL against fastidious Gram-negative pathogens.
authors.affiliation: Combinatorial and Medicinal Chemistry Research, Pharmacia Corporation, Kalamazoo, MI 49001, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Lee
authors.forename: D A
authors.initials: DA
authors.lastname: Allwine
authors.forename: M R
authors.initials: MR
authors.lastname: Barbachyn
authors.forename: K C
authors.initials: KC
authors.lastname: Grega
authors.forename: L A
authors.initials: LA
authors.lastname: Dolak
authors.forename: C W
authors.initials: CW
authors.lastname: Ford
authors.forename: R M
authors.initials: RM
authors.lastname: Jensen
authors.forename: E P
authors.initials: EP
authors.lastname: Seest
authors.forename: J C
authors.initials: JC
authors.lastname: Hamel
authors.forename: R D
authors.initials: RD
authors.lastname: Schaadt
authors.forename: D
authors.initials: D
authors.lastname: Stapert
authors.forename: B H
authors.initials: BH
authors.lastname: Yagi
authors.forename: G E
authors.initials: GE
authors.lastname: Zurenko
authors.forename: M J
authors.initials: MJ
authors.lastname: Genin
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002244:Carbon / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D018432:Drug Resistance, Multiple; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006193:Haemophilus influenzae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D001936:Moraxella catarrhalis / Q000187:drug effects; D010080:Oxazoles; D011720:Pyrazoles; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; C449102:N-((5)-3-(4(1-(cyanomethyl)-1H-pyrazol-4-yl)-3-fluorophenyl-2-oxo-1,3-oxazolidin-5-yl)methyl)ethanethioamide; D010080:Oxazoles; D011720:Pyrazoles; D002244:Carbon