title: Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 2. The "A" group.
abstract: The synthesis and structure-activity relationship (SAR) studies of the effect of varying the "A" group in a series of 5-(acetamidomethyl)oxazolidonone antibacterials (2) are described. Compounds 2 were principally prepared either by the six-step synthesis described previously (J. Med. Chem. 1989, 32, 1673) or by elaboration of the synthetic intermediate 2 (A = H) via electrophilic aromatic substitution or elaboration of the intermediate 2 (A = I) by transition metal catalyzed carbon-carbon bond-forming reactions. Antibacterial evaluation of compounds 2 with A = alkyl, ethenyl, ethynyl, hydroxyalkyl, aldo and keto, oximinoakyl, carboalkoxy, nitro, amino, halo and psi-halo, alkylthio, alkylsulfinyl, and alkysulfonyl against Staphylococcus aureus and Enterococcus faecalis led to the identification of several SAR trends. In several series of homologues (alkyl, ketyl, aximinoalkyl, amino, halo and psi-halo, and alkythio), antibacterial activity increased with increasing lipophilicity. But in series with where A is a substituent with a trior tetrasubstituted (substituent larger than H) quaternary atom attached directly to the aromatic ring (hydroxyalkyl, alkylsulfinyl, alkylsufonyl), the activity peaked at the member of the series with the "tert-butyl" connectivity pattern. Conjugated electron-withdrawing substituents also had increased activity relative to nonconjugated analogues of comparable lipophilicity.
authors.affiliation: Pharmaceuticals and Biotechnology, Medical Products Department, E. I. du Pont de Nemours and Company, Wilmington, Delaware 19880-0353.
authors.forename: W A
authors.initials: WA
authors.lastname: Gregory
authors.forename: D R
authors.initials: DR
authors.lastname: Brittelli
authors.forename: C L
authors.initials: CL
authors.lastname: Wang
authors.forename: H S
authors.initials: HS
authors.lastname: Kezar
authors.forename: R K
authors.initials: RK
authors.lastname: Carlson
authors.forename: C H
authors.initials: CH
authors.lastname: Park
authors.forename: P F
authors.initials: PF
authors.lastname: Corless
authors.forename: S J
authors.initials: SJ
authors.lastname: Miller
authors.forename: P
authors.initials: P
authors.lastname: Rajagopalan
authors.forename: M A
authors.initials: MA
authors.lastname: Wuonola
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D013293:Enterococcus faecalis / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010080:Oxazoles