ANTIBACTERIALS - SYNTHESIS AND STRUCTURE ACTIVITY STUDIES OF 3-ARYL-2-OXOOXAZOLIDINES .2. THE A GROUP

The synthesis and structure–activity relationship (SAR) studies of the effect of varying the “A” group in a series of 5-(acetamidomethyl)oxazolidinone 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, oximinoalkyl, carboalkoxy, nitro, amino, halo and ψ-halo, alkylthio, alkylsulfinyl, and alkylsulfonyl against Staphylococcus aureus and Enterococcus faecalis led to the identification of several SAR trends. In several series of homologues (alkyl, keto, oximinoalkyl, amino, halo and ψ-halo, and alkylthio), 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, alkylsulfonyl), 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. © 1990, American Chemical Society. All rights reserved.