Conformational constraint in oxazolidinone antibacterials. Part 2: Synthesis and structure-activity studies of oxa-, aza-, and thiabicyclo[3.1.0]hexylphenyl oxazolidinones.

A new class of oxazolidinone antibacterials incorporating oxygen-, nitrogen-, or sulfur-containing heterobicyclic C-rings is described. The in vitro potency and in vivo efficacy of these conformationally constrained oxazolidinone analogs are discussed.

Conformational constraint in oxazolidinone antibacterials. Synthesis and structure-activity studies of (azabicyclo[3.1.0]hexylphenyl)oxazolidinones.

The oxazolidinones are a new class of synthetic antibacterials effective against a broad range of pathogenic Gram-positive bacteria, including multi-drug-resistant strains. Linezolid is the first drug from this class to reach the market and has become an important new option for the treatment of serious infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus faecium (VRE). In the search for novel oxazolidinones with improved potency and spectrum, we have prepared and evaluated the antibacterial properties of conformationally constrained analogues in which the morpholine ring of linezolid is replaced with various substituted azabicyclo[3.

Synthesis of aza-, oxa-, and thiabicyclo[3.1.0]hexane heterocycles from a common synthetic intermediate.

[reaction: see text] An efficient and stereospecific approach to the synthesis of structurally constrained aza-, oxa-, and thiabicyclo[3.1.0]hexane heterocycles has been achieved through application of the intramolecular cyclopropanation reaction of diazoacetates.