ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Aza Compounds/chemistry , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Sulfhydryl Compounds/chemistry , Amides/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Aza Compounds/chemical synthesis , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/microbiology , Mice , Molecular Conformation , Oxazolidinones/chemistry , Oxazolidinones/therapeutic use , Structure-Activity RelationshipABSTRACT
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[3.1.0]hexyl ring systems. Several classes of azabicyclic analogues were identified with activity comparable or superior to that of linezolid. These include analogues bearing hydroxyl, amino, amido, or carboxyl groups on the azabicyclic ring. The azabicyclic acid analogue 50 was 4 times more potent than linezolid against key Gram-positive and fastidious Gram-negative pathogens (S. aureus, Streptococcus pneumoniae, and E. faecalis MICs < or = 1 microg/mL; Haemophilus influenzae MIC = 4 microg/mL).
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Aza Compounds/chemical synthesis , Oxazolidinones/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Aza Compounds/chemistry , Aza Compounds/pharmacology , Drug Resistance, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Molecular Conformation , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
[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. The various constrained heterocycles (X = N, O, or S) are conveniently prepared from a common diol intermediate accessible from readily available cinnamyl alcohols. Application of the methodology to the synthesis of conformationally constrained oxazolidinone antibacterials is also discussed.
