linezolid and eperezolid

Oxazolidinone antibacterial agents, where the N-substituted piperazinyl group of eperezolid was replaced with a N-substituted piperidinyloxy moiety, were synthesized and shown to be active against a variety of resistant and susceptible Gram-positive organisms. The effect of ring size, positional isomerism, and fluorine substitution on antibacterial activity was examined.

Topics: Acetamides; Anti-Bacterial Agents; Drug Resistance; Escherichia coli; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Oxazoles; Oxazolidinones; Piperidines; Staphylococcus aureus

Oxazolidinones are a novel class of synthetic antibacterial agents active against gram-positive organisms including methicillin-resistant Staphylococcus aureus as well as selected anaerobic organisms. Important representatives of this class include the morpholine derivative linezolid 2, which is currently in phase III clinical trials, and the piperazine derivative eperezolid 3. As part of an investigation of the structure-activity relationships of structurally related oxazolidinones, we have prepared and evaluated the antibacterial properties of a series of piperazinyl oxazolidinones in which the distal nitrogen of the piperazinyl ring is substituted with a six-membered heteroaromatic ring. Compounds having MIC values

Topics: Acetamides; Anti-Bacterial Agents; Caco-2 Cells; Enterococcus faecalis; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazoles; Oxazolidinones; Permeability; Piperazines; Pyridines; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae; Structure-Activity Relationship; Triazenes

Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.

Topics: Acetamides; Animals; Anti-Infective Agents; Dogs; Drug Resistance, Microbial; Drug Resistance, Multiple; Female; Linezolid; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Microbial Sensitivity Tests; Oxazoles; Oxazolidinones; Rats