SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF U-100592 AND U-100766, 2 OXAZOLIDINONE ANTIBACTERIAL AGENTS FOR THE POTENTIAL TREATMENT OF MULTIDRUG-RESISTANT GRAM-POSITIVE BACTERIAL-INFECTIONS

Bacterial resistance development has become a very serious clinical pr oblem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a ne w mechanism of action which involves very early inhibition of bacteria l protein synthesis. We have prepared two potent, synthetic oxazolidin ones, U-100592 and U-100766, which are currently in clinical developme nt for the treatment of serious multidrug-resistant Gram-positive bact erial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100 592 and U-100766 against representative strains are similar to those o f vancomycin. U-100592 and U-100766 demonstrate potent in vitro activi ty against Mycobacterium tuberculosis. A novel and practical asymmetri c synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been develo ped and is employed for the synthesis of U-100592 and U-100766. This i nvolves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyr ate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones,