Synthesis and Antibacterial Activity of U-100592 and U-100766, Two Oxazolidinone Antibacterial Agents for the Potential Treatment of Multidrug-Resistant Gram-Positive Bacterial Infections

Abstract

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.

Targeting Antibiotic Resistance

“…Research continued in this area (initiated by Upjohn, later Pharmacia, now Pfizer Inc.), and by 1996, two nontoxic oxazolidinones, linezolid and eperezolid, had been developed ( 1 and 2 ; Figure 3). 26 …”

Total synthesis of (±)-naphthacemycin A9, possessing both antibacterial activity against methicillin-resistant Staphylococcus aureus and circumventing effect of β-lactam resistance

“…1,2 Currently, five anti-MRSA drugs are available: vancomycin; 3 teicoplanin; 4 arbekacin; 5 linezolid; 6 and daptomycin. 7 However, owing to problems such as side effects and the emergence of highly drug-resistance strains, the development of new anti-MRSA drugs is a high priority.…”

Toxicity of Oxazolidinone Linezolid on Pathogenic Microorganism Listeria ivanovii

“…Oxazolidinones represent a new synthetic class of antibacterial agents with activity against gram-positive organisms (Brickner et al, 1996). The antimicrobial activities of the oxazolidinones were first described by scientists at E. I. Dupont de Nemours and Co., Inc (Daly et al, 1988;Slee et al, 1987).…”