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

TLDR

Bacterial resistance to many antibiotics is a serious clinical problem, and 3‑aryl‑2‑oxazolidinones represent a new class that inhibits bacterial protein synthesis early. The authors synthesized U‑100592 and U‑100766 via a novel asymmetric route that couples N‑lithioarylcarbamates with (R)‑glycidyl butyrate to produce (5S)‑acetamidomethyl‑2‑oxazolidinones with high yield and enantiomeric purity. Both compounds exhibit in vitro and in vivo activity comparable to vancomycin against multidrug‑resistant Gram‑positive bacteria and show potent activity against *Mycobacterium tuberculosis*.

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.