- Fluorine Substituent

Vcetamlno methyl Group

Aroi R

matic Ring

C-5 (S) Configuration

The three critical structural features needed for good antibacterial activity (red boxes) are: (1) the (S) spatial configuration at C-5; (2) the acetaminomethyl group at C-5 and (3) an aromatic ring attached to the oxazoiidinone nitrogen atom. The fluorine and electron-donating nitrogen substituents on the aromatic ring led to improved efficacy and increased safety of the drug, but are not critical for antibiotic activity.

Linezolid acts by the inhibition of bacterial protein synthesis.3 Specifically, it is thought to bind to the 50S ribosomal subunit so as to prevent its joining with the 30S small ribosomal subunit—mRNA complex and N-formylmethionine— tRNA to form the 70S assembly, which catalyzes protein synthesis. Because N-formylmethionine (fMet) is the initial subunit of a new peptide chain, linezolid functions to block the very first step in the biosynthesis of bacterial proteins, thereby preventing bacterial growth and replication. An X-ray crystal structure has been obtained by T.A. Steitz showing the binding of linezolid to the 50S subunit of the ribosome.

Elongation / 70s Initiation Cycle Elongation Complex Factors

1. Antimicrob. Agents 2005, 604-630; 2. Angew. Chem . Int. Ed. Engl. 2003, 42. 2010-2023; 3. Exp. Opin. Pharmacother. 2005, 6, 2315-2326; Refs. p. 175

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