Synthesis And Antibacterial Activities Of Novel Fluoroquinolone-Oxazolidinone Derivatives

Multidrug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus(MRSA), vancomycin-resistant Enterococci(VRE) have become a significant and growing burden in hospitals. The oxazolidinones are a new class of totally synthetic antibacterials that inhibit protein synthesis via binding to a distinct region of 23S RNA of the 50S ribosomal subunit in prokaryotes. This novel mechanism of action results in an important lack of cross-resistance between oxazolidinones and the existing antibacterial agents. But their antimicrobial spectrum as represented by linezolid is generally limited to Gram-positive species.Another class of synthetic antibacterials, the fluoroquinolones are the inhibitors of DNA gyrase or topoisomerase IV in DNA replication. Though they show broad antibacterial spectrum, the activities against Gram-negative microorganisms are more potent than those against Gram-positive strains. The derivatives with both oxazolidinone and fluoroquinolone pharmacophores may possess the potential of dual mode of action.In order to investigate the structure-activity relationship of novel fluoroquinolone-oxazolidinone derivatives and to discover new potent compounds with better and broader activity, fifty eight target compounds were designed and synthesized, all the target compounds were unknown and confirmed by ~1H-NMR and MS. Some physical and chemical constants such as melting point and specific rotation were measured. These compounds belonged to five series of fluoroquinolone-oxazolidinone derivatives, in which the pharmacophores of fluoroquinolones and oxazolidinones were connected by ethylene. The five series were l,2,8-trisubstituted-7-{3-substituted-4-[2-[2-substituted-4-((5S)-5-acetaminorne thyl-2-oxo-oxazolidin-3-yl)-phenyl]-ethyl]-piperazin-l-yl}-6-fluoro-4-oxo-l,4-dihydr oquinoline-3-carboxylic acids(A and B), 1,2,8-trisubstituted-7-{4-[2-[2-substituted-4-((5S)-5-methoxythiocarbonylaminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-ethyl]-pipe razin-l-yl}-6-fluoro-4-oxo-dihydroquinoline-3-carboxylic acids(C and D),...