Synthesis And Antibacterial Activities Of (S)-5-Substituted Phenyl-3-Substituted Methyl-2-Oxazolidinones

Multi-drug-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) and Mycobacterium tuberculosis have become a serious problem in clinic. The totally synthetic oxazolidinones are a new class of antibacterial agents. One of them, Linezolid, has been launched into the international market for treatment of infections caused by drug-resistant Gram-positive bacteria.In order to investigate the structure-activity relationship of oxazolidinones and to discover new potent compounds for further research, over one hundred new compounds of (S)-5-substituted pheny 1-3-substituted methyl-2-oxazolidinones were designed and synthesized. All the compounds were unknown and confirmed by 'HNMR and elemental analyses or MS. Some physical and chemical constants such as [a]D25 were reported also.Three synthetic routes were taken according to the individual structural characteristics of the target compounds. 3-Halo-4-methylaniline was acylated with benzyl chloroformate, followed by cyclization with (R)-glycidyl butyrate, acylation with methanesulfonyl chloride, substitution with NaNa, reduction with H2+Pd/C or P(OMe)3+HCl, acylation with Ac2O, and bromination with NBS to form bromides VIII a~c, Substitution of the bromides with various amines provided the target compounds A, B, C, D.Some technical improvements of the synthetic process were made, for example, yield of Via was increased from 17% to 45.8% with 1,1,2,2-tetrachloroethane instead of benzene as the solvent, and yield and purity of (±)- glycidyl butyrate were improvedwith anhydrous sodium butyrate as the starting material.Started from the reaction of 3,4-difluoronitrobenzene and piperazine, followed by catalytic reduction, acylation with benzyl chloroformate, cyclization with (R)-glycidyl butyrate, acylation with methanesulfonyl chloride, substitution with NaN3, reduction and acylation with thioacetic acid, catalytic hydrogenation to form (S)-5-acetamido methyl-3-[(3-fluoro-4-piperazinyl-l)phenyl]-2-oxazolidinone(XXIII). The latter reacted with the intermediates of fluoroquinolones to form the title compounds E.For preparation of compound F, (R)-5-methane sulfonyloxymethyl-3- [(3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone(XXXII) were treated with various amines to form title compound F. This nucleophilic substitution has not been found in the literature on synthesizing antibacterial oxazolidinones.One hundred and eleven new compounds were screened in vitro against six Gram-positive and fourteen Gram-negative bacteria by the serial two-fold dilution method. Against some Gram-positive bacteria, 17 compounds showed the activitities equivalent to or more potent than those of Linezolid, and 18 compounds equivalent to or more potent than those of Norfloxacin. These compounds were worth to be investigated further. Structure-activity relationship study showed that the order of anti -G+activities was: E> D> A, B, C , G>F. Compared to Linezolid, the antibacterial spectra of compound D with the antibacterial fluoroquinolone framework were broadened, but the spectra of compound E were just the same as Linezolid, and E showed more potent activities against G+ bacteria. It was interesting to note that although the structural difference between D and E was small, their antibacterial spectra were quite different.