Synthesis And In Vitro Antibacterial Activity Of 3-Substituted-Phenyl-5-Substituted Oxazolidinones

Synthesis and Antibacterial Activity of 3-Substituted-Phenyl-5-Substituted OxazolidinonesM.S candidate: Mr. Jidong Liu Advisor: Mr. Baoyuan He, Prof. Weicheng ZhouAbstractMulti-drug-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) and Mycobacterium tuberculosis have become a serious problem. The totally synthetic oxazolidinones, typified by linezolid, which has been launched into international market, are a new class of antibacterial agents for the treatment of the infections caused by Gram-positive bacteria including drug-resistant pathogens.Our group is being engaged in discovery of new antibacterial agents. According to the structure-activity relationship of the oxazolidinones in the literature, 19 3-substituted-phenyl-5-substituted oxazolidinones were designed and synthesized. All the title compounds were unknown and confirmed by 'HNMR and elemental analyses. Linezolid was also prepared for the antibacterial test as control.The synthesis route was demonstrated as following: p-nitroaniline was acylated with phenyl chloroformate, followed by hydrazinolysis, cyclization and alkylation to form 4-(4-nitro-phenyl)-2-alkyl-3H-l,2,4-triazol-3-one(IVa~d). Alternatively, the nucleo philic substitution of 4-chloro-nitrobenzene or 3,4-difluoro-nitrobenzene with methoxyl- phenyl-piperzines gave 4-(methoxyl-phenyl)-piperzine-nitrobenzenes (IVe~h). Served as the important intermediates, IVa~h gave (S)-5-hydroxy-methyl-3-[4-[ (2-alkyl-3H- l,2,4-triazol-3-one-4-yl) phenyl]]-oxazolidin-2-ones (VIIa~d) and (S)-5- hydroxyl- methyl -3-[4-[4-(methoxyphenyl)- piperzine -l-yl]-phenyl] - oxazo lidin-2-ones (VIIe~h) by the reduction of nitrocompounds followed by acylation, cyclization. (S)-5-acetylamino-3-[4-(2-alkyl-3H-1,2,4-triazol-3-one-4-yl)phenyl]-oxa zolidin-2-ones (XIa~d, XIi~k) and (S)-5-acetylamino-3-[4-[4- (methoxyphenyl)piperzine-l-yl]-phenyl] -oxazolidin-2-ones ( XIe~h ) were synthesized by methansulfonation of VIa~h, followed by reaction with sodium azide, reduction of the azides and acetylation.All the target compounds were tested in vitro against six Gram-positive and fourteen Gram-negative bacteria using serial two-fold dilution method. Some of them exhibited moderate activities against Gram-positive organism. The activities of Xlb and Xlg were more potent than those of others, but less than that of linezolid. The primary structure-activity relationship (SAR) showed that the antibacterial activities of the 5-acetylamino-methyl oxazolidinones were more potent than those of the corresponding 5- hydroxylmethyl analogues. Among the compounds XIa~d, the ethylated compound showed better antibacterial activity than the other alkylated derivatives. And the activities of fluoro-oxazolidinones XIg~h.were better than those of the non-fluoro compounds XIe~f.