Synthesis And Antibacterial Activity Of Bis-Oxazolidinones And 5-Substituted Ethyl Oxazolidinones

Multi-drug-resistant pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci(VRE) and multi-resistant Mycobacterium tuberculosis caused 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 the drug-resistant pathogens.In order to investigate the structure-activity relationship of the oxazolidinones and to get new potent compounds for further research, 1,4-bis[4-(5-substituted methyl-2-oxazolidinonyl-3)-phenyl]piperazine and 1,4-bis(5-substituted methyl-2-oxazolidinonyl-3)benzene derivatives (compounds A) and 5-(substituted ethyl)-3-[4-(morpholinyl-4)-3-fluorophenyl]-2-oxazolidinones (compounds B) were designed and synthesized. The structure of compounds A was characterized by bis-oxazolidinone and compounds B had the substituted ethyl at position 5 in oxazolidinone. The new chemical synthesis for the structural modification of oxazolidinones was developed. 14 New compounds were prepared and their structures were confirmed by ¹HNMR and elemental analyses or MS. Some physical and chemical constants such as [ α ] were determined as well.Phenylene diamines were condensed with R-glycidyl butyrate, followed by cyclization to form the bis-oxazolidinones A_1-2. A_3-4 were obtained by hydrolysis of A_1-2. A_3-4 were converted into A_5-6 by methanesulfonation, substitution with sodium azide, reduction and acetylation(/?)-5-Methanesulfonyloxymethyl-3-[4-(morpholinyl-4)phenyl]-2-oxazolidinone(27) was reacted with the nucleophilic reagents such as diethyl malonate and methyl acetoacetate to give B|, Bi, B5, B7 and Bg. By decarboxylation or hydrolysis, Bj, B4 and B6 were obtained from Bi and B5.13 Target compounds were screened in vitro against six Gram-positive and fourteen Gram-negative bacteria by the serial two-fold dilution method. The result showed that 5 compounds (A3,As,B45Bs and B7) among these 13 had the equivalent or better activity against Staphylococcus enteridis than linezolid and compound A3 was more active than the control against Staphylococcus enteridis, Staphylococcus epidermidis and Staphylococcus nonhemolyticus.