具有手性吡咯烷侧环的噁唑烷酮类化合物的合成及抗菌活性研究

目的 设计合成具有手性吡咯烷侧环的噁唑烷酮类化合物，并考察其体外抗菌活性。方法 以手性脯氨酸和3,4-二氟硝基苯为原料，通过多步反应合成目标化合物；采用微量液体稀释法检测目标化合物的抗菌活性。结果与结论 合成了 8 个新化合物，其结构经 ¹H-NMR、MS 谱确证。体外活性试验表明：由（R）-脯氨酸衍生的化合物7b 对革兰阳性菌[金黄色葡萄球菌、表皮葡萄球菌以及耐甲氧西林金黄色葡萄球菌（MRSA）具有良好的抑制活性，对革兰阴性菌具有较弱的抑制活性。由（S）-脯氨酸衍生的化合物 7a 的抗菌活性明显低于 7b。研究结果表明，吡咯烷侧环的手性因素对抗菌活性具有显著影响。

Synthesis and antibacterial activity of new oxazolidinones with chiral pyrrolidine side ring

Oxazolidinone antibacterials are a new class of synthetic antibacterials for the treatment of drug-resistant Gram-positive pathogen infections.Linezolid is the first clinically approved oxazolidinone antibacterial.To improve the antibacterial spectrum of linezolid and decrease its side effects,further structural modifications are highly desirable.In this study,a series of new oxazolidinones with kept chiral pyrrolidine were designed and synthesized.These compounds were prepared starting from(R)-proline and(S)-proline respectively.The structures of eight new compounds 3a,4a,6a,7a and 3b,4b,6b,7b were characterized by 1H-NMR and MS.Their in vitro antibacterial activities were determined by broth dilution method.(R)-Proline derived compound 7b showed good inhibitive activity(MIC=1~8 μg · mL-1) against Gram-positive bacteria,including Staphylococcus aureus,Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus(MRSA).Weak inhibitive activities against Gram-negative bacteria were observed for compound 7b.The corresponding methyl ester 6b showed lower antibacterial activity against both Gram-positive and Gram-negative bacteria.Compounds 3b and 4b were found to have poor antibacterial activity.On the other hand,the analogous compounds 3a,4a,6a,7a derived from(S)-proline are significantly less active against Gram-positive and Gram-negative bacteria.The results demonstrate that the chirality of C-ring of oxazolidinone antibacterials exerts significant effect on the antibacterial activity.