具有手性吡咯烷侧环的唑烷酮类化合物的合成及抗菌活性研究  

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

作　　者：殷霞[1] 肖国强[1] 侯怀信 鄢明[1] 

机构地区：[1]中山大学药学院,广东广州510006 [2]珠海亿邦制药有限公司,广东珠海519040

出　　处：《中国药物化学杂志》2012年第3期177-183,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(21172270);珠海市科技计划项目(PC20081006)

摘　　要：目的设计合成具有手性吡咯烷侧环的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34,-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。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.

关 键 词：唑烷酮 手性侧环 化学合成 利奈唑胺 抗菌活性 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]