新型大黄酸酯衍生物的合成与生物活性研究  

Synthesis and Bioactivity of Novel Ester Derivatives of Rhein

作　　者：杨家强 赵仕新 安家丽 邓玲 雷廷燕 YANG Jia-qiang;ZHAO Shi-xin;AN Jia-li;DENG Ling;LEI Ting-yan(School of Pharmacy, Zunyi Medical University, Zunyi 563003, China)

机构地区：[1]遵义医科大学药学院

出　　处：《中国药学杂志》2019年第15期1216-1220,共5页Chinese Pharmaceutical Journal

基　　金：贵州省科技厅国际合作项目资助(黔科合外G字[2014]7013);贵州省中医药管理局中医药、民族医药科学技术研究项目资助(QZYY[2018]085);遵义市汇川区科技局资助项目(E-123)

摘　　要：目的为了寻找抗耐甲氧西林金黄色葡萄球菌(MRSA)候选化合物,采用基于片段的药物发现(FBDD)方法,设计合成新型大黄酸酯衍生物,评价其生物活性。方法以大黄酸与α-羟基膦酸酯中间体为原料,通过EDCI/HOBT和[Bmim] BF4体系协同催化,合成目标化合物;采用两倍稀释法对目标物进行体外抗MRSA活性筛选。结果合成了10个结构新颖的大黄酸酯衍生物,经IR、NMR和MS确认结构;活性测试结果表明,该类化合物对所测MRSA有不同程度的抑制活性,其中化合物Ⅱ-3对所测MRSA的MIC和MBC值分别为128和512 μg·mL-1,优于天然产物大黄酸的抗MRSA活性,略优于对照药苯唑西林的抗MRSA活性;活性最突出的是化合物Ⅱ-10,对MRSA的MIC和MBC值分别为32、64 μg·mL-1,抗MRSA活性明显优于大黄酸和对照药苯唑西林。结论该类大黄酸衍生物对MRSA的抑制活性显著,值得进一步深入研究。OBJECTIVE To design and synthesize a series of novel ester derivatives of rhein were designed and synthesized, and evaluate their anti-MRSA activity. METHODS The title compounds were synthesized with rhein and α-hydroxyphosphonate as starting materials, EDCI/HOBT and [Bmim] BF4 as catalyst system. And the anti-MRSA activities of the products were evaluated by the agar dilution method. RESULTS Ten title compounds were synthesized,and their structures were clearly established by IR, NMR and MS. The RESULTS showed that the derivatives have different anti-MRSA activity. Especially, showed potent activity against MRSA with the minimum inhibitory concentration(MIC) and minimum bactericidal concentration(MBC) values of compound Ⅱ-3 was 128, 512 μg·mL-1 respectively,superior to rhein and oxacillin. And the MIC and MBC of compound Ⅱ-10 to MRSA was 32, 64 μg·mL-1, its anti-MRSA activity was obviously better than that of rhein and oxacillin. CONCLUSION The ester derivatives of rhein are significant resistant to MRSA, which is worth for further study.

关 键 词：大黄酸 膦酸酯 合成 抗菌活性 

分 类 号：R914[医药卫生—药物化学]