含有芳杂环及酯基结构的1H-2,5-二氢-1,5-苯并二氮杂䓬类化合物的合成、抑菌活性及构效关系  

Synthesis,Antibacterial Activity and Structure-Activity Relationship of 1H-2,5-Dihydro-1,5-benzodiazepine with Ester Group and the Aromatic Heterocyclic Ring

作　　者：张秀君[1] 王兰芝[1] 闫婧怡[2] 高晨[2] Zhang Xiujun Wang Lanzhi Yan Jingyi Gao Chen(College of Chemistry ＆ Material Science, Hebei Normal University, Shijiazhuang 050024 College of Life Sciences, Hebei Normal University, Shijiazhuang 050024)

机构地区：[1]河北师范大学化学与材料科学学院,石家庄050024 [2]河北师范大学生命科学学院,石家庄050024

出　　处：《有机化学》2017年第2期462-473,共12页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.21276064);河北省自然科学基金(No.B2016205165)资助项目

摘　　要：以2-(2-噻唑基)-3-乙酯基-4-甲基-1H-2,5-二氢-1,5-苯并二氮杂?(A)为模型化合物,设计合成了3个系列30种1H-2,5-二氢-1,5-苯并二氮杂?类衍生物2~6,其结构通过核磁共振波谱、红外光谱、质谱和元素分析确证.采用常规滤纸片扩散法测试了其对真菌(新生隐球菌标准株、临床株、白色念珠菌标准株)和细菌(大肠杆菌标准株和金黄色葡萄球菌标准株)的抑菌活性.研究结果表明,大多数化合物对所测试的菌种都表现出很好的抑制作用,且抑真菌能力大于抑细菌能力;通过对活性较高的化合物2-(2-噻唑基)-3-乙酯基-4-乙基-8-甲基-1H-2,5-二氢-1,5-苯并二氮杂?(4b)和2-(2-噻唑基)-3-乙酯基-4-乙基-8-氟-1H-2,5-二氢-1,5-苯并二氮杂?(4c)的最小抑菌浓度(MIC)和最小杀菌浓度(MFC)测试,发现其对白色念珠菌的MIC和MFC都远低于标准药物氟康唑.进一步构效关系研究表明C-2位的2-噻唑基,C-4位的CH_3、CH_2CH_3和C-8位的CH_3都是该类化合物抑菌的必需基团.Using （ethyl 4-methyl-2-（thiazol-2-yl）-1H-2,5-dihydro-1,5-benzodiazepine-3-carboxylate） （A） as a model compound, thirty 1H-2,5-dihydro-1,5-benzodiazepine derivatives 2~6 were synthesized by nucleophilic addition reaction, elimination reaction and cyclization reaction. The structures of these new compounds were characterized by 1H NMR, 13C NMR, IR, MS and elemental analysis. The antibacterial activities of those compounds were screened using the disk diffusion method against C. neoformans, C. neoformans clinical isolates, C. albicans, E. coli and S. aureus. The bioactive assay results revealed that most of the 1H-2,5-dihydro-1,5-benzodiazepine derivatives exhibited considerable potency against all of the tested strains. In particular, some compounds exhibited excellent antimicrobial activities against the test microorganism MS except E. coli, and exhibited better antimicrobial activity against fungi than against bacteria. Furthermore, ethyl 4-ethyl-8-methyl-2-（thiazol-2-yl）-2,5-dihydro-1,5-benzodiazepine-3-carboxylate （4b） and ethyl 4-ethyl-8-fluoro-2-（thiazol-2-yl）-2,5-dihydro-1,5-benzo-diazepine-3-carboxylate （4c）, which had good antibacterial activities, were subjected to further pharmacological evaluation, including minimum inhibitory concentration （MIC）, minimum fungicidal concentration （MFC） and minimum bactericidal concentration （MBC） against C. neoformans, C. albicans, and S. aureus. The results showed that the MIC and MFC against C. albicans values for above compounds were much lower than those of fluconazole. A further study of the structure-activity rela-tionship revealed that the thiazole ring at C-2, the methyl, ethyl at C-4 and the methyl at C-8 are essential for antibacterial activity.

关 键 词：1H-2 5-二氢-1 5-苯并二氮杂䓬 合成 表征 抑菌活性 构效关系 

分 类 号：O626[理学—有机化学]