新型7-苯甲酰基中氮茚-1-羧酸乙酯类化合物的合成及HIV-1病毒感染因子抑制活性研究  

Synthesis and anti-HIV-1 VIF activities of novel ethyl 7-benzoylindolizine-1-carboxylate derivatives

作　　者：顾海东[1] 黄文林[1] 夏杰[1] 左陶[2] 张亮仁[1] 于湘晖[2] 

机构地区：[1]北京大学医学部天然药物及仿生药物国家重点实验室,北京100191 [2]吉林大学生命科学学院艾滋病疫苗国家工程实验室,吉林长春130012

出　　处：《中国药物化学杂志》2012年第6期459-468,共10页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金面上项目(20972009)

摘　　要：目的设计合成7-苯甲酰基中氮茚-1-羧酸乙酯类化合物,并对其抗HIV-1活性进行初步研究。方法以异烟酸、溴乙酸苄酯、丙炔酸乙酯为原料,经取代、Friedel-Crafts反应、1,3-偶极环加成反应、水解、缩合得到目标化合物;采用荧光筛选方法对目标化合物抗HIV-1病毒感染因子(viral infectivity factor,VIF)活性进行评价。结果共合成30个未经文献报道的新化合物,其结构经1H-NMR、13C-NMR、HRMS确证;活性结果表明,化合物30、31、36、37等4个化合物抗HIV-1活性与先导化合物相当。结论 7-苯甲酰基中氮茚-1-羧酸乙酯类化合物作为HIV-1 VIF复合物抑制剂,中氮茚环与取代芳环之间含3～4个原子长度为保持活性所必须,进一步的构效关系值得继续研究。VIF is one of the six accessory proteins of HIV-1, which plays an important role in surviving and remaining infectious in the body. VEC-5 is a novel HIV-1 VIF inhibitor. We made structural modifications on VEC-5 to improve the water solubility, and to explore the structure-activity relationships. Starting from isonicotinic acid via Friedel-Crafts reaction, 1,3-dipolar cycloaddition reaction and amidation, totally 30 ethyl 7-benzoylindolizine-l-carboxylate derivatives were synthesized and all of them were not reported yet, and their structures were confirmed by MS, 1H-NMR and 13 C-NMR. The in vitro inhibitory activity of the synthe- sized compounds was evaluated via fluorescent screening method. All of the tested compounds show diverse inhibitory activity,among which the compounds 30,31,36 and 37 have the inhibitory activity equivalent to VEC-5. The distance between the indolizine and aromatic ring is very important. Three or four atomic length distance between indolizine and aromatic ring can produce the best inhibitory activity.

关 键 词：中氮茚 HIV-1VIF 化学合成 抗艾滋病活性 

分 类 号：R914.5[医药卫生—药物化学]