含双环哌啶结构HIV-1抑制剂的设计合成及生物活性研究  

Design,synthesis and biological activity of bicyclic piperidine-based HIV-1 inhibitors

作　　者：毛文祥[1,2] 董铭心[2] 朱卫国[1] 姜世勃[3] 戴秋云[2] 

机构地区：[1]湘潭大学化学学院,湖南湘潭411105 [2]军事医学科学院生物工程研究所,北京100071 [3]复旦大学上海医学院分子病毒学教育部/卫生部重点实验室,上海200032

出　　处：《中国药物化学杂志》2011年第3期169-177,共9页Chinese Journal of Medicinal Chemistry

基　　金：“重大新药创制”科技重大专项(2009ZX09103-628,2009ZX09301-022);国家自然科学基金项目(81072676)

摘　　要：目的设计合成一系列具有新型结构特征的双环哌啶类C-C族趋化因子受体5(CCR5)抑制剂并测定其抗HIV-1活性。方法以HIV-1辅助受体CCR5抑制剂Vicriviroc的结构为模板,通过改变左侧哌嗪结构、取代基位置等方法设计并合成一系列新化合物。并利用MS及1H-NMR谱对这些化合物进行结构表征。结果与结论合成了15个新结构化合物,活性测试结果表明,该系列化合物具有较强的抗HIV-1 R5病毒株的活性(IC50=1.20～66.24μmol.L-1)。当R1为芳基结构且两个氮原子满足标准的丙二胺结构时,化合物的活性更好。CCR5 is a major co-receptor for HIV-1 entry into human cells and is also a good target for anti-HIV-1 drug design.Based on the chemical structure of Vicriviroc,a CCR5 antagonist,a series of new compounds were designed by changing its piperazine loop and other group substitutions.In the present study,15 bicyclic piperidine-based compounds were synthesized using a convergent synthetic route,and the structures of the target compounds were confirmed by MS and 1H-NMR.The synthetic routes were as follows：N-Boc-piperidine-4-carboxylic acid,N-Boc-pyrro-3-carboxylic acid and N-Boc-ethylenediamine were coupled with the amine derivatives to give the corresponding compounds 1a-1d,2a-2c,3a-3c,4-piperidinone hydrochloride reacted with 2,6-dimethylbenzoyl chloride,2,6-dichlorobenzoyl chloride and 2,4,6-trimethyl-5-pyrimidine carbonyl chloride to obtain the compounds 4a-4c.Then 4a-4c was reacted with 1a-1d,2a-2c,3a-3c to give the target compounds Ⅰ1-Ⅰ15.Furthermore,the antiviral activity and cell cytotoxicity of these compounds were evaluated with HIV-1 R5 strain in vitro.The results showed that all the target compounds exhibited potent antiviral activity against HIV-1 R5 strain（IC50=1.20-66.24 μmol · L-1）.Preliminary analysis of the structure-activity relationship showed that some compounds with an aryl group and the 1,3-diamino-propane structure between two N atoms exhibited improved anti-HIV-1 activity.This study provides several clues for designing new anti-HIV-1 fusion inhibitors.

关 键 词：CCR5 HIV-1 抑制剂 合成 

分 类 号：R914[医药卫生—药物化学]