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 antiHIV-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-Bocpiperidine-4-carboxylic acid, N-Boc-pyrro-3-carboxylic acid and N-Boc-ethylenediamine were coupled with theamine 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 I 1 - I 15. 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.
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