1-苯甲酰基-4-(4-氯苄基)哌嗪衍生物的设计、合成以及抗炎活性研究

目的:以1-苯甲酰基-4-(4-氯苄基)哌嗪为先导化合物,经进一步的结构优化,期望获得一类抗炎活性更好的多靶点抑制剂。方法:以取代苯甲酸为起始原料,经取代、酰化反应合成18个目标化合物。测定所有化合物对脂多糖(lipopolysaccharide,LPS)诱导RAW264.7细胞分泌肿瘤坏死因子(tumor necrosis factor,TNF)-α和白细胞介素(interleukin,IL)-6的抑制作用,并对活性较好的化合物进行分子对接。结果:所有化合物均经¹H NMR,¹³C NMR,HRMS确定其结构,化合物3d,8k对TNF-α的分泌具有较好的抑制活性,化合物3b,3d对IL-6的分泌具有较好的抑制活性。结论:化合物3d对LPS诱导RAW264.7细胞分泌TNF-α和IL-6具有较好的抑制活性,有进一步研究的价值。

Design,synthesis and anti-inflammatory activity research of 1-benzoyl-4-(phenoxyacetyl)piperazine derivatives

Objective:To obtain a series of multi-target inhibitors with better anti-inflammatory activity by using 1-benzoyl-4-(phenoxyacetyl)piperazine as the lead compound followed by further structure optimization.Methods:Substituted benzoic acid was used as a starting material,and 18 target compounds were synthesized through substitution and acylation reactions.The inhibitory effects of all compounds on lipopolysaccharide(LPS)-induced tumor necrosis factor(TNF)-αand interleukin(IL)-6 secretion in RAW264.7 cells were measured,and molecular docking was performed on the compounds with better anti-inflammatory activity.Results:The structures of all the compounds were confirmed by¹H NMR,¹³C NMR and HRMS.Compounds 3 d and 8 k demonstrated better inhibitory activity on TNF-αsecretion,and compounds 3 b and 3 d showed better inhibitory activity on IL-6 secretion.Conclusion:Compound 3 d has good inhibitory activity on TNF-αand IL-6 secretion in RAW264.7 cells induced by LPS,and is worthy of further study.