新型吲哚-2-甲酰胺衍生物的设计、合成及抗炎活性研究

Design,synthesis,and anti-inflammatory activity research of novel indole-2-carboxamide derivatives

目的设计合成一系列吲哚-2-甲酰胺衍生物,并考察目标化合物体外抗炎活性。方法以2-氨基噻唑-4-甲酸乙酯盐酸盐、2-溴-3′-硝基苯乙酮和5-硝基-1H-吲哚-2-甲酸乙酯为起始原料,经过成环反应、氨基还原、酯基水解、缩合反应和N-烷基化等反应合成9个目标化合物,并测试所有目标化合物对脂多糖诱导RAW264.7细胞一氧化氮、肿瘤坏死因子(TNF-α)和白细胞介素(IL-6)释放的影响。结果与结论合成了9个目标化合物,其结构均经^(1)H-NMR、^(13)C-NMR和HR-MS谱确证。体外抗炎活性试验表明,目标化合物对LPS诱导RAW264.7细胞一氧化氮、TNF-α和IL-6的释放都有显著抑制作用。其中,目标化合物14g具有较好的抑制活性,可能对治疗炎症性疾病有一定的作用,有进一步研究的价值。

Derivatives of indole and imidazo[2,1-b]thiazole have been reported to exhibit diverse biological activities,which include anti-tumor,anti-inflammatory,anti-microbial,anti-tuberculosis effects,and the ring of indole and imidazo[2,1-b]thiazole are their pharmacophore.In order to further develop anti-inflammatory drugs with high efficiency and low toxicity,this study took the ring of indoles and imidazo[2,1-b]thiazole as the main skeleton.The nine new N-1-substituted derivatives of indole-2-carboxyamide-phenylimidazole[2,1-b]thiazole(13,14a-14h)were synthesized by cyclization,amino reduction,ester hydrolysis,dehydration condensation and acyl chloride substitution,which are screened for their anti-inflammatory activities in RAW 264.7 macrophages.A majority of these derivatives effectively inhibited lipopolysaccharides(LPS)-induced expression of nitric oxide(NO),tumor necrosis factor alpha(TNF-α)and interleukin-6(IL-6).Among them,14g was found to effectively reduce LPS-induced over expression of a series of inflammatory mediators,and the inhibition rates were 57.79%,76.00%and 49.09%,respectively.Preliminary structure-activity relationship analysis was also conducted.The results indicate N-benzylation compounds had a positive anti-inflammatory effect,in which the types and position the electrophilicity of the substituent on the benzyl group had potential effects on anti-inflammatory effect,which was worthy of further exploration.