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设计合成了7个栀子酰胺A(GA)-他克林杂合物.首先以京尼平为原料,经5步反应合成10-栀子酰胺A醛(DG),总收率20.4%;再以邻氨基苯甲酸甲酯为原料,经4步反应合成N-末端氨基烷基他克林(TN-n),总收率50.0%~65.4%;随后,DG与TN-n在合适的还原剂作用下还原胺化获得目标化合物,收率37%~54%.所有目标产物的结构均由1H NMR,~(13)C NMR和ESI-MS确证.同时建立了六羟多巴胺(6-OHDA)诱导损伤的PC12细胞模型对系列杂合物进行生物活性评价.发现杂合物TNG-1和TNG-5具有比他克林、GA及其联合用药更好的神经保护作用,推测这两个杂合物可能具有比单体药物更好的类药性.
Seven GAA-tacrine hybrids were designed and synthesized.Using genipin as raw material, 10-Gardenia amide A aldehyde (DG) was synthesized in 5 steps with the total yield of 20.4%. N-terminal aminoalkyl tacrine (TN-n) was synthesized by 4 steps using methyl anthranilate as raw material, and the total yield was 50.0% ~ 65.4%. Then, DG and TN-n Reductive amination with a reducing agent to obtain the target compound in 37% ~ 54% yield.The structures of all the target compounds were confirmed by 1H NMR, 13 C NMR and ESI-MS.At the same time, OHDA) -induced PC12 cell model to evaluate the biological activity of a series of hybrids.It was found that the two compounds TNG-1 and TNG-5 had better neuroprotective effects than tacrine, Heterozygotes may have better drug-like properties than monomeric drugs.