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目的寻找具有新型结构的α-糖苷酶抑制剂类降血糖药物。方法 N-取代-5-对甲苯磺酰氨基酞酰亚胺类目标化合物(Ⅰ1～Ⅰ8)以邻苯二甲酰亚胺为起始物,经硝化后,通过烃化反应在亚胺氮上引入含芳基的不同取代结构,再经还原及磺酰化反应合成;N-取代结构的苯环上含有酚羟基的目标化合物(Ⅱ1～Ⅱ3)采用乙酰化保护后再进行还原及磺酰化、去保护基等步骤制得;目标化合物Ⅱ4和Ⅱ5的合成是以5-硝基酞酰亚胺为原料,先与甲醛反应,在亚胺氮上引入羟甲基,再与酚性结构进行偶联反应引入相应取代基,最后经还原及磺酰化制得。采用4-硝基苯-α-D-吡喃葡萄糖苷反应体系对目标化合物的α-糖苷酶抑制活性进行评价;采用计算机辅助药物设计软件进行分子Docking分析。结果合成了13个未见报道的新化合物,其结构经MS及1H-NMR谱确证。所有目标化合物对酵母α-糖苷酶均表现出明显的抑制活性,其IC50值小于阳性药物阿卡波糖(Acar);Docking分析显示,5-对甲苯磺酰氨基酞酰亚胺与酶活性催化位点的氨基酸残基能形成多个氢键,N-取代结构以疏水作用或氢键与酶分子产生相互作用而影响酶活性。结论 5-对甲苯磺酰氨基酞酰亚胺结构是产生α-糖苷酶抑制活性的有利结构,亚胺氮原子上取代结构对抑酶活性有重要影响,此结果得到分子对接分析的支持。
Aim To find a hypoglycemic drug with a novel structure of α-glycosidase inhibitor. Methods N-substituted-5-p-toluenesulfonylamidophthalimides target compounds (Ⅰ1 ~ Ⅰ8) phthalimide as a starting material, after nitration, by alkylation on the imine nitrogen The different substituted structures containing aryl groups were introduced and then synthesized by reduction and sulfonylation. The target compounds (Ⅱ1 ~ Ⅱ3) containing phenolic hydroxyl group on the N-substituted structure were protected by acetylation and then reduced and sulfonylated , To protect the base and other steps obtained; Synthesis of the target compounds Ⅱ 4 and Ⅱ 5 5-nitro phthalimide as raw material, first with formaldehyde, the introduction of hydroxylamine imine nitrogen, and then with the phenolic structure Coupling reaction to introduce the corresponding substituent, the final reduction and sulfonylation obtained. The 4-nitrobenzene-α-D-glucopyranoside reaction system was used to evaluate the α-glycosidase inhibitory activity of the target compounds. Molecular Docking analysis was performed using computer-aided drug design software. Results Thirteen novel compounds were synthesized and their structures were confirmed by MS and 1H-NMR. All the target compounds showed obvious inhibitory activity on yeast α-glucosidase with IC50 value less than that of Acar. Docking analysis showed that 5-p-toluenesulfonylaminophthalimide reacted with enzyme activity catalysis Amino acid residues at the site can form multiple hydrogen bonds, and the N-substituted structure interacts with the enzyme molecules through hydrophobic interaction or hydrogen bonding to affect enzyme activity. Conclusion The 5-p-toluenesulfonamidophthalimide structure is a favorable structure for producing α-glucosidase inhibitory activity. The substituted structure of imine nitrogen atom has an important effect on the enzyme inhibiting activity, and the result is supported by the molecular docking analysis.