Multiple work has convincingly demonstrated that glycemic fluctuation is more deleterious than chronic sustained hyperglycemia as a key factor in contributing to diabetes and related complications. The α-glucosidase inhibitors reduce glucose fluctuations by inhibiting postprandial hyperglycemia and appear powerful therapeutic in controlling postprandial hyperglycemia in Asian people because of their specific food habits. Discovery of α-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of diabetes and related complications. In this study,a series of N-aromatic substituted-5-(p--toluenesulfonylamino) phthalimide derivatives were designed based on the pharmacophore model of a-glucosidase inhibitors. The target compounds were synthesized with phthalimide as the starting material. Treatment of phthalimide with nitric acid gave 5-nitrophthalimide, which was reacted with different aromatic halo-genated hydrocarbons to afford N-substituted-5-nitrophthalimide and followed by reduction of formamide o-ver Pd/C catalyst and sulfonylation with p-toluenesulfonic acid. The substituted moiety in compounds N-[ (3,4-dihydroxyphenyl)methyl]-5-nitrophthaUmide and N-[ (3-hydroxy-4-hydroxyformylphenyl) methyl]-5-nitrophthalimide were produced by reaction of 5-nitrophthalimide and formaldehyde to afford Af-hydroxym-ethyl-5-nitrophthalimide,which was coupled with catechol and salylic acid respectively. Thirteen target compounds were obtained and their structures were confirmed by 1H-NMR and MS data. The a-glucosidase inhibitory activity of the target compounds was evaluated on yeast a-glucosidase. All of them show obvious α-glucosidase inhibitory activity with much lower IC50, value than that of acarbose. Molecular docking analysis revealed that 5-(p-toluenesulfonamino) phthalimide scaffold is able to bind with amino acids of the active site through forming multiple H-bond and hydrophobic interactions. The N-substituted moiety can also interact with protein by forming H-bond or hydrophobic force,which may impact the intension of the inhibitory activity of compounds. The toluenesulfonylamino phthalimide may be further optimized and other class of α-glucosidase inhibitors may be designed according to the results of this study.%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.
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