Design,Synthesis And α-Glucosidase Inhibitory Activity Of Novel Indole Derivatives

α-glucosidase is a kind of starch hydrolase,which releases absorbable glucose by hydrolyzing polysaccharide glycosidic bond,thus regulating the level of sugar metabolism in human body.By inhibitingα-glucosidase activity,α-glucosidase inhibitors delay the breakdown rate of starch in the gut,thus reducing the level of postprandial blood glucose.α-glucosidase inhibitors are important clinical drugs for type Ⅱ diabetes.Although it can effectively reduce the blood sugar level of patients,it also has the disadvantage of causing side effects such as abdominal pain and diarrhea.Therefore,the development of novelα-glucosidase inhibitors with high efficiency has attracted much attention.Indole and its derivatives are important natural products with extensive pharmacological activities,especiallyα-glucosidase inhibitory activities.Several of indole derivatives with goodα-glucosidase inhibitory activity were previously designed and synthesized by our previous research group.Therefore,indole can be used as a natural skeleton having a broad of biological activities for the development ofα-glucosidase inhibitors.In this study,indoles were taken as the core framework,Thiazolidinedione and Acylhydrazone were introduced into the indole structure.Based on this strategy,three types of compounds was designed and synthesized:tryptamine-thiazolidinedione derivatives（1b～28b）;indole-3-thiazolidinedione derivatives（1e～27e）and indole-diacylhydrazone derivatives（1f～22f）.Finally,77 indole derivatives were obtained.The indole derivatives were characterized by ¹H NMR,¹³C NMR and HMRS,and their hypoglycemic activities were studied in vivo and in vitro.The results ofα-glucosidase inhibition in vitro showed that:Compounds 1b～28b,1e～27e and 1f～22f all showed good inhibitory effects.IC₅₀values ranged from 2.35±0.06μM to23.82±0.11μM,5.11±0.08μM to 73.26±0.19μM,and 1.01±0.26μM to 134.62±8.91μM.Compounds 4b,14e and 10f showed the best inhibitory activity,which were 2.35±0.06μM,5.11±0.08μM and 1.01±0.26μM.Further studies on the inhibition mechanism showed that compound 4b and 10f were reversible and mixed-type inhibitors againstα-glucosidase,while compound 14e was reversible andnon-competitive inhibitors.The results of CD spectroscopy,three dimensional fluorescence spectrometry and Simulation docking demonstrated the interaction between analogues andα-glucosidase from different aspects.In vivo hypoglycemic activity test results showed that compound 4b,14e and 10f were administered at doses of 50 mg/kg and 100 mg/kg,and there was no significant difference in body weight and food intake of diabetic mice,but they could significantly reduce the fasting blood glucose level and oral glucose tolerance of diabetic mice.Compared with the model group,the administration group could effectively reduce the levels of glucose tolerance,total cholesterol,triglyceride and improve the symptoms of type Ⅱ diabetes mice.Therefore,these compounds can be used as leading compounds for the development of hypoglycemic drugs.