Discovery Of α-glucosidase Inhibitors And Anti-diabetes Candidates

Diabetes has become one of the chronic diseases whose society morbidity continues to rise.According to the estimate of World Health Organization（WHO）,there will be up to642 million diabetes in the next 20 years,which account for about 10 percent of the global population.However,Natural products were considered as vital source of drugs and lead compounds due to their novel structures,variable activitis,and low toxicity.Furthermore,more than half of the small molecule drugs approved by the FDA for marketing came from natural products and their derivatives.In this dissertation,a series of acetophenone derivatives were designed and synthesized based on the target of glucose-lowering—with2,4-dihy droxyacetophenone as template which was a natural product with hypoglycemic activity-Combining with the structure-activity relationship pre-existing in our lab.The structures of compounds were verified by MS and NMR;and vitro inhibitory activity on yeast-derivedα-glucosidase of them were evaluated.Compound 3t showed significant inhibitory activity againstα-glucosidase(IC₅₀=1.69±0.17Μm)comparing with standard acarbose(IC₅₀=57.01μM).The result of structure-activity relationship indicated that the long linear alkyl group at theα-position and the esterification of iodomethyl at the4-position in the benzene ring could significantly enhance the inhibitory activity againstα-glucosidase,and according to enzyme kinetic studies,compound 3t showed noncompetitive inhibition toα-glucosidase.What’s more,the interaction mode between compounds and allosteric site of the enzyme were predicted using visual molecular docking technology.Most importantly,the inhibitory activity of compound 3t on ratα-glucosidase was further demonstrated by vitro parenteral inversion experiments,and vivo sucrose loading tests proved that they had obvious postprandial hypoglycemic effects.Besides,compound 3t also had druggability and less cytotoxicity,which further confirmed that the framework had the potential to be developed as anα-glucosidase inhibitor.In addition,the vitro antifungal and antibacterial activity o f compounds were evaluated,and the results showed that numerous derivatives exhibited moderate vitro inhibitory activity against Magnaporthe grisea;Compound 2b displayed eminent inhibitory activity against Cytospora sp(EC₅₀=8.6±0.3μg/m L),which was better than the commercially available drug-Hymexazol(EC₅₀=18.41±0.84μg/m L).Compounds 3t and 2c showed noteworthy inhibitory activity against Staphylococcus aureus and its resistant strains,with IC₅₀values ranging from 3.125 to 6.25μM.Among them,the inhibitory effect of Compound 2c on Staphylococcus aureus（MIC=3.125μM）was equivalent to the selected positive drug ampicillin sodium（MIC=3.125μM）,but the inhibitory effect on its resistant strain MRSA（MIC=6.25μM）was better than ampicillin sodium（MIC=50μM）.In summary,the inhibitory activity of acetophenone derivatives onα-glucosidase were systematically evaluated and the antibacterial activity was evaluated preliminary in this work,which could enrich the library of candidate lead compounds and biological diversity of compounds,and also provide theoretical support for the development of small molecule drugs based on the acetophenone skeleton.