Design,Synthesis Research Of The Novel Insulin Sensitizers Indoles Carboxylic Acids Based On Target AMPK

Objective Type 2 diabetes mellitus and metabolic syndrome have become an increasing health risk. There is an urgent need for research to improve insulin resistance and hyperglycemia drugs. However, In recent years looking for diabetes-related targets is the research hotspots field of diabetes The AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade, which participate in the regulating of glucose metabolism, lipid metabolism, protein metabolism and cardiovascular and plays a key role in energy sensing. Therefore, the synthesis of novel compounds that can stimulate AMPK target is an important research field about anti-type 2 diabetes drugs. Methods In previous study, project team found compounds of GY3, ZG05 had better activity of insulin-sensitizing. In this thesis, firstly, we determined the structural optimization direction of GY3 through computer-aided drug design. Secondly, we used GY3, ZG05 as the lead compound, the following research areas was conducted:1.?1-amide bond of the indole ring of GY3 was transformed in structure, seven compounds were designed. ?. On the basis of the reduction of the 2,3-double bonds, one compound were designed. ?. After extension of 3-carbon chain of the acid,1-amide bond was transformed and 5 compounds were designed. ?On the basis of the reduction of the 2,3-double bonds, 3-carboxylic acid was transformed and 17 compounds were designed.2. All the compounds synthesized by using glucose consumption experiments of HepG2 cells were determined whether the compounds have insulin-sensitizing activity.3.Three dimensional space configuration of synthetic compounds and AMPK receptor is docked.Results In summary, four research lines were designed and 30 compounds were synthesized in this thesis, all the compounds were synthesized for the first time.Conclusion By interaction model of ligand and receptor, whether as agonist of AMPK, The interaction of GY3 and its derivatives and the receptor mainly concentrated in the combined with pockets of amino acid Lys45, Asn67, Cys130, Arg138, Leu140, Lysl41, Ile155 above these binding sites, hydrogen bonding interaction is mainly produced in carboxyl and benzene ring of the ligand molecules, hydrophobic effect is mainly produced in the indole ring and methyl of indole ring. The study may provide a theoretical guidance and candidate for research and development of anti-type 2 diabetes drug in the future.