Design,Synthesis And Anti-Diabetic Activity Evaluation Of Thiazolidinediones Based On Molecular Fragments

Currently,patients suffered from diabetes have increased year by year,and tend to be younger.Diabetes mellitus,mainly type 2 diabetes,is a chronic metabolic disease.It can lead to serious complications,such as diabetic nephropathy,diabetic retinopathy,cardiovascular disease and diabetic foot,etc.One of the main causes of type 2 diabetes is insulin resistance(IR).The body decreases sensitivity to insulin,which causes imbalance of glucose metabolism.Thereinto,PPARγ is one of the key target for insulin resistance.After activation,it promotes gene transcription and translation,and expesses regulatory protein which regulates the metabolism of living matter,thereby enhances the ability of cells to insulin response.However,PPARγagonists are currently used,such as rosiglitazone and pioglitazone etc.,toxicity greater application is limited,and therefore developing new PPARγ agonist drugs is urgent.Objective:1.Design novel PPARγ agonists based on computer-aided drug design(CADD)combined fragments genomics;2.Analyze the structures of PPARγ agonists and synthesis lead compounds;3.Evaluate antidiabetic compounds of PPARγ agonists.Methods:1.According to PPARγ protein crystal structures,the file was downloaded in the PDB database.Perform virtual screen in drugbank database by Discovery Studio3.0(DS3.0),Sybyl X-2.0 software Libdock,CDOCKER and Surflex-Dock docking module,and analyze data to select the best lead compounds;2.Accoring to the structure,reversely synthesis the lead compounds of PPARγ agonist candidates;3.Induce rat model of type 2 diabetes Construction Sprague-Dawley(SD)by feeding high fat,sugar diet and intraperitoneal injection of streptozotocin(STZ);4.Type 2 diabetic rats were given by gavage,and set the normal group,positive group and solvent control group.After gavage,measure the fasting plasma glucose of all rats.After the end of the experiments,the rats were bled,and were removed the liver,pancreas dirty,kidney,skeletal muscle and adipose tissue.Determine their physiological indices,and made the paraffin sections,finally observe the pathological changes;5.Use ELISA methods to measure type 2 diabetic rat serum insulin levels and the expression serum contents of PPARγ protein which were dosed 0701 C,0702C and rosiglitazone.Results:1.Obtain high scoring compounds 07 C,0701C and 0702 C through virtual screening;2.Synthesis target compounds 07 C,0701C and 0702C;3.Successful rate of type 2 diabetic SD rat model is 68.2%;4.During fasting plasma glucose measuring experiment,0702 C can significantly reduce the values of blood glucose at 10mg/kg concentration,and the optimal concentration of 0701 C is 10mg/ kg in SD rat model of type 2 diabetes;5.Reduce serum TG and TC content;6.Reduce serum insulin levels;7.Improve diseased pancreas organ,and liver toxicity of the compounds is not obvious;8.The serum expression of PPARγ protein is increased,and the protein expression increase relatively with the administration concentration.Conclusion:Lead compounds have anti-diabetic activity,and they can reduce serum TG and TCH content effectively.The compounds may improve pancreas organ lesions.Among them,0701 C compound is the best one.The effect of 0701 C reflects the advantages of fragment of genomics,which illustrates that this method of drug design is reasonable.However,the mechanism is relatively brief,and byproduct are found having potential activity of,therefore the future research is necessary.