Design,Synthesis And Biological Activity Of Novel Chromone-like PTP1B Inhibitors Bearing Thiazolidinedione Structure

Protein tyrosine phosphatase 1B（PTP1B）is an important target for the treatment of obesity and type II diabetes.It can induce insulin receptor（IR）dephosphorylation,which leads to the widespread expression of insulin resistance in various cells and tissues.Therefore,an in-depth study of PTP1B and its effective inhibitors is of great significance in the treatment of type II diabetes.In this work,three series of chromone derivatives containing thiazolidinedione structure were designed and synthesized by using chromone as the skeleton,using the principle of pharmacophore splicing,and the target derivatives with high activity were screened out by PTP1B activity test in vitro,and their structure-activity relationship was analyzed to determine their inhibition types and preliminary explore their mechanism of action.The research work is summarized as follows:1.Thirty-three chromone derivatives containing thiazolidinedione-amide structure were synthesized.The results of the PTP1B activity test showed that these derivatives had good PTP1B inhibitory activity.Among them,the compound FL-4-5 showed the best inhibitory activity of PTP1B,IC₅₀=1.40±0.04μM,and it was determined to be a reversible mixed inhibitor by kinetic experiments.The results of circular dichroism showed that the derivative could induce the secondary structure change of PTP1B,and the molecular docking results showed that the characteristic groups such as thiazolidinedione,chromone and amide in the structure were highly compatible with the active sites of PTP1B through hydrogen bonds.2.Thirty thiazolidinedione ethyl ester derivatives containing triazole-chromone structure were synthesized.Activity experiments showed that some derivatives showed good PTP1B inhibitory activity.Among them,the compound FL-5-28 has the best activity,IC₅₀=2.06±0.12μM,and is a reversible mixed inhibitor.The results of circular dichroism and molecular docking showed that the characteristic groups of the target derivative,such as triazole,chromone,thiazolidinedione and ester group,could interact with PTP1B and induce conformational changes of PTP1B,thus making it have good inhibitory activity.The results of the in vivo hypoglycemic activity test showed that the compound FL-5-28 can effectively reduce the fasting blood glucose level of diabetic mice without obvious drug side effects,improve glucose tolerance and reduce cholesterol and triglyceride levels in vivo.3.Thirty chromone ether derivatives containing triazole-thiazolidinedione structure were synthesized.The activity results showed that the inhibitory activity of these derivatives against PTP1B was improved.Among them,the compound FC-4-18 has the best activity,IC₅₀=0.10±0.005μM,and its activity is more than 10 times higher than that of ethyl ester derivatives,so it is a reversible mixed inhibitor.The results of circular dichroism and molecular docking showed that the trifluoromethyl in the structure of the compound FC-4-18interacted with PTP1B through a halogen bond,which changed the content ofα-helix,β-fold,β-rotation angle and random curl of PTP1B,and then made it have good enzyme inhibitory activity.The in vivo hypoglycemic activity test results showed that the compound FC-4-18had no significant effect on the body weight and food intake of diabetic mice.It can significantly reduce the fasting blood sugar level,improve glucose tolerance and reduce the levels of cholesterol and triglyceride in vivo.In this work,93 target derivatives were synthesized,and the structural characteristics and inhibitory types of PTP1B derivatives with high inhibitory activity were summarized.The study of the action mechanism shows that the highly active target derivatives can highly bind to the target protein PTP1B and induce its structural changes,thus having better PTP1B inhibitory activity,and can be used as hypoglycemic lead compounds for in-depth development and research.