Synthesis,Biological Evaluation,and Mole Cular Docking Study Of Novel Allyl-retr Ochalcones As A New Class Of Protein Tyrosine Phosphatase 1B Inhibitors

Diabetes is a group of metabolic diseases characterized by hypergly-cemia The long-term presence of hyperglycemia can eventually lead to chronic d amage and dysfunction in various tissues,especially the eyes,kidneys,heart,blood vessels and nerves.Diabetes is divided into type I and type II diabetes,of which type II diabetes accounts for the vast majority of diabet Tic patients.The main cause is insulin sensitivity or insulin deficiency,casuing insulin signalingpathway disturbance and weakening insulin-insulin receptor interaction.The study found that protein tyrosine phosphatase?PTP1B? is a classical non-receptor tyrosine phosphatase in the family of protei tyrosine phosph a atase in the family of protein tyrosine phosp hates?PTPs?.PTP1B can pass Dephosphorylation of the insulin receptor and its substrate negativetly regulates insulin signaling,attenuating insulin action,and plays nagetive regulatory role in the insulin signaling pathway.Currently,PTP1B regnized as a therapeutic drug target for diabetes and obesity in academia.In recent years a large number of PTP1B inhibitors have been reported or entered clinical studies.Although a large number of inhibitors have good PTP1B in hibitory activity,the presence of macroporous phosphoric acid or carboxylic acid groups in the structure ultimately leads to low fat solubilityy of the inhibitor,and poor drug permeability and low bioavailability.defect In addition,since T-cell protein tyrosine phosphatase?TCPTP?is highly homologous to PTP1B,most of the inhibitors also have poor selectivity and a variety of toxic side effects,which are greatly limited in clinical practice.Therefore,it is of great significance to explore PTP1B-inhibitors with novel structure,good inhibitory activity,and drug-like properties.In this paper,Licochalcone E,a natural product with potential PTP1B inhibitory activity,was previously reported as a lead compound,and the 2,3-dimethylallyl substituent was retained at the 5position of the chalcone Bring.Under the premise of constant modification,structural modification and modification of chalcone was carried out,and 39 new chalcone compounds were designed and synthesized,and their biological evaluation andsynthesized,and their biological evaluation and preliminary structure-activety relationship?S AR?were carried out.And quantitative structure-activety relationship QSAR analysis.Pharmacological activity screening indiccated that most of the compounds had good inhibitory activity against PTP1B,and compound 23 had the best inhibitory effect with an IC₅₀0 Value of 0.57?M.The pharmacological research mechanism revealed that compound 23 showed significant hepatoprotective properties by activating the IR pathway in type 2 diabetic db/db mice.Further,the results of computer-aided molecular docking experiments indicate that compound 23 can effctively convert the WPD ring from the "closed" state of the active site to"open" state,thereby achieving a specific inhibitory effect on PTP1B.The series of studies in this pape provide new lead compounds for the research and development of new and highly effective PTP1B inhibitors.