Design And Synthesis Of 4-thiazolidinone As PTP1B Inhibitors

Objective:Diabetes is a group of metabolic diseases characterized by chronic elevated blood glucose level.With the human standard of living elevating,the incidence of diabetes grows rapidly,ranking the third largest diseases threatening to human life after the cardiovascular disease and cancer.In recent years,remarkable progress has been made in the research on drug targets at the molecular and cellular level,which has discovered a number of new receptors and enzymes ralated to diabetes pathogenesis.These targets provide a solid fundation for the drug design and screening.As the primary negative regulator in the insulin signaling pathway,protein tyrosine phosphatase 1B(PTP1B)dephosphorylates phosphotyrosine residues of the active insulin receptor and insulin receptor substrates,and disrupts the insulin signal transduction.PTP1B has become an improtant drug target for the treatment of typeⅡ diabete and obesity,and low molecule PTP1B inhibitors are providing promising prospects for the discover of antidiabetic drugs.Our research is to design and synthesize antidiabetic lead compounds based on the structure of PTP1B target enzyme.Methods:We identified 4-thiazolidinone as the primary research structure with the hydrophobic alkyl,substituted phenyl and benzyl introduced to the 2-heterocycle to design series of compounds.With the help of Computer-Aided Drug Design technology,the designed compounds were docked into the receptors and then screened to identify the synthetic route and method in consideration of organic synthetic difficulty.With investegations for the optimum synthesis conditions we obtained two series of compounds,which were confirmed by 1HNMR and MS.Results:We chose the representative and commonly used PTP1B crystal structure as the target receptor,and some reported compounds including the original ligand of the receptor as the positive control to dock the 4-thiazolidinone derivatives.Based on the docking results it is to decided to synthesize 5-arylidene-2-phenyl-3-(4-ethoxycarbonylbenzyl)-4-thiazolidinones(TS series)and 5-arylidene-2-phenyl-3-(4-ethoxycarbonylphenyl)-4-thiazolidinones(TCS series)in consideration of organic synthetic difficulty.The activity determination of the compounds is underway in Tianjin institute of pharmaceutical researchThe synthesis of TS and TCS series compounds started with paraaminomethyl benzoic acid and ethyl p-aminobenzoate as the raw material respectively.And the intermediates 2-phenyl-3-(4-ethoxycarbonylbenzyl)-4-thiazolidinone and 2-phenyl-3-(4-ethoxycarbonylphenyl)-4-thiazolidinone were obtained by the esterification and cyclization reactions with the yield of 90%and 80%respectively and high purity both.The TS and TCS target compounds,21 new compounds in all,were obtained from the intermediates by the nucleophilic addition-dehydration reactions with a series of benzaldehyde derivatives,which had high purity.All intermediates and final products were confirmed by 1HNMR and MS.Conclusions:This research selected PTP1B as the target enzyme,based on which we designed 4-thiazolidinone derivatives.The designed compounds were screened using the Computer-Aided Drug Design technology and the synthesized two series of compounds were characterized by 1H-MMR and MS.