Design And Synthesis Of Novel Anti-Diabetic Lead Compounds

Objective:Diabetes mellitus(DM)is a group of metabolic disorders caused by multiple factors and characterized by chronic hyperglycemia,with the hypoinsulinism and/or the role of disability.DM can lead to the metabolic disturbance among sugars,lipids and proteins.In recent years,the global prevalence of diabetes and its complications has a rapid growth,and the type Ⅱ diabetes accounts for about 90%in diabetes patients.From the development process of diabetes,we can draw a conclusion that diabetes is a dysfunction of the same or the related superfamily genes,not a single gene or one target.This is the way of future drug design that could act on multiple targets by comprehensive analysis of disease mechanisms and target structure.PTP1B,PPARa and PPARy have a close relationship with type Ⅱ diabetes,and the structures and mechanisms of these targets have already been quite clear.Our research is to design and synthesis multi-target anti-diabetic lead compounds based on the structures of these target enzymes.Methods:Referred to relevant literatures and combined with the preliminary work,imidazolidinedione and piperazine were identified as the primary research structures.With the help of computer-aided drug design,the designed compounds were docked into the receptors,the PTPT1B,PPARa and PPARy as targets which were retrieved from Brookhaven database.A series of compounds were obtained after virtual screening,according with docking energies.By searching Beilstein and Sci Finder databases,the optimum synthesis conditions was obtained.Using 1-(4-methoxyphenyl)imidazolidine-2,4-dione as raw material,some imidazolidinedione derivatives were obtained by reacting with formaldehyde and ethyl chloroacetate.Using imidazolidine-2,4-dione and 2-hydroxybenzaldehyde as raw materials,the intermediate compound was obtained by the Knoevenagel Reaction,which was further reacted with various chlor-compounds to give the target imidazolidinedione derivatives.Using piperazine hexahydrate and ethyl chloroformate as starting materials at the room temperature in the solvent of glacial acetic acid,1-ethoxycarbonyl piperazine was gained,which was then reacted with various kinds of chlor-compounds to obtain piperazine derivatives.TLC was used to monitor the reaction in the synthesis process.Through extraction,filtration,column chromatography separation,the target compounds were purified and then confirmed by 1HNMR and MS.Results:Molecular docking studies suggest that the imidazolidinedione and piperazine derivatives could play an important role by insersting into the active sites of PTP1B,PPARa and PPARy.In the meanwhile,the docking scores for receptors-ligands are satisfactory,which were obtained from all kinds of docking energies.After searching for the optimum synthesis conditions,15 imidazolidinedione and piperazine derivatives were obtained through the Knoevenagel Reaction and the nucleophilic substitution,with a high level of product purity and yield.The target compounds were confirmed by 1HNMR and MS.Conclusions:Our research selected PTP1B,PPARa and PPARy as the target enzymes,which were the key targets to diabetes and obesity.With the help of computer-aided drug design,we designed compounds with imidazolidinedione and piperazine as parent nucleus,which ensured the feasibility of multi-target antidiabetic compounds designed for PTP1B,PPARa and PPARy.The target compounds were obtained by chemical synthesis and confirmed by 1HNMR and MS.Further assay of these compounds on animal models is being underway by Tianjin Institute of Pharmaceutical Research.