Design,Synthesis And Activity Studies Of Multi-Target Anti-Diabetic Lead Compounds

Objective:Diabetes is a group of metabolic diseases characterized by chronic elevated blood glucose level,and it has become the third largest non-communicable diseases following cardiovascular disease and cancer.In recent years,the global prevalence of diabetes and its complications has a rapid growth,and the type 2 diabetes accounts for about 80%in diabetes patients.According to the studies of pathology and molecular biology,by comprehensive analysis of disease mechanisms and target structure,rationally design drugs that could act on multiple targets and prevent signal generation,transmission so as to treat disease.This is the way of future drug design.PTP1B PPARa and PPARy have a close relationship with type 2 diabetes,and the structures and mechanisms of these targets have already been quite clear.Our research is to design multi-target anti-diabetic lead compounds based on the structures of these target enzymes.Methods:We identified the imidazolidine-2,4-dione as the primary research structure.With the help of Computer-Aided Drug Design,the designed compounds were docked into the receptors.We obtained a series of imidazolidine-2,4-dione derivatives through organic synthetic methods,which were confirmed by 1HNMR and MS.With the Pd-C catalyst,the unsaturated benzylidene of the compounds became saturated by catalytic hydrogenation reaction,which also was confirmed by 1HNMR and MS.The compounds were validated on rats hyperglycemia model caused by glucose.Results:We chose the representative PTP1B,PPARa and PPAR? crystal structures as the receptors and use the effect of the ligands with the receptors as the basic parameters.The imidazolidinedione derivatives as ligands were docked into the receptors.The docking results showed that some compounds had good binding energies.In this study,using the p-hydroxybenzaldehyde as the raw material,in the presence of piperidine as the catalyst,the intermediate 5-(4-hydroxybenzylidene)-imidazoledine-2,4-dione was synthesized by the Knoevenagel reaction.More than 30 compounds were synthesized by the reaction of the intermediate with ethyl bromoacetate and substituted benzyl chloride.TLC was used to monitor the reactions,and more than 30 compounds were obtained by separation and purification,which were comfirmed by 1H-MMR and MS.The benzylidene part of the target compounds contained an unsaturated double bond.In the presence of Pd-C as the catalyst,we made these parts saturated by catalytic hydrogenation reaction.Using 5-(4-(benzyloxy)benzylidene)imidazolidine-2,4-dione as the material,we got 5-(4-(benzyloxy)benzyl)imidazolidine-2,4-dione,and the structure was confirmed by 1H-MMR and MS.The compounds were validated on rats hyperglycemia model caused by glucose,and the results showed that four compounds could reduce the blood glucose,nine compounds could rise blood glucose,and one compound had no effect on the blood glucose.Conclutions:This research selected PTP1B,PPARa and PPARy as the target enzymes,which were the key targets to diabetes and obesity.The designed compounds were docked into the receptors using the Computer-Aided Drug Design technology.The compounds were synthesized and charicterized by 1H-MMR and MS.Some compounds showed antidiabetic activities,which lay the foundation for the discovery of lead compounds with in-depth study value.