Design,Synthesis And Activity Evaluation Of Novel PPARs Pan-agonists

Background Diabetes mellitus is a chronic metabolic disease associated with systemic inflammation and oxidative stress.There are two types of diabetes mellitus: type I diabetes(T1DM)and type II diabetes(T2DM).Type I diabetes is insulin-dependent and must be treated continuously with insulin.Type II diabetes mellitus(T2DM)accounts for 90% of diabetic patients and is mainly caused by pancreatic β-cell damage and insulin resistance.It is mainly characterized by hyperglycemia,insulin resistance and defective insulin secretion.Peroxisome proliferating factor-activated receptors(PPARs)have been regarded as an important target of anti-diabetes by regulating amino acid metabolism,fat metabolism,gluconeogenesis and many other metabolic processes in vivo to regulate the body’s energy balance.PPARs belong to the nuclear receptor superfamily,which mainly includes three subtypes: PPARα,PPARβ and PPARγ.In the treatment of type 2 diabetes,panagonists that simultaneously activate PPARα,PPARβ,and PPARγ receptors have been shown to reduce potential risk factors for diabetes and enhance anti-glucose capacity.With the deepening of research,the existing PPARs agonists include natural agonists and synthetic agonists,and the representative compounds mainly include: Tryptonone derivatives,Bete compounds,Cannabinoids,Honokiol,Indeglitazar and Lanifibranor,etc.These compounds have some problems such as single structure of parent nucleus,lack of novelty and toxic and side effects.The main cause of toxic and side reactions is that the hydrophilic group in the tail is carboxylic acid structure,which easily causes PPARγ to be completely excited.Therefore,the search for PPARs panagonist with low toxicity and high efficiency has become a hot spot in the research and development of anti-diabetic drugs.Firstly,the lead compound was screened by virtual screening technique and a series of derivatives were designed.Secondly,the lead compound and derivatives were synthesized,their activities were evaluated and their structure-activity relationships were analyzed.It provides a basis for the study of PPARs pan-agonists.Research objective In this paper,the lead compound was discovered by virtual screening method,and the structure derivation,synthesis,activity evaluation and structure-activity relationship analysis of all compounds were completed,in order to find new anti-diabetic drugs.Research methods 1)Application of Auto Dock Vina for preliminary screening based on molecular docking.2)Re-screening using Receptor-Ligand Pharmacophore(CBP)pharmacophore.3)Use Discovery Studio 3.0 software Receptor-Ligand Interactions module to study the interaction between receptors and ligands,and perform structural derivation and optimization on this basis.4)Design a synthetic route,synthesize and screen the lead compounds and derivative compounds,and test their activities.5)Analyze and analyze the total structure-efficiency relationship based on the experimental data and interaction of the activity evaluation.Research results We screened the lead compound through the computational aid drug design.Based on this,13 structural derivatives were designed and their activities were evaluated.From the analysis of structure-activity relationship,it can be seen that introducing hydrophobic groups with slightly greater steric hindrance to the active sites of phenyl of the lead compound and corresponding derivatives can enhance the activity.Reactivity can be further enhanced by providing electron-donating groups to reduce overall electronegativity.This paper provides some ideas for the further modification of PPARs panagonist.