Design,Synthesis Chalcone Derivatives As Adipor Agonist For Type 2 Diabetes

Type 2 diabetes has become a major global health challenge of the 21st century,it is associated with population aging and increasing incidence of obesity.Besides,type 2diabetes also lead to a marked increase in cardiovascular risk.Predominantly resulted from insulin resistance and impaired beta cell function,type 2 diabetes is commonly treated by enhancing the sensitivity of tissue to insulin and improving the production of insulin from?-cell of pancreas.Other factors that facilitating the development of type 2diabetes embraces overweight,less exercise and a high-calorie diet lifestyle.As an adipokine secreted by the adipose tissue,adiponectin plays an essential role in ameliorates insulin resistance,and harbors anti-diabetic,anti-atherogenic,as well as anti-inflammatory properties.In respect of its mechanism of action,adiponectin functions as the endogenous agonist of adiponectin receptors,which comprise two subtypes,known as AdipoR1 and AdipoR2.While the former predominantly uses the adenosine monophosphate-activated kinase?AMPK?pathways in skeletal muscle,the latter action is mainly mediated by peroxisome proliferator-activated receptor alpha?PPAR-??pathways in the liver.During our continuous efforts to explore chalcone derivatives as anti-diabetic agents,the key structural features of both chalcone and small-molecule AdipoR agonist adipoRon were merged into a single chemical entity via insertion of carbon-carbon double bond between the carbonyl functionality and the terminal benzene ring.Upon this strategy,compounds of series I with structural novelty were obtained.On the basis of this,compounds of series II were designed via reversing the acryloyl moiety of compounds of series I for SAR study.Additionally,for both series,different substituents on the terminal benzene ring A were introduced to investigate their impact on activity.The structures of all target compounds were identified by IR,ESI-MS,¹³C NMR and ¹H NMR.Two structurally novel series of chalcone derivatives were designed and synthesized as potential agents against type 2 diabetes.As a result of the antidiabetic biological evaluation in streptozotocin?STZ?induced type 2 diabetes animal model,13e,13g and 19f showed more significant reduction in serum Glu,TG,TC levels by contrast to the positive control AdipoRon.In addition to upregulating the expression of AdipoR1and AdipoR2,13e and 19f treatment also increased expression of AMPK and PPAR-?.Taken together,these results suggest that 13e and 19f might be a promising compounds for type 2 diabetes treatment.