Synthesis of chlorogenic acid amides as antihyperglycemic agents

Diabetes mellitus is characterized by high blood glucose levels due to hydrolysis of starch by pancreatic α-amylase and absorption of glucose in the small intestine by α-glucosidase. Diabetes is a significant cause of blindness, kidney failure, heart attacks, stroke, and lower limb amputation. Deaths from diabetes increased by 70% globally between 2000 and 2019. (1) Thus, there is an urgent need in the search of new and effective antidiabetic drugs, besides considering certain side effects showed by commercial antidiabetic drugs. α-Glucosidase and α- amylase inhibition is an established protocol in the search for potential antidiabetic agents with hypoglycemic activity. Many natural products have been reported for their anti-hyperglycemic activity. Among these, phenolic acids, including chlorogenic acid, and some phenolic esters and amides have shown α-glucosidase inhibition. (2-4) In this scenario, the purpose of this study was to obtain new chlorogenic acid amides as potential hypoglycemic agents. The amides are synthesized by condensation of chlorogenic acid, properly activated at carboxyl group, with aliphatic- and alkyl aryl-amines. The methodology furnishes the expected products in good yields without further protection/deprotection steps. The new compounds are evaluated as inhibitors of α-glucosidase and α-amylase activity by in vitro assays based on UV-Vis and fluorescence measurements. Some of the analyzed amides have shown higher inhibitory activity than that of the natural lead chlorogenic acid. The obtained data have given more insights onto the mechanism of interaction/inhibition of the synthesized amides toward the targeted enzymes. The hypoglycemic activity showed by chlorogenic acid amides is supported by in silico molecular docking calculations, highlighting the putative binding mode.