Ugi Adducts: Design and Synthesis of Natural-based α-glucosidase Inhibitors

Abstract

Background: α-Glucosidase inhibitors have been found as the main tool for the treatment of type 2 diabetes. In this respect, the synthesis of a new series of amino-oxoethylcinnamamide derivatives containing α,β-unsaturated carbonyl-based moiety, was developed to be evaluated for their anti-α- glucosidase activity. Methods: The title compounds were synthesized via the Ugi reaction of cinnamic acid, isocyanides, aromatic aldehydes, and amine derivatives at ambient temperature. All newly synthesized derivatives were screened for their in vitro α-glucosidase inhibitory activity. Results: Among synthesized compounds, derivative 5b displayed promising anti-α-glucosidase activity (IC50 = 115.6 μM), approximately 6-fold more potent than the standard drug (acarbose, IC50 = 750.0 μM). Moreover, kinetic characterization of enzyme inhibition was performed to understand the mechanism of inhibition. To determine the mode of binding interactions of prepared compounds with the enzyme, molecular docking studies were also conducted. Conclusions: Ugi products merit to be investigated in anti-diabetic drug discovery developments. This paper is dedicated to our unique teacher of Chemistry and Medicinal Chemistry, Professor Abbas Shafiee (1937-2016).