Regioselective syntheses of 2-oxopyridine carbonitrile derivatives and evaluation for antihyperglycemic and antioxidant potential

Abstract

A library of 2-oxopyridine carbonitriles 1-34 was synthesized by regioselective nucleophilic substitution reactions. In the first step, a one-pot multicomponent reaction yield pyridone intermediates. The resulting pyridone intermediates were then reacted with phenacyl halides in DMF and stirred at 100 °C for an hour to afford the desired compounds in good yields. Structures of synthetic molecules were characterized by EI-MS, HREI-MS, ¹H NMR, and ¹³C NMR, and all thirty-four (34) compounds were found to be new. All synthetic compounds were examined for antidiabetic and antioxidant potential. The compounds exhibited α-glucosidase inhibitory potential in the range of IC₅₀ = 3.00 ± 0.11-43.35 ± 0.67 μM and α-amylase inhibition potential in the range of IC₅₀ = 9.20 ± 0.14-65.56 ± 1.05 μM. Among the tested compounds, 1 showed the most significant α-glucosidase inhibitory activity, with an IC₅₀ value of 3.00 ± 0.11 μM, while the most active compound against α-amylase was 6, with an IC₅₀ value = 9.20 ± 0.14 μM. The kinetic studies and analysis indicated that the compounds followed the competitive mode of inhibition. In addition, the molecular docking studies showed the interaction profile of all molecules with the binding site residues of α-glucosidase and α-amylase enzymes.

Keywords: Antioxidant activity; In silico; In vitro; Pyridine; Synthesis; α-Amylase activity; α-Glucosidase.