Synthesis, Characterization, In Vitro and In Silico α‐Amylase Inhibitory Activity of 2,6‐Di(1,3,4‐Oxadiazol‐2‐Yl)Pyridine Derivatives

Abstract α‐amylase enzymes play a major role in the management of the postprandial hyperglycemia. Therefore, the inhibition of α‐amylase enzyme is a crucial therapeutic approach for managing postprandial hyperglycemia and diabetes. This study reports the synthesis and comprehensive characterization of novel compounds derived from bis‐1,3,4‐oxadiazole, using spectroscopic techniques including 1 H NMR, 13 C NMR, and FTIR‐ATR. The antidiabetic potential of these compounds was investigated through in vitro assays evaluating their inhibitory activity against pancreatic α‐amylase. To further elucidate their mechanism of action and pharmacokinetic profiles, in silico simulations were conducted to analyze their binding interactions with the enzyme's active site and to predict their ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties. The newly synthesized bis‐1,3,4‐oxadiazole derivatives exhibited dose‐dependent inhibitory activity against pancreatic α‐amylase, with compound 5 g showing the most potent effect (IC 50 = 0.084 ± 0.015 mg/mL). Molecular docking studies further supported these results, by revealing strong binding affinities of 5 g to the enzyme's active site. Additionally, molecular dynamics simulation of the α‐amylase‐5g complex confirmed the stability of the interaction. Collectively, these results highlight the potential of bis‐1,3,4‐oxadiazole derivatives, particularly compound 5g , as promising candidates for the development of novel antidiabetic agents targeting pancreatic α‐amylase.