Triazole-Linked Pyridine–Oxadiazole–Thiol Hybrids as Dual α-Amylase and α-Glucosidase Inhibitors: Synthesis, DFT Analysis, Enzyme Kinetics, and In Silico Studies

Triazole-linked pyridine oxadiazolo-thiol hybrids were synthesized by combining numerous pharmacophores into a single structure through esterification, cyclization, and CuAAC coupling, resulting in high yields (70–82%). Structural validation was performed using FT-IR,1H/1³C NMR, and ESI-MS. In vitro enzyme assays indicated considerable dual inhibition of α-glucosidase and α-amylase. Compounds 8j, 8k, and 8l displayed significant α-amylase inhibition (IC50 = 20.87–29.78 µg mL−1), whereas compounds 8c and 8k demonstrated the most significant α-glucosidase inhibition (IC50 = 3.98–4.79 µg mL−1), outperforming the effectiveness of the standard acarbose. Enzyme kinetic experiments identified competitive, mixed, and uncompetitive inhibition mechanisms. Molecular docking validated the experimental results, indicating that compounds 8k, 8j, and 8l demonstrated outstanding binding affinities for α-amylase (binding energy = −9.4 to −8.8 /mol), whereas 8k and 8c attained the best values against α-glucosidase (binding energy = −8.8 to −8.1 kcal/mol). Density functional theory (DFT) study revealed advantageous electronic aspects for 8c. ADME predictions indicated favorable drug-likeness and oral bioavailability. Overall, the study highlights structurally integrated heterocyclic hybrids as promising dual antidiabetic leads with improved inhibitory profiles over existing agents.