α-Glucosidase and α-Amylase Inhibitory Potentials of Quinoline-1,3,4-oxadiazole Conjugates Bearing 1,2,3-Triazole with Antioxidant Activity, Kinetic Studies, and Computational Validation

Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes alpha-glucosidase and alpha-amylase while preventing oxidative stress is deemed a practicable strategy for regulating postprandial glucose levels in DM patients. We report herein the alpha-glucosidase and alpha-amylase inhibition and antioxidant profile of quinoline hybrids 4a-t and 12a-t bearing 1,3,4-oxadiazole and 1,2,3-triazole cores, respectively. Overall, compound 4i with a bromopentyl sidechain exhibited the strongest alpha-glucosidase inhibition (IC50 = 15.85 mu M) relative to reference drug acarbose (IC50 = 17.85 mu M) and the best antioxidant profile in FRAP, DPPH, and NO scavenging assays. Compounds 4a and 12g also emerged as the most potent NO scavengers (IC50 = 2.67 and 3.01 mu M, respectively) compared to gallic acid (IC50 = 728.68 mu M), while notable alpha-glucosidase inhibition was observed for p-fluorobenzyl compound 4k (IC50 = 23.69 mu M) and phenyl-1,2,3-triazolyl compound 12k (IC50 = 22.47 mu M). Moreover, kinetic studies established the mode of alpha-glucosidase inhibition as non-competitive, thus classifying the quinoline hybrids as allosteric inhibitors. Molecular docking and molecular dynamics simulations then provided insights into the protein-ligand interaction profile and the stable complexation of promising hybrids at the allosteric site of alpha-glucosidase. These results showcase these compounds as worthy scaffolds for developing more potent alpha-glucosidase inhibitors with antioxidant activity for effective DM management.