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 α-glucosidase and α-amylase while...
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| Main Authors: | , , , , , |
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| Format: | Book |
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MDPI AG,
2022-08-01T00:00:00Z.
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| Summary: | 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 α-glucosidase and α-amylase while preventing oxidative stress is deemed a practicable strategy for regulating postprandial glucose levels in DM patients. We report herein the α-glucosidase and α-amylase inhibition and antioxidant profile of quinoline hybrids <b>4a</b>-<b>t</b> and <b>12a</b>-<b>t</b> bearing 1,3,4-oxadiazole and 1,2,3-triazole cores, respectively. Overall, compound <b>4i</b> with a bromopentyl sidechain exhibited the strongest α-glucosidase inhibition (IC<sub>50</sub> = 15.85 µM) relative to reference drug acarbose (IC<sub>50</sub> = 17.85 µM) and the best antioxidant profile in FRAP, DPPH, and NO scavenging assays. Compounds <b>4a</b> and <b>12g</b> also emerged as the most potent NO scavengers (IC<sub>50</sub> = 2.67 and 3.01 µM, respectively) compared to gallic acid (IC<sub>50</sub> = 728.68 µM), while notable α-glucosidase inhibition was observed for <i>p</i>-fluorobenzyl compound <b>4k</b> (IC<sub>50</sub> = 23.69 µM) and phenyl-1,2,3-triazolyl compound <b>12k</b> (IC<sub>50</sub> = 22.47 µM). Moreover, kinetic studies established the mode of α-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 α-glucosidase. These results showcase these compounds as worthy scaffolds for developing more potent α-glucosidase inhibitors with antioxidant activity for effective DM management. |
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| Item Description: | 10.3390/ph15081035 1424-8247 |