Oxindole based sulfonyl derivatives synthesized as potent inhibitors of alpha amylase and alpha glucosidase along with their molecular docking study.

Diabetes mellitus, a persistent metabolic disorder, impedes the proper metabolism of proteins, carbohydrates, and lipids, leading to various physiological complications. A spectrum of synthetic alpha-glucosidase inhibitors is employed to mitigate glucose levels; however, prolonged use of these medications has been associated with a range of adverse effects. The current study particularly focuses on piperidin-indolin based sulfonyl derivatives, a class of heterocyclic compounds to assess the inhibitory efficacy of these synthesized compounds against α-amylase and α-glucosidase enzymes. All compounds showed excellent inhibitory activity in the range between 1.90 ± 0.10 to 16.80 ± 0.30 µM (amylase) and 1.20 ± 0.01 to 15.40 ± 0.30 µM (glucosidase). Limited structural activity relationship has been established for all compounds which suggest compound 16 has many folds better potential then standard drug. Molecular docking revealed that the most active compounds established stable hydrogen-bonding and hydrophobic interactions within the catalytic pockets of α-amylase and α-glucosidase, consistent with key active-site residues known to mediate inhibition. Molecular dynamics simulations further confirmed the stability of the ligand-enzyme complexes, particularly the α-glucosidase-compound 7 system, which maintained a Cα RMSD range of 1.5-2.2 Å throughout 200 ns. Binding free energy calculations using MM-GBSA yielded an average ΔGbind of approximately - 25 kcal mol⁻¹, with van der Waals and lipophilic forces providing the primary stabilizing contributions and electrostatic and solvation effects offering additional support.