Novel phthalimido-benzenesulfonamide hybrid as a potent α-glucosidase inhibitor: Synthesis, biological evaluation, molecular docking and in silico ADME prediction

Diabetes mellitus is a global health crisis, recognized as one of the 21st century’s most significant challenges. Therapeutic strategies for managing Type 2 Diabetes mellitus (T2DM) frequently involve α-glucosidase inhibitors (AGIs), which mitigate postprandial glucose excursions by delaying carbohydrate digestion. This study focuses on the synthesis, characterization, and in vitro α-glucosidase inhibitory evaluation of a novel phthalimido-benzenesulfonamide hybrid compound, specifically 4-phthalimido-N-(5-chloro-2-pyridylamino)benzenesulfonamide. Additionally, enzyme kinetics and molecular docking studies were performed on this compound to reveal enzyme inhibition models and ligand-enzyme binding interactions. Furthermore, we used the PreADMET web service to calculate the ADME/Tox properties of the compound. According to the biological activity data, the target compound exhibited α-glucosidase inhibition (IC50 = 1240.52 ± 316.98 µM) comparable to the reference drug acarbose (IC50 = 1210.96 ± 0.17 μM), positioning it as a promising scaffold for future antidiabetic drug development efforts. Molecular docking studies provided informative clues for the ligand-enzyme binding interactions to estimate allosteric cavities (A1-A5) of the homology model of α-glucosidase. Kinetic analysis revealed an uncompetitive inhibition, with reduced Kₘ and Vₘₐₓ, confirming an allosteric mechanism. In silico ADME/Tox predictions suggested that the compound had favorable ADME/Tox properties. Overall, this hybrid compound represents a promising lead for next-generation AGIs with reduced side effects.