Discovery and Synthesis of Novel Furan and Thiophene Sulfonamide-Based Derivatives as Dual-Functional α-Glucosidase Inhibitors

Molecular docking and dynamics simulations identified sulfonamide lead compound <b>4a</b> (ZINC818285131) as an α-glucosidase inhibitor. Subsequent structural modification yielded a novel series of furan/thiophene-containing sulfonamide derivatives (<b>4b</b>-<b>4p</b>). In vitro assays revealed potent α-glucosidase inhibition for compounds <b>4i</b>, <b>4m</b>, <b>4n</b>, and <b>4p</b>, with IC₅₀ values ranging from 2.03 μM to 2.69 μM. Notably, <b>4i</b> and <b>4p</b> (IC₅₀ = 2.03 ± 0.05 μM and 2.14 ± 0.01 μM, respectively) surpassed standard acarbose IC₅₀ = 3.20 ± 0.22 μM. Molecular docking suggested enhanced activity for <b>4i</b> and <b>4p</b> stems from hydrogen bonding and hydrophobic interactions with the enzyme. All compounds complied with Lipinski's rule of five. Comprehensive ADMET profiling indicated favorable properties for the most potent derivative, <b>4i</b>, which also exhibited promising antioxidant and anticancer potential. These findings may advance the discovery of new therapies for type-2 diabetes and bladder cancer.