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

Molecular docking and dynamics simulations identified sulfonamide lead compound 4a (ZINC818285131) as an α-glucosidase inhibitor. Subsequent structural modification yielded a novel series of furan/thiophene-containing sulfonamide derivatives (4b-4p). In vitro assays revealed potent α-glucosidase inhibition for compounds 4i, 4m, 4n, and 4p, with IC₅₀ values ranging from 2.03 μM to 2.69 μM. Notably, 4i and 4p (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 4i and 4p 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, 4i, which also exhibited promising antioxidant and anticancer potential. These findings may advance the discovery of new therapies for type-2 diabetes and bladder cancer.