Macromolecular scaffolds with nitrogen-sulfur motifs: Dual α-glucosidase and urease inhibition with molecular docking and mechanistic evaluation.

This study reports the design, synthesis, and biological evaluation of a new series of indole-thiadiazole-sulfonamide hybrids as potential dual inhibitors of α-glucosidase and urease enzymes. Eighteen derivatives were synthesized and structurally characterized using standard spectroscopic techniques. Several compounds exhibited significant inhibitory activity, with IC₅₀ values ranging from 5.68 ± 1.28 to 45.42 ± 2.51 μM against α-glucosidase and from 12.99 ± 3.80 to 54.63 ± 3.26 μM against urease, compared to the reference inhibitors acarbose (18.73 ± 3.53 μM) and thiourea (21.70 ± 3.80 μM). Structure-activity relationship (SAR) analysis highlighted the influence of nitro, fluoro, trifluoromethyl, and chloro substituents on enzyme inhibition, with several derivatives surpassing the standards in potency. Molecular docking studies revealed key interactions with active-site residues, while ADME profiling indicated favorable drug-likeness. Overall, these findings identify indole-thiadiazole-sulfonamide hybrids as promising scaffolds for the development of multifunctional enzyme inhibitors.