Mughal_2026_RSC.Adv_16_25819

The development of effective cholinesterase inhibitors remains a key strategy for the symptomatic management of Alzheimer's disease (AD); however, the identification of structurally versatile scaffolds capable of dual AChE/BChE inhibition remains limited. In this context, coumarin-sulfonate hybrids offer a promising framework for exploring structure-activity relationships due to their tunable electronic and steric properties. In the present study, a series of nine coumarin-sulfonate derivatives (1-9) were synthesized via a two-step procedure and evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Ellman's assay. Among the tested compounds, derivative 3 (2,4,6-trimethylphenyl sulfonate) exhibited the highest inhibitory activity with IC(50) values of 6.476 nM for AChE and 11.948 nM for BChE, indicating potent dual inhibition. Compound 2 also showed strong dual activity, whereas compound 5 displayed relatively higher selectivity toward BChE. Structure-activity relationship (SAR) analysis revealed that both electronic properties and steric bulk of the aryl sulfonate substituents significantly influenced enzyme inhibition. In addition, computational studies were performed to provide qualitative insights into ligand-enzyme interactions, supporting the experimentally observed activity trends. Overall, the results highlight coumarin-sulfonate derivatives as promising scaffolds for cholinesterase inhibition and provide a basis for further structural optimization toward AD-related targets.