Khan_2026_3.Biotech_16_42

A novel series of thiadiazole-linked thiazolidinone-chalcone derivatives was synthesized and comprehensively evaluated for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Structural characterization was confirmed through (1)H-NMR, (13)C-NMR, and HREI-MS analyses. Among the synthesized compounds, analog 10 exhibited the most potent inhibitory activity with IC(50) values of 3.10 +/- 0.20 microM (AChE) and 3.80 +/- 0.20 microM (BChE), surpassing the standard drug donepezil (IC(50) = 5.50 +/- 0.10 microM and 6.10 +/- 0.20 microM, respectively). Other analogs demonstrated moderate to good activity within the range of 3.10-15.60 microM. In silico analyses, including molecular docking, pharmacophore modeling, molecular dynamics simulations, DFT calculations, and ADMET profiling, supported the experimental results and revealed stable binding conformations and favorable drug-like properties. The strong correlation between computational predictions and experimental data validated the proposed structure-activity relationship. These findings highlight compound 10 as a promising lead molecule for further optimization and development of effective and safe cholinesterase inhibitors for Alzheimer's disease therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04648-0.