From concept to simulations: computational and experimental assessment of thiadiazole-thiazolidinone hybrid chalcones for anti-alzheimer potentials.

UNLABELLED: 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 1H-NMR, 13C-NMR, and HREI-MS analyses. Among the synthesized compounds, analog 10 exhibited the most potent inhibitory activity with IC50 values of 3.10 ± 0.20 µM (AChE) and 3.80 ± 0.20 µM (BChE), surpassing the standard drug donepezil (IC50 = 5.50 ± 0.10 µM and 6.10 ± 0.20 µM, respectively). Other analogs demonstrated moderate to good activity within the range of 3.10-15.60 µM. 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.