Synthesis, characterization and biological evaluation of novel imidazothiazole-based chalcone derivatives as cholinesterase inhibitors through computational and experimental approaches.

In this study, fifteen imidazothiazole-based chalcone derivatives (6-20) were synthesized and evaluated as potential cholinesterase inhibitors through computational and experimental approaches. Fourteen of these compounds are reported for the first time, while the previously known derivative (8) was newly assessed for its AChE and BChE inhibitory activities in relation to Alzheimer's disease (AD). In silico studies, including density functional theory (DFT) calculations, molecular docking, molecular dynamics simulations, binding free energy calculations, and ADMET analyses, suggested that these compounds could act as dual cholinesterase inhibitors. The compounds were synthesized via a three-step route and structurally characterized by 1H NMR, 13C NMR, FT-IR, and mass spectrometry. Their inhibitory activities against AChE and BChE were evaluated using the Ellman method, and kinetic parameters were determined through nonlinear regression and Lineweaver-Burk analyses. All derivatives exhibited inhibitory activity in the picomolar range. Among them, compounds 6, 12, and 20 were the most potent AChE inhibitors, whereas compounds 18, 19, and 6 showed the highest potency against BChE. Notably, compound 6 exhibited potent dual inhibition against both enzymes. Kinetic studies indicated a mixed-type inhibition mechanism, suggesting interactions with both catalytic and peripheral binding sites. Overall, these findings identify imidazothiazole-based chalcone derivatives as promising dual cholinesterase inhibitors and provide a basis for further optimization and investigation as potential therapeutic candidates for AD.