Insight into Antiacetylcholinesterase Potential of Modified Chalcones: Synthesis, Characterization, in Vitro, and Computational Investigation

Abstract Neurological disorders remain a major challenge in modern medicine due to the brain’s complexity and the limited efficacy of genetic therapies. Acetylcholinesterase (AChE) is a key target in the treatment of Alzheimer’s disease. In this study, a series of modified 4‐benzyloxychalcone derivatives (9a–j) were synthesized and structurally characterized using various spectroscopic techniques, including IR, 1H NMR, 13C NMR, and HRMS. Quantum chemical calculations, along with MM/GBSA and MM/PBSA analyses, were performed to evaluate the electronic properties and binding free energies of the compounds. All compounds met Lipinski’s criteria. Molecular docking and dynamics simulations revealed that compound 9c exhibited the most stable interaction with AChE (PDB ID: 4EYZ), supported by a strong binding profile. Additionally, the small HOMO–LUMO energy gap indicates the compounds' potent anticholinesterase capabilities via the POM/DFT approach. Furthermore, high hyperpolarizability and polarizability values suggest additional potential as pharmacophores. The derivatives demonstrated favorable binding with active site residues of the enzyme, suggesting their potential as effective AChE inhibitors. Overall, the findings indicate that benzyloxychalcones (9a–j) bind key amino acids in the 4EYZ binding pocket, highlighting their potential as candidates for Alzheimer’s disease treatment.