Novel isoxazolone derivatives as acetylcholinesterase inhibitors: design, synthesis, in silico and in vitro evaluation

Abstract

Acetylcholinesterase (AChE) plays a pivotal role in Alzheimer's disease by accelerating acetylcholine breakdown, leading to cognitive decline. In this study, a series of novel isoxazolone derivatives were synthesized and structurally characterized using spectroscopic methods. The compounds were evaluated for their AChE inhibitory activity, where several candidates demonstrated stronger inhibition than the standard drug Donepezil. Molecular docking supported these findings, highlighting favorable interactions within the enzyme's active site. Selected compounds also exhibited promising antioxidant properties in the DPPH assay. A developed QSAR model provided insights into structural features contributing to bioactivity. In silico ADMET profiling indicated drug-like behavior, and molecular dynamics simulations confirmed the stability of the top ligand–enzyme complexes. Collectively, the results underscore the potential of isoxazolone-based scaffolds as multifunctional agents for managing Alzheimer's disease. Further biological evaluation is recommended to explore their therapeutic applicability.