Lu_2025_Mol.Divers__

A series of novel 2-(2-phenylethyl)chromone and 2/3-styrylchromone derivatives (A1-A16, B1-B43) were designed, synthesized, and systematically evaluated for their multi-target activities against key pathological factors of Alzheimer's disease (AD). In vitro studies demonstrated that compound B22 exhibited potent and selective acetylcholinesterase (AChE) inhibition (IC50 = 2.52 +/- 1.11 microM) with negligible activity against butyrylcholinesterase (BuChE) (IC50 > 500 microM), along with strong monoamine oxidase-B (MAO-B) inhibition (93.6% inhibition at 1 microM). Thioflavin T (ThT) fluorescence assays revealed that B18 and B22 effectively inhibited the aggregation of both Abeta40/42 peptides (IC50 = 1.44 and 1.00 microM, respectively) and Tau fibrillization (IC50 = 2.61 and 3.32 microM), while promoting the disaggregation of pre-formed amyloid fibrils. Molecular docking and molecular dynamics (MD) simulations indicated that B22 exhibited favorable binding affinities (deltaG = - 7.3 kcal/mol) and stable interactions within the AChE active site. Furthermore, B22 significantly attenuated reactive oxygen species (ROS) levels (by up to 89.5%) and rescued Abeta-induced cytotoxicity in SHSY5Y cells, restoring cell viability to 85.7% at 20 microM. Collectively, these results highlight chromone-based scaffolds, particularly compound B22, as promising multifunctional candidates for the development of disease-modifying therapeutics targeting AD.