Yang_2024_Chem.Biol.Drug.Des_103_e14529

With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (1-4) were designed, synthesized, and characterized by (1)H NMR, (13)C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and beta-amyloid (Abeta) aggregation inhibition in vitro were evaluated. The results showed that 1-4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu(2+) ions), antioxidation, self-induced, Cu(2+)-induced, and AChE-induced Abeta aggregation inhibition activities, and suitable blood-brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10(-8) M magnitude) and BuChE (10(-7) M magnitude) and showed the best inhibition on AChE-induced Abeta aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.