Design, Synthesis, Biological Evaluation and Docking Studies of 2-hydroxy-4-benzyloxy Chalcone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, but no drugs can cure this disease. Chalcones possess good antioxidant activity, anti-neuroinflammatory activity, neuroprotective effects, inhibitory effects on A beta aggregation, and A beta disaggregation ability. Therefore, chalcones are ideal lead compounds, and the discovery of novel anti-AD agent-based chalcones is necessary. Methods: Hydroxy groups and aryl benzyl ether groups were introduced into chalcone scaffolds to obtain a series of 2-hydroxyl-4-benzyloxy chalcone derivatives. These derivatives were further synthesized, biologically evaluated, and docked. Results: Most target derivatives exhibited good anti-AD activities. In particular, compound 11d had excellent inhibitory effects on self-induced A beta(1-42) aggregation (90.8% inhibition rate at 25 mu M) and Cu2+ induced A beta(1-42) aggregation (93.4% inhibition rate at 25 mu M). In addition, it also exhibited good A beta(1-42) fibril disaggregation ability (64.7% at 25 mu M), significant antioxidative activity (ORAC = 2.03 Trolox equivalent), moderate MAO-B inhibition (IC50 = 4.81 mu M), selective metal chelation, appropriate BBB permeation, and dramatic anti-neuroinflammatory ability. In addition, compound 11d relieved AD symptoms and protected hippocampal neurons in vivo. Conclusion: Compound 11d is a promising multifunctional anti-A beta agent.