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

作者：Wei Li, Jing Huang, Zhixin Chen, Dan Zhang, Lin He, Yan Ying Guo, Lei Zhong, Chenwu Yang, Chunyan Yang, Mei Zeng, Jiang Zhu, Jiang Zhu, Zhongcheng Cao · 发表于：Current Medicinal Chemistry · 年份：2025 · DOI：10.2174/0109298673328877241113091539 · 被引用次数：4 · 研究领域：Cholinesterase and Neurodegenerative Diseases、Alzheimer's disease research and treatments、Synthesis and biological activity

Objectives: 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 Aβ aggregation, and Aβ 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 Aβ1-42 aggregation (90.8% inhibition rate at 25 μM) and Cu2+ induced Aβ1-42 aggregation (93.4% inhibition rate at 25 μM). In addition, it also exhibited good Aβ1-42 fibril disaggregation ability (64.7% at 25 μM), significant antioxidative activity (ORAC = 2.03 Trolox equivalent), moderate MAO-B inhibition (IC50 = 4.81 μM), 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-Aβ agent.