Novel Ferulic Acid-donepezil Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease with Butyrylcholinesterase, Amyloid-β, Antioxidant and Neuroprotective Properties

作者：Li, Tianping; Pan, Wanli; Wang, Keren; Liu, Wenmin; Ma, Qianwen; Sang, Zhipei^*

来源：Letters in Drug Design and Discovery, 2017, 14(8): 918-929.

DOI：10.2174/1570180814666170421181517

• Alzheimer's disease
• ferulic acid-donepezil hybrids
• antioxidant activity
• BuChE inhibitor
• A beta aggregation
• neuroprotective effects
• blood-brain barrier

Background: A series of ferulic acid-donepezil hybrids were designed, synthesized and evaluated as multifunctional agents for Alzheimer's disease (AD) in vitro. @@@ Methods: Among the synthesized compounds, compound TM-I-3 acted as an antioxidant (1.1eq of Trolox), showed the highest BuChE inhibitory activity with IC50 value of 3.4 +/- 0.21 mu M, the result of molecular provided a possible mechanism for its unexpected inhibitory activity against BuChE. In addition, compound TM-I-3 inhibited and disaggregated self-induced A beta(1-42) aggregation by 61.1 +/- 1.8% and 53.1 +/- 3.4% at 25 mu M respectively, which was consistent with the transmission electron microscopy (TEM) and molecular modeling study. Moreover, TM-I-3 exhibited a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in PC12 cells. Furthermore, our investigation proved that TM-I-3 could penetrate the blood-brain barrier (BBB) in vitro, and abided by the Lipinski's rule of five. @@@ Results and Conclusion: These data suggest that compound TM-I-3, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery development against the advanced stages of AD.

• 出版日期2017
• 单位南阳师范学院; 四川大学