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

[ Vol. 14 , Issue. 8 ]

Author(s):

Tianping Li, Wanli Pan, Keren Wang, Wenmin Liu, Qianwen Ma and Zhipei Sang*   Pages 918 - 929 ( 12 )

Abstract:


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 μM, 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 Aβ1-42 aggregation by 61.1±1.8% and 53.1 ±3.4% at 25μM 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 drugdiscovery development against the advanced stages of AD.

Keywords:

Alzheimer's disease, ferulic acid-donepezil hybrids, antioxidant activity, BuChE inhibitor, Aβ aggregation, neuroprotective effects, blood-brain barrier.

Affiliation:

Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, Nanyang Normal University Hospital, Nanyang Normal University, Nanyang 473061, College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061

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