Title:Novel Ferulic Acid-donepezil Hybrids as Multifunctional Agents for th e Treatment of Alzheimer’s Disease with Butyrylcholinesterase, Amyloid- β, Antioxidant and Neuroprotective Properties
VOLUME: 14 ISSUE: 8
Author(s):Tianping Li, Wanli Pan, Keren Wang, Wenmin Liu, Qianwen Ma and Zhipei Sang*
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
Keywords:Alzheimer's disease, ferulic acid-donepezil hybrids, antioxidant activity, BuChE inhibitor, Aβ aggregation, neuroprotective
effects, blood-brain barrier.
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.
