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.
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