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.