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Design, Synthesis, and Evaluation of Novel Ferulic Acid Derivatives as Multi-Target-Directed Ligands for the Treatment of Alzheimer’s Disease

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journal contribution
posted on 12.12.2018 by Zhipei Sang, Keren Wang, Xue Han, Mengxiao Cao, Zhenghuai Tan, Wenmin Liu
A novel series of ferulic acid derivatives was designed and synthesized on the basis of the multi-target-directed ligands strategy for the treatment of Alzheimer’s disease (AD). In vitro results revealed that all the target compounds were highly effective and selective butyryl­cholin­esterase (BuChE) inhibitors. In particular, compound TM-10 showed the best BuChE inhibitory activity, with IC50 = 8.9 nM, and remarkable mono­amine oxidase A and B inhibitory potency, with IC50 = 6.3 and 8.6 μM, respectively. TM-10 could inhibit (53.9%) and disaggregate (43.8%) self-induced amyloid-β peptide (Aβ) aggregation. In addition, TM-10 exhibited potent antioxidant activity (ORAC = 0.52 equiv) and neuroprotective effect against Aβ1–42-mediated SH-SY5Y neurotoxicity, and it acted as an autophagic activator. TM-10 also showed good blood–brain barrier penetration. Furthermore, TM-10 exhibited a favorable dyskinesia recovery rate and response efficiency on an AlCl3-induced zebrafish AD model and a potent neuroprotective effect on Aβ1–40-induced zebrafish vascular injury. Further, in vivo assays demonstrated that TM-10 showed low acute toxicity, and the step-down passive avoidance test indicated that this compound could improve scopol­amine-induced memory deficit in mice. Therefore, the present study displays evidence that TM-10 is a potent, multi-functional agent against AD and could be a promising lead candidate for anti-Alzheimer’s disease drug development.

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