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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ID: 125666
2019
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Abstract
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 IC = 8.9 nM, and remarkable monoamine oxidase A and B inhibitory potency, with IC = 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 Aβ-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 AlCl-induced zebrafish AD model and a potent neuroprotective effect on Aβ-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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sang2019designacs Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Sang, Zhipei;Wang, Keren;Han, Xue;Cao, Mengxiao;Tan, Zhenghuai;Liu, Wenmin;
Journal ACS chemical neuroscience
Year 2019
DOI
10.1021/acschemneuro.8b00530
URL
Keywords
alzheimer’s disease zebrafish model design and synthesis ferulic acid derivatives multi-target agents scopalamine-induced cognitive impairment

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