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

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 Aβ_1-42-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 Aβ_1-40-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.