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

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 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.

Structure and therapeutic uses of butyrylcholinesterase: Application in detoxification, Alzheimer's disease, and fat metabolism

“…Similar to cinnamic acid, ferulic acid (FA; Figure 10) is also widely distributed in plants. It was reported to be a natural free radical scavenger, with abilities to inhibit self‐aggregation of Aβ 179 . Its benefits and low side‐effects guide it to be a promising agent for treating AD.…”

“…Based on the modified FA, Sang et al 179 previously unveiled compounds 16 ( ee AChE IC 50 = 2.13 µM, eqBChE IC 50 = 0.021 µM, Figures 10) and 17 ( eq BChE IC 50 = 3.4 µM, Figure 10) as BChE inhibitors with high selectivity 179 . In 2018, to further improve the inhibitory activity of 16 and develop MTDLs, they fused these two ligands to obtain novel FA derivatives 179 . Compound 18 ( ee AChE IC 50 = 12.1 µM, eq BChE IC 50 = 0.009 µM, Figure 10) displayed elevated inhibitory activity and selectivity toward eq BChE compared to 16 .…”

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

“…Additionally, 149 was tested in an AlCl 3 -induced zebrafish AD model, showing significantly improved dyskinesia recovery rate and potent protective effect on Aβ1-40-induced vascular injury, with very low in vivo acute toxicity. To our knowledge, these sets of results highlight compound 149 as one of the most advanced MTDL drug candidate prototypes reported in the recent literature [ 154 ].…”

Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery

“…TM-10 shows influence on BuChE, MAO and self-induced Aβ aggregation. Moreover, memory loss is improved by TM-10 in scopolamine-induced zebrafish and vascular injury is protected in Aβ40-induced zebrafish (Sang et al, 2019). The newly designed and synthesized cinnamic acid hybrid, compound 4e, can inhibit Aβ42 accumulation, and shows reversible BuChE activity and MAO-B inhibitory activity.…”