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<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which the multi-target-directed ligand (MTDL) strategy offers a promising therapeutic approach. In this study, a caffeic acid-dopamine hybrid was designed and evaluated for its multifunctional activities. Subsequently, two derivatives incorporating a carbamate fragment were synthesized. Among these, compound <b>3</b> demonstrated excellent antioxidant activity, significant inhibition of self-induced A<i>β</i><sub>1–42</sub> aggregation, anti-inflammatory properties, and neuroprotective effects, though it exhibited weak cholinesterase inhibition and limited blood-brain barrier (BBB) permeability. In contrast, the derivative <b>TM-2</b> showed potent butyrylcholinesterase inhibition (IC<sub>50</sub> = 0.36 μM), potential antioxidant activity, and significant inhibition of self-induced A<i>β</i><sub>1–42</sub> aggregation (48.9%). <b>TM-2</b> also reduced NO and IL-6 levels, provided significant anti-inflammatory effects, and exhibited neuroprotective effects against Glu-/A<i>β</i><sub>25–35</sub>-induced injury in PC12 cells. Importantly, <b>TM-2</b> demonstrated BBB permeability in vitro and significantly improved memory impairment in a scopolamine-induced mouse model. These findings suggest that <b>TM-2</b> is a promising multifunctional agent for the treatment of AD.</p><p></p>

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Development of novel caffeic acid derivatives as multifunctional agents for the treatment of AD

  • 期刊论文

  • 发表日期：

    2025年5月5日

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  • Kerong Hu,
  • Jing Yang,
  • Qiyao Zhang,
  • Xinxin Wang,
  • Yujie Xu,
  • Yuxin Zhang,
  • Zhenghuai Tan,
  • Wenmin Liu,
  • Rui Chen,
  • Zhipei Sang

摘要

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which the multi-target-directed ligand (MTDL) strategy offers a promising therapeutic approach. In this study, a caffeic acid-dopamine hybrid was designed and evaluated for its multifunctional activities. Subsequently, two derivatives incorporating a carbamate fragment were synthesized. Among these, compound 3 demonstrated excellent antioxidant activity, significant inhibition of self-induced Aβ1–42 aggregation, anti-inflammatory properties, and neuroprotective effects, though it exhibited weak cholinesterase inhibition and limited blood-brain barrier (BBB) permeability. In contrast, the derivative TM-2 showed potent butyrylcholinesterase inhibition (IC50 = 0.36 μM), potential antioxidant activity, and significant inhibition of self-induced Aβ1–42 aggregation (48.9%). TM-2 also reduced NO and IL-6 levels, provided significant anti-inflammatory effects, and exhibited neuroprotective effects against Glu-/Aβ25–35-induced injury in PC12 cells. Importantly, TM-2 demonstrated BBB permeability in vitro and significantly improved memory impairment in a scopolamine-induced mouse model. These findings suggest that TM-2 is a promising multifunctional agent for the treatment of AD.