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<p>A series of novel 2-(2-phenylethyl)chromone and 2/3-styrylchromone derivatives (<b>A1</b>–<b>A16</b>, <b>B1</b>–<b>B43</b>) were designed, synthesized, and systematically evaluated for their multi-target activities against key pathological factors of Alzheimer’s disease (AD). In vitro studies demonstrated that compound <b>B22</b> exhibited potent and selective acetylcholinesterase (AChE) inhibition (IC₅₀ = 2.52 ± 1.11&#xa0;μM) with negligible activity against butyrylcholinesterase (BuChE) (IC₅₀ &gt; 500&#xa0;μM), along with strong monoamine oxidase-B (MAO-B) inhibition (93.6% inhibition at 1 μM). Thioflavin T (ThT) fluorescence assays revealed that <b>B18</b> and <b>B22</b> effectively inhibited the aggregation of both <b>Aβ40/42</b> peptides (IC₅₀ = 1.44 and 1.00&#xa0;μM, respectively) and Tau fibrillization (IC₅₀ = 2.61 and 3.32&#xa0;μM), while promoting the disaggregation of pre-formed amyloid fibrils. Molecular docking and molecular dynamics (MD) simulations indicated that <b>B22</b> exhibited favorable binding affinities (ΔG ≈ − 7.3&#xa0;kcal/mol) and stable interactions within the AChE active site. Furthermore, <b>B22</b> significantly attenuated reactive oxygen species (ROS) levels (by up to 89.5%) and rescued Aβ-induced cytotoxicity in SHSY5Y cells, restoring cell viability to 85.7% at 20&#xa0;μM. Collectively, these results highlight chromone-based scaffolds, particularly compound <b>B22</b>, as promising multifunctional candidates for the development of disease-modifying therapeutics targeting AD.</p>

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Synthesis and multi-target evaluation of 2-(2-phenylethyl)/2,3-styrylchromone derivatives as potential anti-Alzheimer’s disease agents

  • 期刊论文

  • 发表日期：

    2025年7月13日

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  • JiaHao Lu,
  • YingQI Qiu,
  • ChenHao Zhao,
  • Ai-Qun Wu,
  • Haiou Jiang,
  • Li-Qun Shen

摘要

A series of novel 2-(2-phenylethyl)chromone and 2/3-styrylchromone derivatives (A1–A16, B1–B43) were designed, synthesized, and systematically evaluated for their multi-target activities against key pathological factors of Alzheimer’s disease (AD). In vitro studies demonstrated that compound B22 exhibited potent and selective acetylcholinesterase (AChE) inhibition (IC₅₀ = 2.52 ± 1.11 μM) with negligible activity against butyrylcholinesterase (BuChE) (IC₅₀ > 500 μM), along with strong monoamine oxidase-B (MAO-B) inhibition (93.6% inhibition at 1 μM). Thioflavin T (ThT) fluorescence assays revealed that B18 and B22 effectively inhibited the aggregation of both Aβ40/42 peptides (IC₅₀ = 1.44 and 1.00 μM, respectively) and Tau fibrillization (IC₅₀ = 2.61 and 3.32 μM), while promoting the disaggregation of pre-formed amyloid fibrils. Molecular docking and molecular dynamics (MD) simulations indicated that B22 exhibited favorable binding affinities (ΔG ≈ − 7.3 kcal/mol) and stable interactions within the AChE active site. Furthermore, B22 significantly attenuated reactive oxygen species (ROS) levels (by up to 89.5%) and rescued Aβ-induced cytotoxicity in SHSY5Y cells, restoring cell viability to 85.7% at 20 μM. Collectively, these results highlight chromone-based scaffolds, particularly compound B22, as promising multifunctional candidates for the development of disease-modifying therapeutics targeting AD.