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

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

  • Mol Divers. 2025 Jul 13. doi: 10.1007/s11030-025-11284-6.
JiaHao Lu 1,  YingQI Qiu 1,  ChenHao Zhao 1 2,  Ai-Qun Wu 1,  Haiou Jiang 3,  Li-Qun Shen 4
Affiliations

Affiliations

  • 1 College of Chemistry and Chemical Engineering, Guangxi Minzu University, Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Engineering Research Center of Low-Carbon and High-Quality Utilization of Forest Biomass, University of Guangxi, Nanning, 530006, China.
  • 2 Institute of Biomedicine, Hunan University of Medicine, Huaihua, 418000, China.
  • 3 Institute of Biomedicine, Hunan University of Medicine, Huaihua, 418000, China. hhjiangh@126.com.
  • 4 College of Chemistry and Chemical Engineering, Guangxi Minzu University, Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Engineering Research Center of Low-Carbon and High-Quality Utilization of Forest Biomass, University of Guangxi, Nanning, 530006, China. liqunshen@126.com.
PMID: 40652414 DOI: 10.1007/s11030-025-11284-6
Abstract

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.

Keywords

Acetylcholinesterase; Alzheimer’s disease; Aβ40/42; Chromone; Tau.

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