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

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-07-13 DOI:10.1007/s11030-025-11284-6

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

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引用次数: 0

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.

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2-（2-苯乙基）/2,3-苯乙烯基色素衍生物的合成及多靶点评价

设计、合成了一系列新的2-（2-苯乙基）色素和2/3-苯乙烯基色素衍生物（A1-A16, B1-B43），并对其对阿尔茨海默病（AD）关键病理因子的多靶点活性进行了系统评价。体外研究表明，化合物B22具有有效和选择性的乙酰胆碱酯酶（AChE）抑制作用（IC₅₀= 2.52±1.11 μM），对丁基胆碱酯酶（BuChE）（IC₅₀> 500 μM）的活性可以忽略，同时具有强单胺氧化酶- b （MAO-B）抑制作用（1 μM处抑制93.6%）。硫黄素T （ThT）荧光分析显示，B18和B22有效地抑制了a - β40/42肽（IC₅₀分别= 1.44和1.00 μM）和Tau纤化（IC₅₀= 2.61和3.32 μM）的聚集，同时促进了预形成的淀粉样蛋白原纤维的分解。分子对接和分子动力学（MD）模拟表明，B22具有良好的结合亲和力（ΔG≈- 7.3 kcal/mol），在AChE活性位点内具有稳定的相互作用。此外，B22显著降低了SHSY5Y细胞的活性氧（ROS）水平（高达89.5%），恢复了a β诱导的细胞毒性，在20 μM下将细胞存活率恢复到85.7%。总的来说，这些结果突出了基于色素的支架，特别是化合物B22，作为开发针对AD的疾病修饰疗法的有希望的多功能候选物。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;