新型白藜芦醇激发的噻吩并苯并咪唑和噻吩并恶唑-合成、选择性丁酰胆碱酯酶抑制和分子模拟
Novel resveratrol-inspired thieno-benzimidazoles and thieno-oxazoles - Synthesis, selective butyrylcholinesterase inhibition and molecular modeling.
摘要(中文译文)
本研究报道了新型白藜芦醇启发的噻吩-苯并咪唑和噻吩-噁唑衍生物的设计、合成及生物学评价，旨在将其作为阿尔茨海默病的潜在治疗药物。该研究基于胆碱能假说，该假说认为认知功能下降与乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）酶解作用导致的乙酰胆碱水平降低有关。鉴于BChE在疾病晚期阶段日益凸显的重要性，研究重点放在开发选择性BChE抑制剂上。通过多步有机反应合成了14个化合物，包括Wittig反应、Vilsmeier甲酰化反应和环化策略。通过NMR和质谱确认了结构。所研究的乙酰化衍生物由于在紫外照射下发生高效的顺反异构化及后续次级过程而表现出光化学不稳定性，因此在处理、储存和应用过程中需要严格避光。生物学评价显示，所有化合物均选择性抑制BChE，未观察到显著的AChE抑制作用。其中，氨基甲酸酯-噁唑衍生物14表现出最高效力（IC = 0.248 μM），优于参照药物利斯的明。其他多个衍生物显示出中等至较强的活性，噁唑类化合物总体上优于苯并咪唑类似物。除酶抑制外，还采用DPPH和CUPRAC法评估了抗氧化活性。化合物8表现出最强的自由基清除活性，与Trolox相当。分子对接和动力学模拟揭示了结合相互作用的机制，突出了BChE活性位点内关键的π-π堆积和氢键作用。此外，计算机遗传毒性分析表明，活性最强的化合物不具有致突变潜力。总体而言，该研究确定了兼具选择性BChE抑制、抗氧化特性和良好安全性特征的有前景的多功能候选化合物，支持其作为阿尔茨海默病治疗先导化合物的潜力。
Abstract
This study reports the design, synthesis, and biological evaluation of novel resveratrol-inspired thieno-benzimidazole and thieno-oxazole derivatives as potential therapeutics for Alzheimer's disease. The research is grounded in the cholinergic hypothesis, which links cognitive decline to reduced acetylcholine levels due to enzymatic degradation by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Given the increasing relevance of BChE in later disease stages, the focus was placed on developing selective BChE inhibitors. A series of 14 compounds was synthesized using multi-step organic reactions, including Wittig reactions, Vilsmeier formylation, and cyclization strategies. Structural confirmation was achieved through NMR and mass spectrometry. The studied acetylated derivatives exhibit photochemical instability due to efficient trans-cis isomerization and subsequent secondary processes under UV irradiation, necessitating strict light protection during handling, storage, and application. Biological evaluation revealed that all compounds selectively inhibited BChE, with no significant AChE inhibition observed. Among them, carbamate-oxazole derivative 14 exhibited the highest potency (IC = 0.248 μM), outperforming the reference drug rivastigmine. Several other derivatives showed moderate to strong activity, with oxazole-based compounds generally outperforming benzimidazole analogs. In addition to enzyme inhibition, antioxidant activity was assessed using the DPPH and CUPRAC assays. Compound 8 exhibited the strongest radical-scavenging activity, comparable to that of Trolox. Molecular docking and dynamics simulations provided insight into binding interactions, highlighting key π-π stacking and hydrogen bonding within the BChE active site. Furthermore, in silico genotoxicity analysis indicated that the most active compounds lack mutagenic potential. Overall, the study identifies promising multifunctional candidates combining selective BChE inhibition, antioxidant properties, and favorable safety profiles, supporting their potential as lead compounds for Alzheimer's disease therapy.
如何引用
AMA
Milena Mlakić, Stanislava Talić, Ilijana Odak, Sunčica Roca, Ivana Šagud, Danijela Barić, et al. Novel resveratrol-inspired thieno-benzimidazoles and thieno-oxazoles - Synthesis, selective butyrylcholinesterase inhibition and molecular modeling.. Bioorganic chemistry. 2026; doi:10.1016/j.bioorg.2026.110096.
APA
Milena Mlakić, Stanislava Talić, Ilijana Odak, Sunčica Roca, Ivana Šagud, Danijela Barić, et al (2026). Novel resveratrol-inspired thieno-benzimidazoles and thieno-oxazoles - Synthesis, selective butyrylcholinesterase inhibition and molecular modeling.. Bioorganic chemistry. https://doi.org/10.1016/j.bioorg.2026.110096
GB/T 7714
Milena Mlakić, Stanislava Talić, Ilijana Odak, Sunčica Roca, Ivana Šagud, Danijela Barić, et al. Novel resveratrol-inspired thieno-benzimidazoles and thieno-oxazoles - Synthesis, selective butyrylcholinesterase inhibition and molecular modeling.[J]. Bioorganic chemistry, 2026 doi:10.1016/j.bioorg.2026.110096.
在 PubMed增强版 阅读全文
翻译全文 · AI 文献问答 · PDF 原文下载 · 引用导出