Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer's disease
Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer's disease
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DOI：
10.1016/j.ejmech.2016.12.048
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发表时间：
2017-02-15
影响因子：
6.7
通讯作者：
Bolognesi, Maria Laura
中科院分区：
文献类型：
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作者：
Jerabek, Jakub;Uliassi, Elisa;Bolognesi, Maria Laura
多靶点药物发现是中枢神经系统（CNS）活性药物治疗领域，特别是阿尔茨海默病（AD）新药研究的热点之一。这是因为创新的多靶向配体（MTDL）可以更充分地解决这种病理状况的复杂性。在我们针对一系列新的抗AD MTDL的继续努力中，我们将胆碱酯酶抑制剂药物他克林的结构特征与白藜芦醇的结构特征相结合，白藜芦醇以其据称的抗氧化和抗神经炎症活性而闻名。最令人感兴趣的杂合化合物（5、8、9和12）在微摩尔浓度下抑制人乙酰胆碱酯酶，并在体外有效地调节A β自聚集。此外，12在神经元和神经胶质AD细胞模型中显示出有趣的抑制和免疫调节特性。重要的是，MTDL谱伴随着高预测的血脑屏障渗透性和对原代神经元的低细胞毒性。(C)2016 Elsevier Masson SAS。All rights reserved.
Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated A beta self-aggregation in vitro. In addition, 12 showed intriguing antiinflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons. (C) 2016 Elsevier Masson SAS. All rights reserved.