Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer's disease.
Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer's disease.
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DOI：
10.1038/s41598-018-22747-2
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发表时间：
2018-03-13
影响因子：
4.6
通讯作者：
Fais A
中科院分区：
文献类型：
--
作者：
Kumar A;Pintus F;Di Petrillo A;Medda R;Caria P;Matos MJ;Viña D;Pieroni E;Delogu F;Era B;Delogu GL;Fais A
阿尔茨海默病 (AD) 是一种神经退行性疾病，是导致痴呆症的主要原因，影响着全球近 4400 万人。 AD 的特点是胆碱能系统中乙酰胆碱水平进行性下降，导致严重的记忆丧失和认知障碍。人们注意到丁酰胆碱酯酶 (BChE) 的表达水平和活性在 AD 晚期显着增加，从而使其成为可行的药物靶点。设计、合成了一系列羟基化2-苯基苯并呋喃化合物，并评估了它们对乙酰胆碱酯酶（AChE）和BChE酶的抑制活性。两种化合物（15和17）对BChE表现出较高的抑制活性，IC50值分别为6.23μM和3.57μM，并且具有良好的抗氧化活性，EC50值分别为14.9μM和16.7μM。相同的化合物进一步表现出针对 BChE 而非 AChE 的选择性抑制活性。计算研究用于比较蛋白质结合袋并评估化合物的相互作用指纹。分子模拟显示化合物之间存在保守的蛋白质残基相互作用网络，从而产生相似的相互作用能值。因此，生物化学和计算方法的结合可以为这些羟基苯并呋喃衍生物的进一步结构修饰作为未来治疗 AD 的药物提供合理的指导。
Alzheimer’s disease (AD) is a neurodegenerative disorder representing the leading cause of dementia and is affecting nearly 44 million people worldwide. AD is characterized by a progressive decline in acetylcholine levels in the cholinergic systems, which results in severe memory loss and cognitive impairments. Expression levels and activity of butyrylcholinesterase (BChE) enzyme has been noted to increase significantly in the late stages of AD, thus making it a viable drug target. A series of hydroxylated 2-phenylbenzofurans compounds were designed, synthesized and their inhibitory activities toward acetylcholinesterase (AChE) and BChE enzymes were evaluated. Two compounds (15 and 17) displayed higher inhibitory activity towards BChE with IC50 values of 6.23 μM and 3.57 μM, and a good antioxidant activity with EC50 values 14.9 μM and 16.7 μM, respectively. The same compounds further exhibited selective inhibitory activity against BChE over AChE. Computational studies were used to compare protein-binding pockets and evaluate the interaction fingerprints of the compound. Molecular simulations showed a conserved protein residue interaction network between the compounds, resulting in similar interaction energy values. Thus, combination of biochemical and computational approaches could represent rational guidelines for further structural modification of these hydroxy-benzofuran derivatives as future drugs for treatment of AD.
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