New Tacrine-4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties
New Tacrine-4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties
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DOI：
10.1021/jm201460y
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发表时间：
2012-02-09
影响因子：
7.3
通讯作者：
Rodriguez-Franco, Maria Isabel
中科院分区：
文献类型：
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作者：
Fernandez-Bachiller, Maria Isabel;Perez, Concepcion;Rodriguez-Franco, Maria Isabel
通过使用片段赋予有趣的和互补的特性，用于治疗阿尔茨海默氏病（AD），一个新的家庭他克林-4-氧代-4H-色烯杂合物已被设计，合成，并进行生物学评价。选择他克林片段是因为其抑制胆碱酯酶，并且选择衍生自4-氧代-4H-色烯的类黄酮支架是因为其自由基捕获和β-分泌酶1（BACE-1）抑制活性。在纳摩尔和皮摩尔浓度下，新的他克林-4-氧代-4H-色烯杂合体抑制人乙酰胆碱酯酶和丁酰胆碱酯酶（h-AChE和h-BuChE），比母体抑制剂他克林更有效。它们也是人类BACE-1的有效抑制剂，优于母体黄酮类化合物芹菜素。它们显示出有趣的抗氧化特性，并且根据体外PAMPA-BBB测定能够渗透到CNS中。在所研究的杂合体中，6-羟基-4-氧代- N-{10-[（1，2，3，4-四氢吖啶-9-基）氨基]癸基}-4H-色烯-2-甲酰胺（19）显示出对人BACE-1和ChE的有效联合抑制，以及良好的抗氧化和CNS渗透性质。
By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H-chromene was chosen for its radical capture and beta-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.