Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer's Disease
Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer's Disease
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DOI：
10.1021/jm200853t
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发表时间：
2011-12-22
影响因子：
7.3
通讯作者：
Samadi, Abdelouahid
中科院分区：
文献类型：
--
作者：
Bolea, Irene;Juarez-Jimenez, Jordi;Samadi, Abdelouahid
合成了一个新的多靶点分子家族，该家族能够与乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）以及与单氨基氧化酶（MAO）A和B相互作用。已经使用结合方法设计了新的化合物（3-9），所述结合方法将AChE抑制剂多奈哌齐（1）的苄基哌啶部分和MAO抑制剂N-[（5-苄氧基-1-甲基-1H-吲哚-2-基）甲基]-N-甲基丙-2-炔-1-胺（2）的吲哚基炔丙基氨基部分结合，通过低聚亚甲基连接基连接。最有前途的杂合物（5）是MAO-A（IC 50 = 5.2 +/- 1.1 nM）和MAO-B（IC 50 = 43 +/- 8.0 nM）的强效抑制剂，是AChE（IC 50 = 0.35 +/- 0.01 μ M）和BuChE（IC 50 = 0.46 +/- 0.06 μ M）的中度强效抑制剂。此外，分子模拟和动力学研究支持的双重结合位点的乙酰胆碱酯酶，这解释了对A β聚集施加的抑制作用。总的来说，这些结果表明，新化合物是有希望的多靶点候选药物，对阿尔茨海默病治疗具有潜在影响。
A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 +/- 1.1 nM) and MAO-B (IC50 = 43 +/- 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 +/- 0.01 mu M) and BuChE (IC50 = 0.46 +/- 0.06 mu M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A beta aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.