Multi-target-directed drug design strategy: From a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease
Multi-target-directed drug design strategy: From a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease
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DOI：
10.1021/jm701225u
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发表时间：
2007-12-27
影响因子：
7.3
通讯作者：
Melchiorre, Carlo
中科院分区：
文献类型：
--
作者：
Bolognesi, Maria Laura;Cavalli, Andrea;Melchiorre, Carlo
提出了一种将双结合位点AChE抑制剂转化为三功能化合物的设计策略，该化合物具有抗多因素综合征（如阿尔茨海默病）的体外特性。对先导化合物bis（7）-tacrine（2）进行适当修饰，使新分子具有螯合金属的能力，参与神经退行性过程。所述多功能化合物显示出抗人AChE的活性，能够抑制AChE诱导的淀粉样蛋白-β聚集，并螯合金属，如铁和铜。
A design strategy to convert a dual-binding site AChE inhibitor into triple functional compounds with promising in vitro profile against multifactorial syndromes, such as Alzheimer's disease, is proposed. The lead compound bis(7)-tacrine (2) was properly modified to confer to the new molecules the ability of chelating metals, involved in the neurodegenerative process. The multifunctional compounds show activity against human AChE, are able to inhibit the AChE-induced amyloid-beta aggregation, and chelate metals, such as iron and copper.