Multi-target strategy to address Alzheimer's disease: Design, synthesis and biological evaluation of new tacrine-based dimers

被引:42
作者
Rizzo, Stefano [2 ]
Bisi, Alessandra [1 ]
Bartolini, Manuela [1 ]
Mancini, Francesca [1 ]
Belluti, Federica [1 ]
Gobbi, Silvia [1 ]
Andrisano, Vincenza [1 ]
Rampa, Angela [1 ]
机构
[1] Alma Mater Studiorum Univ Bologna, Dept Pharmaceut Sci, I-40126 Bologna, Italy
[2] Max Planck Inst Mol Physiol, Abt Chem Biol, D-44227 Dortmund, Germany
关键词
Alzheimer's disease; bis(7)-tacrine analogs; Drug design; Heterodimers; Indenoquinoline; BETA-AMYLOID AGGREGATION; ACETYLCHOLINESTERASE INHIBITORS; CHOLINESTERASE-INHIBITORS; CHOLINERGIC HYPOTHESIS; PERIPHERAL SITE; BUTYRYLCHOLINESTERASE; TARGET; DERIVATIVES; GENERATION; SECRETASE;
D O I
10.1016/j.ejmech.2011.07.004
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The multifactorial nature of Alzheimer's disease (AD) offers us a textbook example where parental compounds, mostly marketed, are modified with the aim of improving and/or conferring two or even more biological activities to contrast or less frequently revert the disease's symptoms. This is the case of tacrine and its dimeric derivative bis(7)-tacrine which, for instance, paved the way for the development of a broad collection of very interesting homo- and heterodimeric structures, conceived in light of the emerging multi-target approach for AD-related drug discovery. As a contribution to the topic, we report here the design, synthesis and biological evaluation of 12 compounds referable to bis(7)-tacrine. In addition to the cholinesterase activity, some of the selected compounds (7-9 and 12) were capable of inhibiting the non-enzymatic function of AChE and/or showed a remarkable activity against BACE1. Thus, the present study outlines a series of newly synthesized molecules, structurally related to bis(7)-tacrine, endowed with extended biological profile in agreement with the emerging multi-target paradigm. (C) 2011 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:4336 / 4343
页数:8
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