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

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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Twelve new dimeric derivatives were designed and synthesized. ► The biological profile was evaluated toward cholinesterases, Aβ aggregation, BACE1. ► The majority of the new derivatives were active in the nanomolar range against AChE. ► Compounds 7–9 and 12 inhibited the non-enzymatic function of AChE. ► 8 and 12 also showed a remarkable activity against BACE1.