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Royal Society of Chemistry, Organic and Biomolecular Chemistry, 4(9), p. 1140-1147

DOI: 10.1039/c0ob00393j

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Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds

This paper is available in a repository.
This paper is available in a repository.

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Abstract

The multifaceted nature of Alzheimer's disease (AD) has led to the development of multi-targeted compounds based on the classical AD drug, tacrine, first known to inhibit the acetylcholine-degrading enzyme acetylcholinesterase (AChE). In the present work, we explore the potentiality of multimers of tacrine in this field. The synthesis using the so-called "click chemistry" and the in vitro study of the conjugates are described. Two or four copies of the tacrine molecule are "clicked" on a constrained cyclopeptide template proven to be a convenient tool for multimeric presentation. The multimers significantly inhibit self-induced amyloid fibril formation from Aβ(40) at low inhibitor to Aβ molar ratios at which the tacrine monomer is fully inactive (Thioflavin T assays and AFM observation). Moreover, they have the capacity to bind to Aβ(40) fibrils (SPR assays) while retaining the AChE inhibitory activity of the parent tacrine.