Multifunctional cholinesterase and amyloid Beta fibrillization modulators. Synthesis and biological investigation

ACS Med Chem Lett. 2013 Oct 6;4(12):1178-82. doi: 10.1021/ml4002908. eCollection 2013 Dec 12.

Abstract

In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (Aβ). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with Aβ aggregation and with the Aβ self-oligomerization process (2a). Compounds 2a-c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site. These moieties are likely responsible for the observed reduction of hAChE-induced Aβ aggregation since they physically hamper Aβ binding to the enzyme surface. Moreover, 2a was able to significantly interfere with Aβ self-oligomerization, while 2b,c showed improved inhibition of hAChE-induced Aβ aggregation.

Keywords: Alzheimer’s disease; Cholinesterase inhibitors; amyloid beta oligomers; amyloid beta-peptides; bivalent ligands; multifunctional tools.