Butini_2013_ACS.Med.Chem.Lett_4_1178

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 (Abeta). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with Abeta aggregation and with the Abeta 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 Abeta aggregation since they physically hamper Abeta binding to the enzyme surface. Moreover, 2a was able to significantly interfere with Abeta self-oligomerization, while 2b,c showed improved inhibition of hAChE-induced Abeta aggregation.