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

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

SUBMITTER: Butini S 

PROVIDER: S-EPMC4027481 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature