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

Stefania Butini, Margherita Brindisi, Simone Brogi, Samuele Maramai, Egeria Guarino, Alessandro Panico, Ashima Saxena, Ved Chauhan, Raffaella Colombo, Laura Verga, Ersilia De Lorenzi, Manuela Bartolini, Vincenza Andrisano, Ettore Novellino, Giuseppe Campiani, Sandra Gemma

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1178-1182
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume4
Issue number12
DOIs
Publication statusPublished - Dec 12 2013

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Keywords

  • Alzheimer's disease
  • amyloid beta oligomers
  • amyloid beta-peptides
  • bivalent ligands
  • Cholinesterase inhibitors
  • multifunctional tools

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Butini, S., Brindisi, M., Brogi, S., Maramai, S., Guarino, E., Panico, A., Saxena, A., Chauhan, V., Colombo, R., Verga, L., De Lorenzi, E., Bartolini, M., Andrisano, V., Novellino, E., Campiani, G., & Gemma, S. (2013). Multifunctional cholinesterase and amyloid beta fibrillization modulators. Synthesis and biological investigation. ACS Medicinal Chemistry Letters, 4(12), 1178-1182. https://doi.org/10.1021/ml4002908