Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: Synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine

Abdelouahid Samadi, Cristóbal De Los Ríos, Irene Bolea, Mourad Chioua, Isabel Iriepa, Ignacio Moraleda, Manuela Bartolini, Vincenza Andrisano, Enrique Gálvez, Carolina Valderas, Mercedes Unzeta, José Marco-Contelles

Research output: Contribution to journalArticleResearchpeer-review

58 Citations (Scopus)

Abstract

The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC 50 = 31 ± 2 nM) and a moderately selective eqBuChE inhibitor (IC 50 = 4.7 ± 0.2 μM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC 50 = 25 ± 3 nM, K i = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit Aβ aggregation induced by hAChE by 30.6%. © 2012 Elsevier Masson SAS. All rights reserved.
Original languageEnglish
Pages (from-to)251-262
JournalEuropean Journal of Medicinal Chemistry
Volume52
DOIs
Publication statusPublished - 1 Jun 2012

Keywords

  • Alzheimer's disease
  • Amyloid β
  • EeAChE
  • eqBuChE
  • Indoles
  • Inhibition mechanism
  • Kinetic analysis
  • MAO-A
  • MAO-B
  • Molecular modeling
  • Multipotent molecules
  • Naphthyridines

Fingerprint Dive into the research topics of 'Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: Synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine'. Together they form a unique fingerprint.

  • Cite this

    Samadi, A., De Los Ríos, C., Bolea, I., Chioua, M., Iriepa, I., Moraleda, I., Bartolini, M., Andrisano, V., Gálvez, E., Valderas, C., Unzeta, M., & Marco-Contelles, J. (2012). Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: Synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine. European Journal of Medicinal Chemistry, 52, 251-262. https://doi.org/10.1016/j.ejmech.2012.03.022