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.

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%.

• Authors: 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
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 52 Pg. 251-62 (Jun 2012) ISSN: 1768-3254 [Electronic] France
• PMID: 22503231 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Cholinesterase Inhibitors
• Heterocyclic Compounds
• Monoamine Oxidase Inhibitors
• Peptide Fragments
• Propylamines
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• propargylamine
• Pargyline
• Monoamine Oxidase
• Acetylcholinesterase
• Butyrylcholinesterase
• Cholinesterases

Topics

• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (chemistry)
• Animals
• Butyrylcholinesterase (metabolism)
• Chemistry Techniques, Synthetic
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Cholinesterases (chemistry, metabolism)
• Electrophorus
• Heterocyclic Compounds (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Humans
• Kinetics
• Models, Molecular
• Monoamine Oxidase (chemistry, metabolism)
• Monoamine Oxidase Inhibitors (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Pargyline (analogs & derivatives, chemistry)
• Peptide Fragments (chemistry)
• Propylamines (chemistry)
• Protein Multimerization (drug effects)
• Protein Structure, Secondary
• Rats