Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease.

Abstract

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

• Authors: Li Wang, Gerard Esteban, Masaki Ojima, Oscar M Bautista-Aguilera, Tsutomu Inokuchi, Ignacio Moraleda, Isabel Iriepa, Abdelouahid Samadi, Moussa B H Youdim, Alejandro Romero, Elena Soriano, Raquel Herrero, Ana Patricia Fernández Fernández, Ricardo-Martínez-Murillo, José Marco-Contelles, Mercedes Unzeta
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 80 Pg. 543-61 (Jun 10 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 24813882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Chelating Agents
• Cholinesterase Inhibitors
• Hydroxyquinolines
• Indans
• Monoamine Oxidase Inhibitors
• Piperidines
• Propylamines
• propargylamine
• Donepezil
• Pargyline
• Monoamine Oxidase
• Acetylcholinesterase

Topics

• Acetylcholinesterase (chemistry, metabolism)
• Alzheimer Disease (drug therapy)
• Animals
• Chelating Agents (metabolism, pharmacology, therapeutic use, toxicity)
• Cholinesterase Inhibitors (metabolism, pharmacology, therapeutic use, toxicity)
• Donepezil
• Hep G2 Cells
• Humans
• Hydroxyquinolines (chemistry)
• Indans (chemistry)
• Male
• Memory (drug effects)
• Molecular Docking Simulation
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (metabolism, pharmacology, therapeutic use, toxicity)
• Pargyline (analogs & derivatives, chemistry)
• Piperidines (chemistry)
• Propylamines (chemistry)
• Rats