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Eur J Med Chem. 2014 Jun 10;80:543-61. doi: 10.1016/j.ejmech.2014.04.078. Epub 2014 Apr 29.

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

Author information

1
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
2
Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
3
Laboratorio de Química Médica (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
4
Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Ctra. Madrid-Barcelona, Km. 33,6, 28871 Alcalá de Henares, Madrid, Spain.
5
Eve Topf Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa 31096, Israel.
6
Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.
7
SEPCO, IQOG (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain.
8
Neurovascular Research Group, Department of Molecular, Cellular and Developmental Neurobiology, Instituto Cajal (CSIC) Av. Doctor Arce 37, 28002 Madrid, Spain.
9
Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Electronic address: Mercedes.Unzeta@uab.cat.

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.

KEYWORDS:

Alzheimer's disease; ChE and MAO inhibitors; Donepezil + Propargylamine + 8-Hydroxyquinoline hybrids; Fe/Cu/Zn chelators; In vivo scopolamine-induced long-term memory deficit; Multifunctional drugs

PMID:
24813882
DOI:
10.1016/j.ejmech.2014.04.078
[Indexed for MEDLINE]

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