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Eur J Med Chem. 2016 Oct 4;121:864-879. doi: 10.1016/j.ejmech.2015.10.001. Epub 2015 Oct 9.

Donepezil-like multifunctional agents: Design, synthesis, molecular modeling and biological evaluation.

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
European Research Centre for Drug Discovery and Development (NatSynDrugs) and Department of Biotechnology, Chemistry and Pharmacy, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
4
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.
5
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. Electronic address: inokuchi@cc.okayama-u.ac.jp.
6
European Research Centre for Drug Discovery and Development (NatSynDrugs) and Department of Biotechnology, Chemistry and Pharmacy, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. Electronic address: butini3@unisi.it.
7
Laboratory of Medicinal Chemistry (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: iqoc21@iqog.csic.es.

Abstract

Currently available drugs against Alzheimer's disease (AD) are only able to ameliorate the disease symptoms resulting in a moderate improvement in memory and cognitive function without any efficacy in preventing and inhibiting the progression of the pathology. In an effort to obtain disease-modifying anti-Alzheimer's drugs (DMAADs) following the multifactorial nature of AD, we have recently developed multifunctional compounds. We herein describe the design, synthesis, molecular modeling and biological evaluation of a new series of donepezil-related compounds possessing metal chelating properties, and being capable of targeting different enzymatic systems related to AD (cholinesterases, ChEs, and monoamine oxidase A, MAO-A). Among this set of analogues compound 5f showed excellent ChEs inhibition potency and a selective MAO-A inhibition (vs MAO-B) coupled to strong complexing properties for zinc and copper ions, both known to be involved in the progression of AD. Moreover, 5f exhibited moderate antioxidant properties as found by in vitro assessment. This compound represents a novel donepezil-hydroxyquinoline hybrid with DMAAD profile paving the way to the development of a novel class of drugs potentially able to treat AD.

KEYWORDS:

ADME+T properties; Alzheimer's disease; Antioxidant properties; Human acetylcholinesterase; Human butyrylcholinesterase; MAO-A; MAO-B; Metal chelating properties; Molecular docking; Molecular modeling

PMID:
26471320
DOI:
10.1016/j.ejmech.2015.10.001
[Indexed for MEDLINE]

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