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

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Wu MY,Esteban G,Brogi S,Shionoya M,Wang L,Campiani G,Unzeta M,Inokuchi T,Butini S,Marco-Contelles J

doi

10.1016/j.ejmech.2015.10.001

subject

Has Abstract

pub_date

2016-10-04 00:00:00

pages

864-879

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(15)30283-X

journal_volume

121

pub_type

杂志文章

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