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

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

Research output: Contribution to journalArticleResearchpeer-review

61 Citations (Scopus)

Abstract

© 2015 Elsevier Masson SAS 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.
Original languageEnglish
Pages (from-to)864-879
JournalEuropean Journal of Medicinal Chemistry
Volume121
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

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

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