Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer's disease therapy

Irene Pachón-Angona; Bernard Refouvelet; Rudolf Andrýs; Helène Martin; Vincent Luzet; Isabel Iriepa; Ignacio Moraleda; Daniel Diez-Iriepa; María-Jesús Oset-Gasque; José Marco-Contelles; Kamil Musilek; Lhassane Ismaili

doi:10.1080/14756366.2018.1545766

Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer's disease therapy

J Enzyme Inhib Med Chem. 2019 Dec;34(1):479-489. doi: 10.1080/14756366.2018.1545766.

Authors

Affiliations

¹ a Neurosciences intégratives et cliniques, Pôle Chimie Organique et Thérapeutique , University Bourgogne Franche-Comté , Besançon , France.
² b Faculty of Science, Department of Chemistry , University of Hradec Kralove , Hradec Kralove , Czech Republic.
³ c PEPITE EA4267, Laboratoire de Toxicologie Cellulaire , University Bourgogne Franche-Comté , Besançon , France.
⁴ d Department of Organic Chemistry and Inorganic Chemistry , Alcalà University , Madrid , Spain.
⁵ e Institute of Chemical Research Andrés M. del Río , Alcalà University , Madrid , Spain.
⁶ f Instituto de Investigación en Neuroquímica , Universidad Complutense de Madrid , Madrid , Spain.
⁷ g Department of Biochemistry and Molecular Biology, School of Pharmacy , Plaza de Ramòn y Cajal , Madrid , Spain.
⁸ h Laboratory of Medicinal Chemistry (IQOG, CSIC) , Madrid , Spain.

Abstract

We describe herein the design, multicomponent synthesis and biological studies of new donepezil + chromone + melatonin hybrids as potential agents for Alzheimer's disease (AD) therapy. We have identified compound 14n as promising multitarget small molecule showing strong BuChE inhibition (IC₅₀ = 11.90 ± 0.05 nM), moderate hAChE (IC₅₀ = 1.73 ± 0.34 μM), hMAO A (IC₅₀ = 2.78 ± 0.12 μM), and MAO B (IC₅₀ = 21.29 ± 3.85 μM) inhibition, while keeping a strong antioxidant power (3.04 TE, ORAC test). Consequently, the results reported here support the development of new multitarget Donepezil + Chromone + Melatonin hybrids, such as compound 14n, as a potential drug for AD patients cure.

Keywords: Antioxidant; MAO-A; MAO-B; ORAC; Ugi-4MCR; cholinesterases; donepezil.

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Butyrylcholinesterase / metabolism
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Chromones / chemistry
Chromones / pharmacology*
Donepezil / chemistry
Donepezil / pharmacology*
Dose-Response Relationship, Drug
Humans
Melatonin / chemistry
Melatonin / pharmacology*
Molecular Docking Simulation
Molecular Structure
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Chromones
Monoamine Oxidase Inhibitors
Donepezil
Monoamine Oxidase
Acetylcholinesterase
Butyrylcholinesterase
Melatonin

Grants and funding

LI thanks the Regional Council of Franche-Comté [2016YC-04540 and 04560] for financial support. JMC and MJOG thank Universidad Camilo José Cela (UCJC) for support [Grants 2015–12 and 2015–21]. RA and KM were supported by ERDF/ESF project PharmaBrain [no. CZ.02.1.01/0.0/0.0/16_025/0007444] and University of Hradec Kralove [no. IRP1902/2018, VT2201/2018].