Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy

Rosaria Perone; Claudia Albertini; Elisa Uliassi; Flaminia Di Pietri; Pedro de Sena Murteira Pinheiro; Sabrina Petralla; Nicola Rizzardi; Romana Fato; Lenka Pulkrabkova; Ondrej Soukup; Anna Tramarin; Manuela Bartolini; Maria Laura Bolognesi

doi:10.1002/cmdc.202000484

Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy

ChemMedChem. 2021 Jan 8;16(1):187-198. doi: 10.1002/cmdc.202000484. Epub 2020 Aug 31.

Authors

Affiliations

¹ Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6/Via Irnerio 48/Via Selmi 3, 40126, Bologna, Italy.
² Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
³ Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
⁴ Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska, 1575.

PMID: 32716144
DOI: 10.1002/cmdc.202000484

Abstract

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

Keywords: Alzheimer's disease; drug design; medicinal chemistry; multi-target drug discovery; polypharmacology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Antioxidants / chemistry
Antioxidants / metabolism
Antioxidants / pharmacology
Blood-Brain Barrier / diagnostic imaging
Blood-Brain Barrier / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / metabolism
Cholinesterase Inhibitors / pharmacology
Cholinesterase Inhibitors / therapeutic use
Donepezil / chemistry*
Donepezil / metabolism
Donepezil / pharmacology
Donepezil / therapeutic use
Drug Design
Humans
Indans / chemistry
Ligands*
Neuroprotective Agents / chemistry*
Neuroprotective Agents / metabolism
Neuroprotective Agents / pharmacology
Neuroprotective Agents / therapeutic use
Oxidative Stress / drug effects
Protein Aggregates / drug effects
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Antioxidants
Cholinesterase Inhibitors
Indans
Ligands
Neuroprotective Agents
Protein Aggregates
Donepezil
indacrinone
Acetylcholinesterase