1. Turning Donepezil into a Multi‐Target‐Directed Ligand through a Merging Strategy
- Author
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Elisa Uliassi, Flaminia Di Pietri, Ondrej Soukup, Manuela Bartolini, Claudia Albertini, Anna Tramarin, Lenka Pulkrabkova, Maria Laura Bolognesi, Sabrina Petralla, Rosaria Carmela Perone, Nicola Rizzardi, Romana Fato, Pedro de Sena Murteira Pinheiro, Perone R., Albertini C., Uliassi E., Di Pietri F., de Sena Murteira Pinheiro P., Petralla S., Rizzardi N., Fato R., Pulkrabkova L., Soukup O., Tramarin A., Bartolini M., and Bolognesi M.L.
- Subjects
Cell Survival ,Computational biology ,Ligands ,01 natural sciences ,Biochemistry ,Antioxidants ,Protein Aggregates ,Structure-Activity Relationship ,Multi target ,Alzheimer Disease ,medicinal chemistry ,Cell Line, Tumor ,Biological property ,Drug Discovery ,medicine ,Humans ,Idebenone ,Donepezil ,Polypharmacology ,General Pharmacology, Toxicology and Pharmaceutics ,Pharmacology ,polypharmacology ,Amyloid beta-Peptides ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,multi-target drug discovery ,Alzheimer's disease ,Ligand (biochemistry) ,0104 chemical sciences ,Oxidative Stress ,010404 medicinal & biomolecular chemistry ,Safety profile ,Neuroprotective Agents ,Blood-Brain Barrier ,Drug Design ,Indans ,Acetylcholinesterase ,Molecular Medicine ,Cholinesterase Inhibitors ,medicine.drug - 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.
- Published
- 2020