Turning Donepezil into a Multi‐Target‐Directed Ligand through a Merging Strategy
| Autor: | 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 |
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| Přispěvatelé: | 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., Bolognesi M.L. |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | ChemMedChem. 16:187-198 |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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