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.

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

Perone R.;Albertini C.;Uliassi E.;Petralla S.;Rizzardi N.;Fato R.;Tramarin A.;Bartolini M.;Bolognesi M. L.
2021

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.
2021
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.
File in questo prodotto:
File Dimensione Formato  
Turning Donepezil into a Multi-Target Post print.pdf

Open Access dal 09/01/2022

Descrizione: Accepted Manuscript
Tipo: Postprint
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione - Non commerciale - Non opere derivate (CCBYNCND)
Dimensione 663.27 kB
Formato Adobe PDF
663.27 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/786577
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 9
  • ???jsp.display-item.citation.isi??? 9
social impact