Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer’s drug candidates

Abstract

A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer’s disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC₅₀=4.0–30.0 μΜ) and moderate ability for inhibition of Aβ_1–42 self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ₄₂ aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ_1–42 induced toxicity. Structure–activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.

Graphical Abstract

Keywords:

• Alzheimer’s disease
• multipotent drugs
• donepezil mimetics
• AChE inhibitors
• anti-Aβ aggregation

Acknowledgements

The authors thank the financial support to the Portuguese Fundação para a Ciência e Tecnologia (FCT) for the projects UID/QUI/00100/2013 and PEst-C/SAU/LA0001/2011–2013. Acknowledgements are also due to the Portuguese NMR (IST-UL Center) and Mass Spectrometry Networks (Node IST-CTN) for providing access to their facilities. The authors acknowledge also Dr. Lucia Gambacorta and CNR-ISPA (Bari, Italy) for HPLC-HRMS analyses. L.P. thanks Fondo di Sviluppo e Coesione 2007–2013–APQ Ricerca Regione Puglia “Programma regionale a sostegno della specializzazione intelligente e della sostenibilità sociale ed ambientale - Future In Research”. Project ID: I2PCTF6.

Disclosure statement

No potential conflict of interest was reported by the authors.