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

Journal of Enzyme Inhibition and Medicinal Chemistry
Luca PiemonteseM Amélia Santos

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 Aβ1-42 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 Aβ1-42 induced toxicity. Structure-activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.

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Citations

Jun 6, 2019·Expert Opinion on Drug Discovery·Juan F GonzálezJose María Sánchez-Montero
Nov 26, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Gaia FancelluM Amélia Santos
Jan 10, 2020·Journal of Biomolecular Structure & Dynamics·Mahesh Kumar TeliMi-Hyun Kim
Jan 26, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yan GuoZongliang Liu
Feb 6, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Luca PiemonteseVito Capriati
Feb 10, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rajeshwari RajeshwariM Amélia Santos
Jul 29, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Agnieszka Zagórska, Anna Jaromin
Sep 29, 2019·Expert Opinion on Therapeutic Patents·Kamal M Dawood
Feb 27, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sílvia ChavesM Amélia Santos
Jan 4, 2021·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Rodrigo R V CarvalhoBreno P Espósito
Mar 23, 2021·Journal of Alzheimer's Disease : JAD·Roger GaudreaultCharles Ramassamy
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fausto QuedaM Amélia Santos
Jun 18, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Yinling YunXiaojing Wang
Aug 27, 2021·Journal of Drug Targeting·Yang XieLinhong Ning

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Methods Mentioned

BETA
transmission electron microscopy
column chromatography
X-ray
NMR

Software Mentioned

GOLD
Astex
Maestro
Ghemical
QikProp

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