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Title: Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease
Authors: Chaves, Sílvia
Resta, Simonetta
Rinaldo, Federica
Costa, Marina
Josselin, Romane
Gwizdala, Karolina
Piemontese, Luca
Capriati, Vito
Santos, A. Raquel Pereira 
Cardoso, Sandra M. 
Santos, M. Amélia
Keywords: hydroxyphenyl-benzimidazole; donepezil; anti-neurodegeneratives; Alzheimer´s disease; multifunctional drugs; metal chelation
Issue Date: 22-Feb-2020
Publisher: MDPI
Serial title, monograph or event: Molecules
Volume: 25
Issue: 4
Abstract: A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.
ISSN: 1420-3049
DOI: 10.3390/molecules25040985
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais

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