Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease

Autor: M. Amélia Santos, Karolina Gwizdala, Federica Rinaldo, Sílvia Chaves, Vito Capriati, Marina Costa, A. Raquel Pereira-Santos, Romane Josselin, Sandra M. Cardoso, Simonetta Resta, Luca Piemontese
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Denticity
Pharmaceutical Science
Ligands
hydroxyphenyl-benzimidazole
01 natural sciences
Antioxidants
Analytical Chemistry
chemistry.chemical_compound
multifunctional drugs
Piperidines
Drug Discovery
Moiety
Donepezil
Chelating Agents
Molecular Structure
Biological activity
hemic and immune systems
Acetylcholinesterase
3. Good health
donepezil
Molecular Docking Simulation
Chemistry (miscellaneous)
Molecular Medicine
alzheimer´s disease
medicine.drug
Indazoles
chemical and pharmacologic phenomena
010402 general chemistry
Article
lcsh:QD241-441
Structure-Activity Relationship
lcsh:Organic chemistry
Alzheimer Disease
medicine
Humans
Chelation
Physical and Theoretical Chemistry
Piperazine
Amyloid beta-Peptides
010405 organic chemistry
organic chemicals
Organic Chemistry
Combinatorial chemistry
0104 chemical sciences
chemistry
metal chelation
Nitro
anti-neurodegeneratives
Cholinesterase Inhibitors
Zdroj: Molecules, Vol 25, Iss 4, p 985 (2020)
Molecules
Volume 25
Issue 4
ISSN: 1420-3049
Popis: 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&rsquo
s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and &beta
&ndash
amyloid (A&beta
) 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 A&beta
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.
Databáze: OpenAIRE
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