Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease
| العنوان: | Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease |
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| المؤلفون: | 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 |
| المصدر: | Molecules, Vol 25, Iss 4, p 985 (2020) Molecules Volume 25 Issue 4 |
| بيانات النشر: | MDPI AG, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1420-3049 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::33e01e0194479869baa90bad387fe4f5 https://www.mdpi.com/1420-3049/25/4/985 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....33e01e0194479869baa90bad387fe4f5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14203049 |
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