2. Academic Validation
  3. Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease

Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2017 Apr 21:130:440-457. doi: 10.1016/j.ejmech.2017.02.043.
Kris Simone T Dias 1,  Cynthia T de Paula 1,  Thiago Dos Santos 1,  Isis N O Souza 2,  Marina S Boni 2,  Marcos J R Guimarães 2,  Fernanda M R da Silva 2,  Newton G Castro 2,  Gilda A Neves 2,  Clarice C Veloso 3,  Márcio M Coelho 4,  Ivo Souza F de Melo 4,  Fabiana C V Giusti 5,  Alexandre Giusti-Paiva 5,  Marcelo L da Silva 6,  Laurent E Dardenne 7,  Isabella A Guedes 7,  Letizia Pruccoli 8,  Fabiana Morroni 9,  Andrea Tarozzi 8,  Claudio Viegas Jr 10
Affiliations

Affiliations

  • 1 PeQuiM- Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
  • 2 Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
  • 3 Pharmaceutical Sciences Faculty, Federal University of Amazonas (UFAM), 69067-005, Manaus, AM, Brazil.
  • 4 Department of Pharmaceutical Products, Pharmaceutical Faculty, Federal University of Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
  • 5 Department of Physiological Sciences, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
  • 6 Physiotherapy Department, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
  • 7 National Laboratory of Scientific Computation, 25651-075, Petrópolis, RJ, Brazil.
  • 8 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
  • 9 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
  • 10 PeQuiM- Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil. Electronic address: cvjviegas@gmail.com.
PMID: 28282613 DOI: 10.1016/j.ejmech.2017.02.043
Abstract

A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC50 = 0.46 μM. In addition, these three most promising compounds exhibited significant in vivo anti-inflammatory activity in the mice paw edema, pleurisy and formalin-induced hyperalgesy models, in vitro metal chelator activity for Cu2+ and Fe2+, and neuroprotection of human neuronal cells against oxidative damage. Molecular docking studies corroborated the in vitro inhibitory mode of interaction of these active compounds on AChE. Based on these data, compound 12a was identified as a novel promising drug prototype candidate for the treatment of AD with innovative structural feature and multitarget effects.

Keywords

Alzheimer's disease; Feruloyl-donepezil hybrids; Multitarget-directed ligands.

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