title: Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease.
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.
authors.affiliation: PeQuiM- Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
authors.forename: Kris Simone T
authors.initials: KS
authors.lastname: Dias
authors.affiliation: PeQuiM- Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: de Paula
authors.affiliation: PeQuiM- Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
authors.forename: Thiago
authors.initials: T
authors.lastname: Dos Santos
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Isis N O
authors.initials: IN
authors.lastname: Souza
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Boni
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Marcos J R
authors.initials: MJ
authors.lastname: Guimarães
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Fernanda M R
authors.initials: FM
authors.lastname: da Silva
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Newton G
authors.initials: NG
authors.lastname: Castro
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Gilda A
authors.initials: GA
authors.lastname: Neves
authors.affiliation: Pharmaceutical Sciences Faculty, Federal University of Amazonas (UFAM), 69067-005, Manaus, AM, Brazil.
authors.forename: Clarice C
authors.initials: CC
authors.lastname: Veloso
authors.affiliation: Department of Pharmaceutical Products, Pharmaceutical Faculty, Federal University of Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Márcio M
authors.initials: MM
authors.lastname: Coelho
authors.affiliation: Department of Pharmaceutical Products, Pharmaceutical Faculty, Federal University of Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Ivo Souza F
authors.initials: IS
authors.lastname: de Melo
authors.affiliation: Department of Physiological Sciences, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
authors.forename: Fabiana C V
authors.initials: FC
authors.lastname: Giusti
authors.affiliation: Department of Physiological Sciences, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Giusti-Paiva
authors.affiliation: Physiotherapy Department, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil.
authors.forename: Marcelo L
authors.initials: ML
authors.lastname: da Silva
authors.affiliation: National Laboratory of Scientific Computation, 25651-075, Petrópolis, RJ, Brazil.
authors.forename: Laurent E
authors.initials: LE
authors.lastname: Dardenne
authors.affiliation: National Laboratory of Scientific Computation, 25651-075, Petrópolis, RJ, Brazil.
authors.forename: Isabella A
authors.initials: IA
authors.lastname: Guedes
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Pruccoli
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Morroni
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tarozzi
authors.affiliation: PeQuiM- Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, 37130-000, Alfenas, MG, Brazil. Electronic address: cvjviegas@gmail.com.
authors.forename: Claudio
authors.initials: C
authors.lastname: Viegas
mesh_terms: D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002460:Cell Line; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000077265:Donepezil; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy / Q000379:methods*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000179:Acrylates; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D007189:Indans; D018696:Neuroprotective Agents; D010880:Piperidines; D000077265:Donepezil; C036658:acrylic acid
keywords: Alzheimer's disease; Feruloyl-donepezil hybrids; Multitarget-directed ligands