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

• DOI: 10.1016/j.ejmech.2017.02.043
• Publication Date: 2017-02-21T05:45:41Z
• Authors: Kris Simone T. Dias; Cynthia T. de Paula; Thiago dos Santos; Isis N.O. Souza; Marina S. Boni; Marcos J.R. Guima...; Fernanda M.R. da ...; Newton G. Castro; Gilda A. Neves; Clarice C. Veloso; Márcio M. Coelho; Ivo Souza F. de Melo; Fabiana C.V. Giusti; Alexandre Giusti-...; Marcelo L. da Silva; Laurent E. Dardenne; Isabella A. Guedes; Letizia Pruccoli; Fabiana Morroni; Andrea Tarozzi; Claudio Viegas
• Keywords: Alzheimer's disease; Feruloyl-donepezil hybrids; Multitarget-directed ligands; Acrylates; Alzheimer Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Cells, Cultured; Cholinesterase Inhibitors; Drug Design; Humans; Indans; Male; Mice; Molecular Docking Simulation; Molecular Targeted Therapy; Neurons; Neuroprotective Agents; Piperidines; Structure-Activity Relationship; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Male; Neurons; 0303 health sciences; Anti-Inflammatory Agents; Antioxidants; Cell Line; 3. Good health; Molecular Docking Simulation; Mice; Structure-Activity Relationship; 03 medical and health sciences; Neuroprotective Agents; Acrylates; Piperidines; Alzheimer Disease; Drug Design; Indans; Animals; Humans; Donepezil; Cholinesterase Inhibitors; Molecular Targeted Therapy; Cells, Cultured

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.