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

作者：Dias Kris Simone T; de Paula Cynthia T; dos Santos Thiago; Souza Isis N O; Boni Marina S; Guimaraes Marcos J R; da Silva Fernanda M R; Castro Newton G; Neves Gilda A; Veloso Clarice C; Coelho Marcio M; de Melo Ivo Souza F; Giusti Fabiana C V; Giusti Paiva Alexandre; da Silva Marcelo L; Dardenne Laurent E; Guedes Isabella A; Pruccoli Letizia; Morroni Fabiana; Tarozzi Andrea; Viegas Claudio Jr^*

来源：European Journal of Medicinal Chemistry, 2017, 130: 440-457.

DOI：10.1016/j.ejmech.2017.02.043

• Feruloyl-donepezil hybrids
• Alzheimer's disease
• Multitarget-directed ligands

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 mu M. 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.

• 出版日期2017-4-21