A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AbetaO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AbetaO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.
Dias Viegas FP, de Freitas Silva M, Divino da Rocha M, Castelli MR, Riquiel MM, Machado RP, Vaz SM, Simoes de Lima LM, Mancini KC, Marques de Oliveira PC, Morais EP, Gontijo VS, da Silva FMR, D'Alincourt da Fonseca Pecanha D, Castro NG, Neves GA, Giusti-Paiva A, Vilela FC, Orlandi L, Camps I, Veloso MP, Leomil Coelho LF, Ionta M, Ferreira-Silva GA, Pereira RM, Dardenne LE, Guedes IA, de Oliveira Carneiro Junior W, Quaglio Bellozi PM, Pinheiro de Oliveira AC, Ferreira FF, Pruccoli L, Tarozzi A, Viegas C, Jr. (2018) Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates Eur Journal of Medicinal Chemistry147: 48-65
Dias Viegas FP, de Freitas Silva M, Divino da Rocha M, Castelli MR, Riquiel MM, Machado RP, Vaz SM, Simoes de Lima LM, Mancini KC, Marques de Oliveira PC, Morais EP, Gontijo VS, da Silva FMR, D'Alincourt da Fonseca Pecanha D, Castro NG, Neves GA, Giusti-Paiva A, Vilela FC, Orlandi L, Camps I, Veloso MP, Leomil Coelho LF, Ionta M, Ferreira-Silva GA, Pereira RM, Dardenne LE, Guedes IA, de Oliveira Carneiro Junior W, Quaglio Bellozi PM, Pinheiro de Oliveira AC, Ferreira FF, Pruccoli L, Tarozzi A, Viegas C, Jr. (2018) Eur Journal of Medicinal Chemistry147: 48-65
