Design, Synthesis and Biological Evaluation of Novel Triazole <em>N</em>-acylhydrazone Hybrids for Alzheimer’s Disease
Matheus de Freitas Silva,
Ellen Tardelli Lima,
Letizia Pruccoli,
Newton G. Castro,
Marcos Jorge R. Guimarães,
Fernanda M. R. da Silva,
Nathalia Fonseca Nadur,
Luciana Luiz de Azevedo,
Arthur Eugen Kümmerle,
Isabella Alvim Guedes,
Laurent Emmanuel Dardenne,
Vanessa Silva Gontijo,
Andrea Tarozzi,
Claudio Viegas
Affiliations
Matheus de Freitas Silva
Laboratory of Research in Medicinal Chemistry (PeQuiM), Federal University of Alfenas, Jovino Fernandes Sales Avenue, 2600, Alfenas 37130000, MG, Brazil
Ellen Tardelli Lima
Laboratory of Research in Medicinal Chemistry (PeQuiM), Federal University of Alfenas, Jovino Fernandes Sales Avenue, 2600, Alfenas 37130000, MG, Brazil
Letizia Pruccoli
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy
Newton G. Castro
Laboratory of Molecular Pharmacology, Federal University of Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Rio de Janeiro 21941590, RJ, Brazil
Marcos Jorge R. Guimarães
Laboratory of Molecular Pharmacology, Federal University of Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Rio de Janeiro 21941590, RJ, Brazil
Fernanda M. R. da Silva
Laboratory of Molecular Pharmacology, Federal University of Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Rio de Janeiro 21941590, RJ, Brazil
Nathalia Fonseca Nadur
Laboratory of Molecular Diversity and Medicinal Chemistry (LaDMol-QM), Federal Rural University of Rio de Janeiro—UFRRJ, BR-465, Km 7 Seropédica-Rio de Janeiro 23890000, RJ, Brazil
Luciana Luiz de Azevedo
Laboratory of Molecular Diversity and Medicinal Chemistry (LaDMol-QM), Federal Rural University of Rio de Janeiro—UFRRJ, BR-465, Km 7 Seropédica-Rio de Janeiro 23890000, RJ, Brazil
Arthur Eugen Kümmerle
Laboratory of Molecular Diversity and Medicinal Chemistry (LaDMol-QM), Federal Rural University of Rio de Janeiro—UFRRJ, BR-465, Km 7 Seropédica-Rio de Janeiro 23890000, RJ, Brazil
Isabella Alvim Guedes
Grupo de Modelagem Molecular em Sistemas Biológicos (GMMSB), National Laboratory for Scientific Computing—LNCC, Avenida Getúlio Vargas, 333, Petrópolis 25651-076, RJ, Brazil
Laurent Emmanuel Dardenne
Grupo de Modelagem Molecular em Sistemas Biológicos (GMMSB), National Laboratory for Scientific Computing—LNCC, Avenida Getúlio Vargas, 333, Petrópolis 25651-076, RJ, Brazil
Vanessa Silva Gontijo
Laboratory of Research in Medicinal Chemistry (PeQuiM), Federal University of Alfenas, Jovino Fernandes Sales Avenue, 2600, Alfenas 37130000, MG, Brazil
Andrea Tarozzi
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy
Claudio Viegas
Laboratory of Research in Medicinal Chemistry (PeQuiM), Federal University of Alfenas, Jovino Fernandes Sales Avenue, 2600, Alfenas 37130000, MG, Brazil
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Aβ42 oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics.
