2. Academic Validation
  3. Synthesis and pharmacological evaluation of novel N-aryl-cinnamoyl-hydrazone hybrids designed as neuroprotective agents for the treatment of Parkinson's disease

Synthesis and pharmacological evaluation of novel N-aryl-cinnamoyl-hydrazone hybrids designed as neuroprotective agents for the treatment of Parkinson's disease

  • Bioorg Chem. 2024 Sep:150:107587. doi: 10.1016/j.bioorg.2024.107587.
Matheus de Freitas Silva 1,  Cindy Juliet Cristancho Ortiz 2,  Letícia Ferreira Coelho 2,  Letizia Pruccoli 3,  Barbara Pagliarani 3,  Leonardo Pisani 4,  Marco Catto 4,  Giulio Poli 5,  Tiziano Tuccinardi 5,  Fabiana Cardoso Vilela 6,  Alexandre Giusti-Paiva 7,  Marina Amaral Alves 8,  Hygor M Ribeiro de Souza 8,  Andrea Tarozzi 3,  Vanessa Silva Gontijo 2,  Claudio Viegas Jr 9
Affiliations

Affiliations

  • 1 PeQuiM - Laboratory of Research in Medicinal Chemistry, Federal University of Alfenas, Jovino Fernandes Sales Avenue 2600, 37133-840 Alfenas, Brazil; Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • 2 PeQuiM - Laboratory of Research in Medicinal Chemistry, Federal University of Alfenas, Jovino Fernandes Sales Avenue 2600, 37133-840 Alfenas, Brazil.
  • 3 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • 4 Department of Pharmacy-Pharmaceutical Sciences, University Aldo Moro of Bari, Via E. Orabona 4, 70125 Bari, Italy.
  • 5 Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy.
  • 6 Center of Innovation and Pre-clinical Assays- CIEnP, 88056-000 Florianopolis, Brazil.
  • 7 Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianopolis, Brazil.
  • 8 LabMeta, Metabolomics Laboratory, Institute of Chemistry, Federal University of Rio de Janeiro, 21941-598 Rio de Janeiro, Brazil.
  • 9 PeQuiM - Laboratory of Research in Medicinal Chemistry, Federal University of Alfenas, Jovino Fernandes Sales Avenue 2600, 37133-840 Alfenas, Brazil. Electronic address: claudio.viegas@unifal-mg.edu.br.
PMID: 38941700 DOI: 10.1016/j.bioorg.2024.107587
Abstract

Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1β, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.

Keywords

Cinnamic acid hybrids; Keap1/Nrf2 pathway; Molecular hybridization; N-aryl-cinnamoyl-hydrazones; Neurodegenerative diseases; Parkinson’s disease.

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