Molecular Hybridization Strategy on the Design, Synthesis, and Structural Characterization of Ferrocene-<i>N</i>-acyl Hydrazones as Immunomodulatory Agents
Laís Peres Silva,
Ivanilson Pimenta Santos,
Dahara Keyse Carvalho Silva,
Bruna Padilha Zurita Claro dos Reis,
Cássio Santana Meira,
Marcos Venícius Batista de Souza Castro,
José Maurício dos Santos Filho,
João Honorato de Araujo-Neto,
Javier Alcides Ellena,
Rafael Gomes da Silveira,
Milena Botelho Pereira Soares
Affiliations
Laís Peres Silva
Department of Life Sciences, State University of Bahia (UNEB), Salvador 41150-000, BA, Brazil
Ivanilson Pimenta Santos
Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, BA, Brazil
Dahara Keyse Carvalho Silva
Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, BA, Brazil
Bruna Padilha Zurita Claro dos Reis
Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, BA, Brazil
Cássio Santana Meira
Department of Life Sciences, State University of Bahia (UNEB), Salvador 41150-000, BA, Brazil
Marcos Venícius Batista de Souza Castro
Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed®, Center for Technology and Geosciences, Federal University of Pernambuco, Recife 50740-521, PE, Brazil
José Maurício dos Santos Filho
Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed®, Center for Technology and Geosciences, Federal University of Pernambuco, Recife 50740-521, PE, Brazil
João Honorato de Araujo-Neto
Multiuser Laboratory of Structural Crystallography, Institute of São Carlos, University of São Paulo, São Carlos 13566-590, SP, Brazil
Javier Alcides Ellena
Multiuser Laboratory of Structural Crystallography, Institute of São Carlos, University of São Paulo, São Carlos 13566-590, SP, Brazil
Rafael Gomes da Silveira
Multiuser Laboratory of Structural Crystallography, Institute of São Carlos, University of São Paulo, São Carlos 13566-590, SP, Brazil
Milena Botelho Pereira Soares
Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, BA, Brazil
Immunomodulatory agents are widely used for the treatment of immune-mediated diseases, but the range of side effects of the available drugs makes necessary the search for new immunomodulatory drugs. Here, we investigated the immunomodulatory activity of new ferrocenyl-N-acyl hydrazones derivatives (SintMed(141–156). The evaluated N-acyl hydrazones did not show cytotoxicity at the tested concentrations, presenting CC50 values greater than 50 µM. In addition, all ferrocenyl-N-acyl hydrazones modulated nitrite production in immortalized macrophages, showing inhibition values between 14.4% and 74.2%. By presenting a better activity profile, the ferrocenyl-N-acyl hydrazones SintMed149 and SintMed150 also had their cytotoxicity and anti-inflammatory effect evaluated in cultures of peritoneal macrophages. The molecules were not cytotoxic at any of the concentrations tested in peritoneal macrophages and were able to significantly reduce (p SintMed150 did not show signs of acute toxicity in animals treated with 50 or 100 mg/kg. Finally, we observed that ferrocenyl-N-acyl hydrazone SintMed150 at 100 mg/kg reduced the migration of neutrophils (44.6%) in an acute peritonitis model and increased animal survival by 20% in an LPS-induced endotoxic shock model. These findings suggest that such compounds have therapeutic potential to be used to treat diseases of inflammatory origin.
