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Molecular Hybridization Strategy on the Design, Synthesis, and Structural Characterization of Ferrocene- N -acyl Hydrazones as Immunomodulatory Agents.

Laís Peres SilvaIvanilson Pimenta SantosDahara Keyse Carvalho SilvaBruna Padilha Zurita Claro Dos ReisCássio Santana MeiraMarcos Venícius Batista de Souza CastroJosé Maurício Dos Santos FilhoJoão Honorato de Araujo-NetoJavier Alcides EllenaRafael Gomes da SilveiraMilena Botelho Pereira Soares
Published in: Molecules (Basel, Switzerland) (2022)
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 CC 50 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 < 0.05) the production of nitrite, TNF-α, and IL-1β. Interestingly, both molecules significantly reduced the production of IL-2 and IFN-γ in cultured splenocytes activated with concanavalin A. Moreover, 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.
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