| Summary: | 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-<i>N</i>-acyl hydrazones derivatives (<b>SintMed</b>(<b>141</b>–<b>156</b>). The evaluated <i>N</i>-acyl hydrazones did not show cytotoxicity at the tested concentrations, presenting CC<sub>50</sub> values greater than 50 µM. In addition, all ferrocenyl-<i>N</i>-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-<i>N</i>-acyl hydrazones <b>SintMed149</b> and <b>SintMed150</b> 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 (<i>p</i> < 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, <b>SintMed150</b> did not show signs of acute toxicity in animals treated with 50 or 100 mg/kg. Finally, we observed that ferrocenyl-<i>N</i>-acyl hydrazone <b>SintMed150</b> 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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