N-acyl hydrazone derivatives reduce pro-inflammatory cytokines, iNOS and COX-2 in acute lung inflammation model

N-acyl hydrazone derivatives are widely employed in medicinal chemistry due to the simplicity of their synthesis and wide range of pharmacological activities described in the literature. In this study, the toxicity and anti-inflammatory activity of four N-acyl hydrazone derivatives were evaluated. The N-acyl hydrazone derivatives JR-13, JR-15, JR-17, and JR-18 were subjected to acute toxicity testing in accordance with the OECD 426 method. Cytotoxic activity was assessed in normal cells, whereas anti-inflammatory activity was evaluated in macrophages in vitro and in an animal model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). The derivatives did not show any changes indicative of in vitro or in vivo toxicity. A reduction in the levels of nitric oxide (NO) and the cytokines IL-18 and TNF-α was observed in the in vitro anti-inflammatory activity test. In the ALI model, the derivatives JR-13, JR-15, JR-17, and JR-18 inhibited cell migration, with a percentage of inflammation inhibition of 62.8 %, 40.9 %, 83.2 %, and 86.9 %, respectively, when compared to the control. The derivatives also reduced NO concentration in bronchoalveolar lavage, myeloperoxidase (MPO) and malondialdehyde (MDA) activity in lung tissue. Immunohistochemical analyses of lung tissue showed decreased COX-2 and iNOS levels. The compounds JR-17 and JR-18 decreased the levels of pro-inflammatory cytokines IL-6, IL-18 and TNF-α and increased the levels of anti-inflammatory cytokines IL-4 and IL-10 in the ALI model. In conclusion, the N-acyl hydrazone derivatives demonstrated the capacity to attenuate inflammation in vitro and in vivo assays, involving the reduction of COX-2, iNOS, and pro-inflammatory cytokines.