Background:
Paracetamol (p-aminophenol) and salicylates are nonsteroidal antiinflammatory
drugs that are widely used in the general population. The adverse effects of both drugs
continue to be a focus of the pharmaceutical industry in the development of new molecules that will
increase treatment safety. In this context, we tested nine compounds derived from paracetamol and salicylates,
synthesized in our laboratory, for their safety and ex vivo and in vivo anti-inflammatory activity.
Methods:
We analyzed the cytotoxicity of the compounds in ex vivo mice neutrophils, and their ability
to inhibit the production of pro-inflammatory mediators (nitric oxide and interleukin-6) after stimulating
with LPS. Next, in the selected molecules, we evaluated the anti-inflammatory effect on an in vivo inflammatory
model of acute lung injury in mice. All nine compounds were also submitted to the cytotoxicity
assay, like the original compounds.
Results:
None of the compounds showed cytotoxicity under the cells used. However, of the initial compounds,
only five demonstrated anti-inflammatory effect, inhibiting Nitric Oxide (NO) and interleukin 6
(IL-6) production by neutrophils stimulated with Lipopolysaccharide (LPS). After this initial trial, four
modified compounds were able to reduce leukocyte migration and fluid leakage in the bronchoalveolar
lavage of mice. However, only the compound 5a1, derived from the esterification of gentisic acid, was
able to significantly inhibit the levels of all pro-inflammatory cytokines and increase the levels of antiinflammatory
cytokines evaluated.
Conclusion:
In conclusion, all compounds showed a good safety profile, and many of them had an antiinflammatory
effect. However, the compound derived from gentisic acid is highlighted for its significant
effects ex vivo and in vivo and in this context, we believe that this compound is a potential candidate for
the development of a new anti-inflammatory drug.