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The in vitro anti-inflammatory activity of N-antipyrine-3,4-dichloromaleimide derivatives is due to an immunomodulatory effect on cytokines environment.

BACKGROUND AND AIM
Inflammation is the immune response to a harmful stimulus, and its purpose is to destroy foreign agents so that the affected site can be repair. When uncontrolled or unresolved, inflammation can lead to significant tissue damage. Many classes of compounds are used today as anti-inflammatory drugs. However, there is an ongoing demand for new, more effective molecules with higher safety margins. In this regard, the anti-inflammatory effect of six synthetic compounds of N-antipyrine-3,4-dichloromaleimide was evaluated.


METHODS
RAW 264.7 cells were used to evaluate the cytotoxicity and the anti-inflammatory activity, by measuring the effect of these molecules on nitric oxide, IL-1β, IL-6, MCP-1 (CCL2), TNF-α, INF-γ, IL-4, and IL-13 levels, as well as under NF-κB activation.


RESULTS
Some of the tested compounds showed significant cytotoxicity (CC50 < 100 µM). Subsequently, the potential of nitric oxide (NO) inhibition as screening for potential anti-inflammatory action was evaluated. Three of the compounds tested showed a promising profile (1, 3, and 5). When the effect of these compounds was evaluated on the production of IL-1β, IL-6, MCP-1 (CCL2), TNF-α, and INF-γ, only N-antipyrine-3,4-dichloromaleimide (1) and N-antipyrine-3-chloro-4-(3,4-dichloroaniline) maleimide (3) showed significant inhibition profiles. These two compounds were also able to increase the production of cytokines known for having an anti-inflammatory profile (IL-4 and IL-13) and inhibit the phosphorylation of the p-p65 NF-κB subunit significantly.


CONCLUSION
In conclusion, these two compounds present a significant and unusual anti-inflammatory mechanism (increasing the production of anti-inflammatory mediators). They are therefore considered promising prototypes for the development of new anti-inflammatory drugs with immunomodulatory characteristics.