Novel Cinnamic Acid Derivatives Containing Naproxen as NLRP3 Inhibitors: Synthesis and Evaluation of Their Biological Activity

Long-term use of naproxen can lead to serious side effects. Inspired by the biological activity of cinnamic acid, a series of cinnamic acid derivatives containing naproxen were designed and synthesized, and their anti-inflammatory activities and mechanisms were explored in vitro. Our results indicated that all of naproxen derivatives showed more significant inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) production and had a lower degree of cytotoxicity than that of naproxen. The present studies revealed that compound 23 (IC₅₀ = 5.66 ± 1.66 µM) markedly inhibited the LPS-induced NO production and the over-expression of pro-inflammatory cytokines, including interleukin (IL)-1β, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2). Furthermore, it blocked the activation of NF-κB signaling pathway and pyrin domain-containing protein 3 (NLRP-3) inflammasome in a concentration-dependent manner. Additionally, docking studies confirmed that compound 23 exhibited a well-fitting into the NLRP3 active site. Considering these results, compound 23 might be a novel NLRP3 inhibitor to treat inflammatory diseases.