Synthesis and anti‐inflammatory activity of novel firocoxib analogues with balanced COX inhibition

The adverse effects caused by nonselective and selective cyclooxygenase‐2 (COX‐2) inhibitors remain a challenge for current anti‐inflammatory medications. A balanced inhibition of COX‐1/−2 represents a promising strategy for the development of novel COX‐2 inhibitors. In this study, we present the design and synthesis of a novel series of firocoxib analogues incorporating an amide bond to facilitate essential hydrogen bonding with amino residues in COX‐2. The synthesized analogs were evaluated for their inhibitory activity against both COX‐1 and COX‐2 enzymes. Among them, compound 9d demonstrated potent and balanced inhibition. Inhibition of COX enzymes by 9d in lipopolysaccharide (LPS)‐stimulated murine RAW264.7 macrophages resulted in the suppression of the NF‐κB signaling pathway to reduced expression of pro‐inflammatory factors such as inducible nitric oxide synthase (iNOS), COX‐2, nitric oxide (NO), and reactive oxygen species (ROS). The remarkable in vitro anti‐inflammatory activity exhibited by 9d positions it as a promising candidate for further development as a novel lead compound for inflammation treatment. This study presents a design strategy, synthesis, and evaluation of balanced COX inhibitors derived from paracetamol and firocoxib, highlighting their potential therapeutic value in the context of inflammation.