Design, synthesis, and in vitro evaluation of novel 2-(5,8-dimethyl-2-naphthyl) propanoic acid derivatives as selective COX-2 inhibitors

Selective cyclooxygenase-2 (COX-2) inhibitors are important therapeutic agents for the management of inflammatory disorders due to their reduced gastrointestinal adverse effects compared to nonselective NSAIDs. Naproxen is a widely used anti-inflammatory drug; however, its limited COX-2 selectivity necessitates the development of improved analogs with enhanced efficacy and safety profiles. Santonin, a naturally occurring sesquiterpene lactone, offers a valuable scaffold for the semi-synthesis of novel bioactive compounds. The present study aimed to design and synthesize novel 2-(5,8-dimethyl-2-naphthyl)-propanoic acid derivatives as naproxen analogs from santonin and evaluate their potential as selective COX-2 inhibitors with enhanced anti-inflammatory activity. A series of novel derivatives was designed through docking studies and semi-synthesized from santonin using molecular iodine as a catalyst. The synthesized compounds were structurally characterized and evaluated for their inhibitory activity against COX isoforms in vitro. MD simulation of the compound 12-COX-2 complex was performed to determine the stability of the protein-ligand complex. Among the synthesized derivatives, 2-(7-methoxy-5,8-dimethylnaphthalen-2-yl) propanoic acid (12) emerged as the most promising candidate. These findings demonstrate that santonin-derived naproxen analogs represent a promising class of selective COX-2 inhibitors, with 12 showing significant potential for further development as an anti-inflammatory therapeutic agent.