Recent Advances in the Synthesis of Selective COX-2 Inhibitors: A Scaffold-Based Structure–Activity Relationship Review

Cyclooxygenase-2 (COX-2) is an inducible enzyme that plays a central role in inflammation and has long been recognized as a compelling target for anti-inflammatory therapy. The introduction of selective COX-2 inhibitors marked a major advance, offering improved gastrointestinal safety over traditional nonsteroidal anti-inflammatory drugs. However, concerns about increased cardiovascular risk with prolonged use, which is largely linked to the suppression of prostacyclin synthesis, have underscored the need for safer and more balanced therapeutic strategies. In response, substantial research efforts have focused on designing and synthesizing new COX-2 inhibitors with enhanced selectivity, optimized pharmacological profiles, and reduced adverse effects. This review provides a critical and up-to-date overview of recent advances in COX-2-targeted anti-inflammatory agents, emphasizing key chemical scaffolds, structure–activity relationship insights, and biological evaluation data. By bringing these findings together, this study aims to offer practical guidance and inspiration for medicinal and organic chemists working toward the development of next-generation anti-inflammatory therapies.