Design, Synthesis, and Evaluation of Bis-Chalcones and Bis-Flavones as Selective COX-2 Inhibitors.

Over the past two decades, the search for safe and effective COX-2 inhibitors has spurred extensive research on flavonoids. Within this context, synthetic flavonoid dimers have emerged as a promising subclass with potential anti-inflammatory activity. To investigate whether dimerization enhances their potency and selectivity, novel A-fused bis-chalcones and A-fused bis-flavones were synthesized and evaluated for their inhibitory activity against isolated human COX-1 and COX-2 enzymes, as well as their effects on prostaglandin E2 production in whole human blood. Interestingly, the most active compound identified was a monomeric chalcone sharing the same substitution pattern as the top-performing bis-chalcone, suggesting that key structural features drive activity regardless of dimerization. While the dimeric nature of bis-chalcones did not enhance COX-2 inhibition or selectivity in this study, these results provide valuable insights into structure-activity relationships. Furthermore, all active compounds against the isolated enzyme showed reduced potency in whole blood, possibly due to plasma protein binding limiting bioavailability. This study highlights the importance of rational design for further development of dimeric flavonoids, in particular strategies aimed at optimizing bioavailability.