Design, Synthesis, and Evaluation of New Polyhydroxylated Bis-Chalcones as Potential COX-2 Selective Inhibitors

Selective inhibition of COX-2 is considered one of the best strategies for treating chronic inflammatory diseases. However, the currently available options still have significant side effects due to exacerbated selectivity. Bis-chalcone derivatives have shown promising anti-inflammatory properties with reduced side effects. In this study, a family of polyhydroxylated bis-chalcones was synthesized and tested in vitro for their ability to inhibit human COX-2 and COX-1 and to assess selectivity. To further understand their mechanism of action, inhibitory kinetic analysis and in silico molecular docking calculations were performed. The results showed that bis-chalcone 31, with hydroxy groups at positions 3' and 4' of the B rings and three hydroxy groups at the center, was the most active. It was recognized as a mixed-type inhibitor with balanced selectivity. With molecular docking, it was observed that this substitution pattern provided bis-chalcone 31 with additional bulk that hindered its access to the active pocket of COX-1 over COX-2. Also, compound 31 establishes additional hydrogen bonds within the COX-2 pocket that bis-chalcone 30 did not, therefore explaining the selectivity and superior potency of bis-chalcone 31. In conclusion, bis-chalcone 31 with multiple hydroxy groups in its structure shows promising properties for the design of new COX-2 selective inhibitors.