Design, Synthesis, and Evaluation of New Polyhydroxylated B is ‐Chalcones as Potential COX‐2 Selective Inhibitors

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Abstract
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.
Funding Information
  • Fundação para a Ciência e a Tecnologia (UID/50006)
  • Fundação para a Ciência e a Tecnologia (UI/BD/151269/2021)

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