Design, Synthesis, Computational and Biological Evaluation of Two New Series of 1, 3-and 1,6-dihydroxy Xanthone Derivatives as Selective COX-2 Inhibitors

Background: Over the years, the xanthone nucleus has been serving as an interesting scaffold for the design of derivatives aiming at anti-inflammatory drug development. Objective: The objective of the current work was to design and synthesize two series of novel 3-(5'-substituted pentyloxy)-1-hydroxy xanthone & 6-(5'-substituted pentyloxy)-1-hydroxy xanthone derivatives. The designed compounds were examined in vivo for anti-inflammatory activity. The effect of the synthesized xanthone derivatives on the serum expression of IL-10 and TNF-alpha was evaluated to understand the underlying molecular mechanisms. Methods: The title compounds were virtually designed and screened for ADME/T properties and docked onto the COX-2 protein. The synthesis of the xanthone derivatives was achieved by the condensation of salicylic acid derivatives and a suitable phenol in the presence of a mixture of phosphorus pentoxide-methanesulfonic acid as an acylation catalyst. The compounds were evaluated for in vivo anti-inflammatory activity by carrageenan induced paw edema method and serum expression of cytokines was evaluated using ELISA assays. Results: The selected compounds exhibited docking scores ranging between -10.7 to -6.8 (Kcal/mol), respectively, as compared with standard Celecoxib (-7.9 Kcal/mol) and the non-selective COX inhibitor Indomethacin (-6.4 Kcal/mol). Among the tested compounds, 9u has shown the highest activity with 65.6 % reduction in edema (69.8% for Celecoxib). Immunoassay results showed a significant drop in serum TNF-alpha and an elevation in serum IL-10. Conclusion: The findings highlight that some of the synthesized xanthone derivatives displayed marked anti-inflammatory activity, which can be further investigated to render efficient and novel non-ulcerogenic anti-inflammatory agents.