Synthesis of acetyl and benzoyl esters of xanthorrhizol and its oxidation products and evaluation of their inhibitory activity against nitric oxide production

Abstract

Objective: Xanthorrhizol is known to have anti-inflammatory activity. However, new xanthorrhizol derivatives with improved anti-inflammatory activity and reduced toxicity are needed. Methods: In this study, the derivatives of xanthorrhizol were synthesized and spectroscopically characterized, and their inhibitory activities against nitric oxide [NO] production were evaluated in RAW 264.7 macrophage cells. Results: The first stage of synthesis produced compounds 2a and 2b in 58.49% and 63.26% yields, respectively. Compounds 2a and 2b were oxidized using potassium permanganate, giving compounds 3a and 3b in yields of 51.92% and 43.78%, respectively. Compounds 1, 2a, 3a, and 3b along with diclofenac sodium [the positive control] exhibited IC50 values for NO production of 31.82, 73.85, 354.05, 97.19, and 78.43 µM, respectively. In contrast, compound 2b did not show any inhibitory activity. Based on cytotoxicity assay, compounds 1, 2a, 2b, 3a, 3b, and diclofenac sodium had LD50 values of 30.97, 65.15, 31.15, 117.86, 53.40, and 51.67 µM, respectively. The NO inhibitory activities of compounds 2a, 3a, and 3b were lower than that of xanthorrhizol [compound 1]. However, cytotoxicity tests showed that compounds 2a, 3a, and 3b had reduced toxicities compared to xanthorrhizol. Conclusion: The modification of xanthorrhizol through esterification and oxidation produced derivative compounds with weaker anti-inflammatory activity but reduced cytotoxicity.