SYNTHESIS OF ACETYL AND BENZOYL ESTERS OF XANTHORRHIZOL AND ITS OXIDATION PRODUCTS AND EVALUATION OF THEIR INHIBITORY ACTIVITY AGAINST NITRIC OXIDE PRODUCTION

MAYA DAMAYANTI RAHAYU,SUSI KUSUMANINGRUM,HAYUN HAYUN

doi:10.22159/ijap.2020.v12s1.ff030

MAYA DAMAYANTI RAHAYU, SUSI KUSUMANINGRUM + Show 1 more

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https://doi.org/10.22159/ijap.2020.v12s1.ff030

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Abstract

Objective: Xanthorrhizol is known to have anti-inflammatory activity. However, new xanthorrhizol derivatives with improved anti-inflammatoryactivity and reduced toxicity are needed.Methods: In this study, the derivatives of xanthorrhizol were synthesized and spectroscopically characterized, and their inhibitory activities againstnitric 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 oxidizedusing potassium permanganate, giving compounds 3a and 3b in yields of 51.92% and 43.78%, respectively. Compounds 1, 2a, 3a, and 3b alongwith 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. Incontrast, compound 2b did not show any inhibitory activity. Based on cytotoxicity assay, compounds 1, 2a, 2b, 3a, 3b, and diclofenac sodium had LD50values 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 thatof 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-inflammatoryactivity but reduced cytotoxicity.

Highlights

Inflammation is a protective immune response designed to protect against pathogenic infections and tissue injuries [1]
We have recently reported the oxidation of 1-O-acetyl-xanthorrhizol using permanganate to obtain an α-hydroxyl ketone of the compound, but the synthesis of other derivatives and evaluation of their biological activities have not been reported [15]
2-Methyl-5-(6-methylhept-5-en-2-yl)phenyl benzoate (2b) Compound 2b was obtained as a yellow oil in 63.2% yield: Fourier transform infrared (FTIR) (KBr) cm−1, 2962.75 and 2924.22 (C–H aliphatic), 1737.90 (C=O ester), 1263.59 (C–O ester). 1H-Nuclear magnetic resonance (NMR) (500 MHz, CDCl3), δ: 8.23 (1H, d, J = 8.55, Ar-H), 7.52 (1H, m, Ar-H), 7.64 (1H, m, Ar-H), 7.18 (1H, d, J = 7.8, Ar-H), 7.02 (1H, d, J = 7.75, Ar-H), 6.96 (1H, s, Ar-H), 5.09 (1H, m, CH2– CH=C), 2.7 (1H, m, CH–Ar), 2.19 (3H, s, CH3–Ar), 1.92 (2H, m, CH2–CH2– CH), 1.67 (3H, s, CH3–C), 1.6 (2H, m, CH–CH2–CH2), 1.54 (3H, s, CH3–C), The 4th International Conference on Global Health 2019

Summary

Introduction

Inflammation is a protective immune response designed to protect against pathogenic infections and tissue injuries [1]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed. NSAIDs work by inhibiting cyclooxygenase (COX) enzymes, which catalyze the conversion of arachidonic acid into the inflammatory mediators prostaglandin and thromboxane [2,3]. When developing anti-inflammatory drugs, an alternative to COX enzyme inhibition is the hindrance of nitric oxide (NO) production. In addition to COX inhibition, some NSAIDs inhibit NO production by restraining inducible NO synthase (iNOS) expression. Diclofenac sodium, an NSAID, inhibits iNOS gene expression at the transcription level by suppressing nuclear factor kappa B activity. The inhibition of iNOS gene expression results in a reduction in NO production [5] and NOS inhibitors found to be effective in treating experimentally induced arthritis [6]

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