Synthesis and sar study of diarylpentanoid analogues as new anti-inflammatory agents

• Published in: Molecules (Basel, Switzerland) Switzerland), 2014-10, Vol.19 (10), p.16058-16081
• Main Authors: Leong, Sze Wei, Faudzi, Siti Munirah Mohd, Abas, Faridah, Aluwi, Mohd Fadhlizil Fasihi Mohd, Rullah, Kamal, Wai, Lam Kok, Bahari, Mohd Nazri Abdul, Ahmad, Syahida, Tham, Chau Ling, Shaari, Khozirah, Lajis, Nordin H
• Format: Article
• Language: English
• Subjects: Animals; anti-inflammatory; Anti-inflammatory agents; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Cell Line; curcumin; Curcumin - pharmacology; Cytokines; diarylpentanoid; Drug Stability; Electronic mail systems; Food science; Hydrogen Bonding; Inhibitory Concentration 50; Interferon-gamma; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Molecular Conformation; Molecular Structure; Nitric oxide; Nitric Oxide - metabolism; pharmacophore; Quantitative Structure-Activity Relationship; RAW 264.7; SAR; Tumor necrosis factor-TNF
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules191016058

A series of ninety-seven diarylpentanoid derivatives were synthesized and evaluated for their anti-inflammatory activity through NO suppression assay using interferone gamma (IFN-γ)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Twelve compounds (9, 25, 28, 43, 63, 64, 81, 83, 84, 86, 88 and 97) exhibited greater or similar NO inhibitory activity in comparison with curcumin (14.7 ± 0.2 µM), notably compounds 88 and 97, which demonstrated the most significant NO suppression activity with IC50 values of 4.9 ± 0.3 µM and 9.6 ± 0.5 µM, respectively. A structure-activity relationship (SAR) study revealed that the presence of a hydroxyl group in both aromatic rings is critical for bioactivity of these molecules. With the exception of the polyphenolic derivatives, low electron density in ring-A and high electron density in ring-B are important for enhancing NO inhibition. Meanwhile, pharmacophore mapping showed that hydroxyl substituents at both meta- and para-positions of ring-B could be the marker for highly active diarylpentanoid derivatives.