Abstract
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.
Highlights
Diarylpentanoids may be considered as analogues of curcumin, the major constituent of Curcuma domestica, differing structurally by the replacement of the heptane bridge with a shorter, pentane bridge.They may be considered as analogues of zerumbone, a natural sesquiterpenoid isolated fromZingiber zerumbet, based on the common feature of a dienone moiety
The new and known compounds are differentiated by the presence of a reference melting point as presented in Table S1 in Supplementary Data
All benzaldehydes and naphthaldehydes were successfully converted into the respective acrylic acids with greater than 85% conversion
Summary
Diarylpentanoids may be considered as analogues of curcumin, the major constituent of Curcuma domestica, differing structurally by the replacement of the heptane bridge with a shorter, pentane bridge.They may be considered as analogues of zerumbone, a natural sesquiterpenoid isolated fromZingiber zerumbet, based on the common feature of a dienone moiety. Diarylpentanoids may be considered as analogues of curcumin, the major constituent of Curcuma domestica, differing structurally by the replacement of the heptane bridge with a shorter, pentane bridge. They may be considered as analogues of zerumbone, a natural sesquiterpenoid isolated from. Occurring diarylpentanoids have been reported as minor constituents from Curcuma domestica and found to exhibit strong antioxidant activity [1]. Diarylpentanoids and zerumbone have gained increasing attention for their excellent pharmacological activities and better bioavailability compared to curcumin. We have previously shown that 2,6-bis-(4hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), a diarylpentanoid synthesized by our group, is a potent anti-inflammatory agent in preventing lethality of cecal ligation and puncture (CLP)-induced sepsis [5]. The compound was further shown to exhibit anti-nociceptive activity in a mouse model [6]
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