Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-<i>O</i>-Amide Hesperetin Derivatives

Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-<i>O</i>-Amide Hesperetin Derivatives

Yilong Zhang, Yan Zheng, Wen Shi, Yahui Guo, Tao Xu, Zeng Li, Cheng Huang, Jun Li

To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 &#956;M, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-&#945;), interleukin-6 (IL-6) and interleukin-1&#946; (IL-1&#946;) than indomethacin and celecoxib at 10 &#956;M. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-&#954;B) signaling pathway.

2019

hesperetin derivatives, Synthesis, Inflammatory, NF-κB, structure-activity relationships

DOI: 10.3390/molecules24203663

Molecules

MDPI AG

Organic chemistry

EN