| Summary: | To develop new anti-inflammatory agents, a series of 7-<i>O</i>-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-<i>O</i>-(2-(Propylamino)-2-oxoethyl)hesperetin (<b>4d</b>) and 7-<i>O</i>-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (<b>4k</b>) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC<sub>50</sub> = 19.32 and 16.63 μM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) than indomethacin and celecoxib at 10 μM. The structure-activity relationships (SARs) suggested that the 7-<i>O</i>-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound <b>4d</b> 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-κB) signaling pathway.
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