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New myricetin-pentadienone hybrids with anti-inflammatory was discovered which could significantly decreased production of NO, IL-6 and TNF-α LPS-stimulated. Preliminary mechanism indicated that it could inhibit thioredoxin reductase expression, resulting in inhibiting of cell signaling pathway. • New myricetin-pentadienone hybrids were synthesized. • Compounds showed anti-inflammatory activity against IL-6、NO and TNF-α. • Preliminary mechanisms of anti-inflammatory action were discovered. Some important pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-α and nitric oxide are thought to play key roles in the destruction of cartilage and bone tissue in joints affected by rheumatoid arthritis. In the present study, a series of new myricetin-pentadienone hybrids were designed and synthesized. Majority of them effectively inhibited the expressions liposaccharide-induced secretion of IL-6, TNF-α and NO in RAW264.7. The most prominent compound 5o could significantly decrease production of above inflammatory factors with IC 50 values of 5.22 µM, 8.22 µM and 9.31 µM, respectively. Preliminary mechanism studies indicated that it could inhibit the expression of thioredoxin reductase, resulting in inhibiting of cell signaling pathway nuclear factor (N-κB) and mitogen-activated protein kinases. Significantly, compound 5o was found to effectively inhibit Freund's complete adjuvant induced rat adjuvant arthritis in vivo. [ABSTRACT FROM AUTHOR]