Curcumin was reported as an anti-inflammatory agent. However, curcumin's poor bioavailability limited its clinical utility. Here, thirty ortho-substituted mono-carbonyl curcumin derivatives, containing acetone, cyclopentanone, cyclohexanone or 4-piperidione (NH, N-methyl or N-acrylyl) moieties replacing β-diketone moiety of curcumin, were investigated for anti-inflammatory activity. Two active ortho-trifluoromethoxy-substituted 4-piperidione-containing derivatives 22 and 24 owned good cell uptake ability, and displayed excellent anti-inflammatory activity in both lipopolysaccharide-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. They inhibited the production of nitric oxide, reactive oxygen species, malonic dialdehyde and cyclooxygenase-2; and the expression of pro-inflammatory cytokines interleukin-1β, tumor necrosis factor-α and myeloperoxidase; the phosphorylation of mitogen-activated protein kinases; and the nucleus translocation of p65. What's more, 22 or 24 oral administered reduced the severity of clinical symptoms of ulcerative colitis (body weight and disease activity index), and reduced obviously DSS-induced colonic pathological damage (the colon length and histopathology analysis). These results suggested that ortho-trifluoromethoxy-substituted 4-piperidione-containing mono-carbonyl curcumin derivatives 22 and 24 were potential anti-inflammatory agents; and offered the important information for design and discovery of more potent anti-inflammatory drug candidates.
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