Synthesis and Evaluation of Bakuchiol Derivatives as Potent Anti-inflammatory Agents <i>in Vitro</i> and <i>in Vivo</i>

Abstract

Bakuchiol, a prenylated phenolic monoterpene derived from the fruit of <i>Psoralen corylifolia</i> L. (Buguzhi), is widely used to treat tumors, viruses, inflammation, and bacterial infections. In this study, we designed and synthesized 30 bakuchiol derivatives to identify new anti-inflammatory drugs. The anti-inflammatory activities of the derivatives were screened using lipopolysaccharide-induced RAW264.7 cells. To evaluate the anti-inflammatory activity of the compounds, we measured nitric oxide (NO), interleukin-6, and tumor necrosis factor-α production. Based on the screening results, compound <b>7a</b> displayed more pronounced activity than bakuchiol and celecoxib. Furthermore, the mechanistic studies indicated that <b>7a</b> inhibited pro-inflammatory cytokine release, which was correlated with activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway and blockade of the nuclear factor-κB/mitogen-activated protein kinase signaling pathway. The <i>in vivo</i> anti-inflammatory activity in zebrafish indicated that <b>7a</b> inhibited NO and reactive oxygen species production in a dose-dependent manner. These results indicate that <b>7a</b> is a potential candidate for development as an anti-inflammatory agent.