Discovery of Coixol Derivatives as Potent Anti-inflammatory Agents

Coixol,a derivative of 2-benzoxazolinone extracted from coix (Coixlachryma-jobi L. var. ma-yuen Stapf),has demonstrated promising anti-inflammatory activity and low cytotoxicity.In this study, 26 coixol derivatives were designed and synthesizedby hybridization with cinnamic acid to identify new anti-inflammatoryagents. The anti-inflammatory activities of the derivatives were screenedusing LPS-induced overexpression of nitric oxide (NO) in RAW264.7macrophages. On the basis of the screening results, compounds containingfuran (9c) or nitrofuran (9j) moieties displayedmore pronounced activity than coixol and celecoxib. Mechanistic investigationsrevealed that 9c and 9j suppressed the expressionof induced nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-& alpha;,interleukin (IL)-6, and IL-1 & beta;, which was associated with theinhibition of the nuclear factor (NF)-& kappa;B signaling pathway. In vivo studies confirmed the anti-inflammatoryactivity of 9c and 9j in a xylene-inducedmice auricles edema model. The preliminary in vitro and in vivo researchfindings suggest that 9c and 9j have thepotential to be developed as anti-inflammatory agents.