Evaluation\nof Phenazine Derivatives from the Lichen-Associated <i>Streptomyces\nflavidovirens</i> as Potent Antineuroinflammatory\nAgents In Vitro and In Vivo

Eighteen\nnitrogen-containing compounds (<b>1</b>–<b>18</b>) were isolated from cultures of the lichen-associated <i>Streptomyces\nflavidovirens</i> collected from the Qinghai-Tibet\nPlateau, including seven phenazine derivatives with three new ones,\nnamed subphenazines A–C (<b>2</b>–<b>4</b>), two new furan pyrrolidones (<b>8</b>–<b>9</b>), and nine known alkaloids. The structures were elucidated by spectroscopic\ndata analysis, and absolute configurations were determined by single-crystal\nX-ray diffraction and ECD calculations. The phenazine-type derivatives,\nin particular compound <b>3</b>, exhibited significantly better\nantineuroinflammatory activity than other isolated compounds (<b>8</b>–<b>18</b>). Compound <b>3</b> inhibited\nthe release of proinflammatory cytokines including IL-6, TNF-α,\nand PGE<sub>2</sub>, and the nuclear translocation of NF-κB;\nit also reduced the oxidative stress and activated the Nrf2 signaling\npathway in LPS-induced BV2 microglia cells. In vivo anti-inflammatory\nactivity in zebrafish indicated that <b>3</b> inhibited LPS-stimulated\nROS generation. These findings suggested that compound <b>3</b> might be a potent antineuroinflammatory agent through the regulation\nof the NF-κB/Nrf2 signaling pathways.