Eighteen
nitrogen-containing compounds (1–18) were isolated from cultures of the lichen-associated Streptomyces
flavidovirens collected from the Qinghai-Tibet
Plateau, including seven phenazine derivatives with three new ones,
named subphenazines A–C (2–4), two new furan pyrrolidones (8–9), and nine known alkaloids. The structures were elucidated by spectroscopic
data analysis, and absolute configurations were determined by single-crystal
X-ray diffraction and ECD calculations. The phenazine-type derivatives,
in particular compound 3, exhibited significantly better
antineuroinflammatory activity than other isolated compounds (8–18). Compound 3 inhibited
the release of proinflammatory cytokines including IL-6, TNF-α,
and PGE2, and the nuclear translocation of NF-κB;
it also reduced the oxidative stress and activated the Nrf2 signaling
pathway in LPS-induced BV2 microglia cells. In vivo anti-inflammatory
activity in zebrafish indicated that 3 inhibited LPS-stimulated
ROS generation. These findings suggested that compound 3 might be a potent antineuroinflammatory agent through the regulation
of the NF-κB/Nrf2 signaling pathways.