Details

Autor(en) / Beteiligte

• Yang, Yang
• Gao, Zhong-Fei
• Hou, Gui-Ge
• Meng, Qing-Guo
• Hou, Yun

Titel

Discovery of anti-neuroinflammatory agents from 1,4,5,6-tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidin-2-amine derivatives by regulating microglia polarization

Ist Teil von

• European journal of medicinal chemistry, 2023-11, Vol.259, p.115688-115688, Article 115688

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Neuroinflammation mediated by microglia activation leads to various neurodegenerative and neurological disorders. In order to develop more and better options for this disorders, a series of 3,4-dihydrobenzo[b]oxepin-5(2H)-one derivatives (BZPs, 6–19) and novel 1,4,5,6-tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidin-2-amine derivatives (BPMs, 20–33) were synthesized and screened the anti-neuroinflamamtion effects. 3,5-bis-trifluoromethylphenyl-substituted BPM 29 showed more potent anti-neuroinflammatory activity and no toxicity to BV2 microglia cells in vitro. 29 significantly reduced the number of M1 phenotype of microglia cells, but significantly increased the number of M2 phenotype of microglia cells in lipopolysaccharide (LPS)-induced BV2 microglia cells. 29 significantly reduced the secretion of inflammatory cytokines (IL-18, IL-1β, TNF-α), but increased the secretion of anti-inflammatory cytokines (IL-10) from LPS-induced BV2 microglia cells. Also, 29 inhibited the NOD-like receptor NLRP3 inflammasome formation, and down-regulated the expression of M2 isoform of pyruvate kinase in LPS-induced BV2 microglia cells. In vivo, 29 reduced the neuroinflammation in cuprizone-induced inflammatory and demyelinating mice by reducing the expression of inducible nitric-oxide synthase, but increased the expression of CD206. Taken together, 29 might be a prospective anti-neuroinflammatory compound for neuroinflammatory and demyelinating disease by alleviating microglia activation. Twenty-eight BZPs (6–19) and BPMs (20–33) were synthesized. 3,5-Bis-trifluoromethylphenyl-substituted 29 exhibited potential anti-neuroinflammatory activity with no toxicity. 29 shifted LPS-induced BV2 cell polarization to M2 phenotype. 29 promoted IL-10, and inhibited IL-18, IL-1β, TNF-α secretion from LPS-induced BV2 cells. 29 reduced neuroinflammation by modulating microglia polarization in cuprizone-induced mice. [Display omitted] •Twenty-eight BZPs (6–19) and BPMs (20–33) were synthesized.•Double CF3-substituted 29 exhibited potential anti-neuroinflammatory activity.•29 shifted LPS-induced BV2 microglia cell polarization to M2 phenotype.•29 promoted IL-10, and inhibited IL-18, IL-1β, TNF-α secretion from LPS-induced BV2 cells.•29 reduced neuroinflammation by modulating microglia polarization in cuprizone-induced mice.