2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2023 Nov 5;259:115688. doi: 10.1016/j.ejmech.2023.115688.
Yang Yang 1,  Zhong-Fei Gao 2,  Gui-Ge Hou 3,  Qing-Guo Meng 4,  Yun Hou 5
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, PR China.
  • 2 School of Pharmacy, The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai, 264003, PR China.
  • 3 School of Pharmacy, The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai, 264003, PR China. Electronic address: guigehou@163.com.
  • 4 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China. Electronic address: qinggmeng@163.com.
  • 5 School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, PR China. Electronic address: houyun820424@163.com.
PMID: 37544188 DOI: 10.1016/j.ejmech.2023.115688
Abstract

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.

Keywords

1,4,5,6-tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidin-2-amine; Anti-neuroinflammation; BV2 microglial cells; Microglia polarization; PKM2.

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