Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells

Eur J Med Chem. 2018 May 10:151:462-481. doi: 10.1016/j.ejmech.2018.03.023. Epub 2018 Mar 9.


Screening a compound library of quinolinone derivatives identified compound 11a as a new P2X7 receptor antagonist. To optimize its activity, we assessed structure-activity relationships (SAR) at three different positions, R1, R2 and R3, of the quinolinone scaffold. SAR analysis suggested that a carboxylic acid ethyl ester group at the R1 position, an adamantyl carboxamide group at R2 and a 4-methoxy substitution at the R3 position are the best substituents for the antagonism of P2X7R activity. However, because most of the quinolinone derivatives showed low inhibitory effects in an IL-1β ELISA assay, the core structure was further modified to a quinoline skeleton with chloride or substituted phenyl groups. The optimized antagonists with the quinoline scaffold included 2-chloro-5-adamantyl-quinoline derivative (16c) and 2-(4-hydroxymethylphenyl)-5-adamantyl-quinoline derivative (17k), with IC50 values of 4 and 3 nM, respectively. In contrast to the quinolinone derivatives, the antagonistic effects of the quinoline compounds (16c and 17k) were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1β, from LPS/IFN-γ/BzATP-stimulated THP-1 cells (IC50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.

Keywords: Antagonist; Anti-glioma; EtBr; IL-1β; Inflammation; P2X7 receptor; Quinoline; Quinolinone.

MeSH terms

  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cell Line, Tumor
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Purinergic P2X Receptor Antagonists / chemical synthesis
  • Purinergic P2X Receptor Antagonists / chemistry
  • Purinergic P2X Receptor Antagonists / pharmacology*
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • Receptors, Purinergic P2X7 / metabolism
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Purinergic P2X Receptor Antagonists
  • Quinolines
  • Quinolones
  • Receptors, Purinergic P2X7
  • quinoline