Synthesis of 1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2-morpholinoethane-1,2-dione analogues and their inhibitory activities with reduced cytotoxicity in lipopolysaccharide-induced BV2 cells

Bioorg Med Chem Lett. 2023 Jan 1:79:129061. doi: 10.1016/j.bmcl.2022.129061. Epub 2022 Nov 9.

Abstract

A series of rimonabant analogues, where the N-aminopiperidine moiety was replaced by various amines and an additional carbonyl group, were synthesized and their inhibition of nitric oxide (NO) production was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells. Among the synthesized compounds, the morpholine analogue 7y (IC50 = 4.71 ± 0.11 μM) showed significantly higher inhibitory activity than rimonabant (IC50 = 16.17 ± 0.56 μM), and suppressed NO production dose-dependently without cytotoxicity. In addition, 7y inhibited the expression of iNOS, COX-2 and pro-inflammatory cytokines and attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB) and ERK MAPK phosphorylation in BV2 cells. These results demonstrated that 7y exerted anti-inflammatory effects by ERK pathway in BV2 cells, which can be used for the prevention and treatment of neuroinflammatory diseases.

Keywords: Anti-inflammatory effect; BV2 cell; Oxoacetamide analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents* / pharmacology
  • Cyclooxygenase 2 / metabolism
  • Lipopolysaccharides* / pharmacology
  • Microglia
  • NF-kappa B / metabolism
  • Nitric Oxide
  • Nitric Oxide Synthase Type II / metabolism
  • Rimonabant* / analogs & derivatives
  • Rimonabant* / chemistry
  • Rimonabant* / pharmacology

Substances

  • Anti-Inflammatory Agents
  • Cyclooxygenase 2
  • Lipopolysaccharides
  • NF-kappa B
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Rimonabant