Synthesis and evaluation of the anti-inflammatory activity of novel 8-quinolinesulfonamide derivatives as TLR4/MD-2 inhibitors with efficacy in adjuvant-induced arthritis

Bioorg Chem. 2021 Sep:114:105037. doi: 10.1016/j.bioorg.2021.105037. Epub 2021 May 31.

Abstract

In this study, a series of 8-quinolinesulfonamidederivatives was synthesized, and their anti-inflammatory activity was evaluated. Among them, compound 3l was found to be the best anti-inflammatory agent, with IC50 values of 2.61 ± 0.39, 9.74 ± 0.85, and 12.71 ± 1.34 μM against NO, TNF-α and IL-1β production respectively. And 3l could significantly prevent lipopolysaccharide (LPS)-induced expression of inflammatory mediators (iNOS and COX-2). Molecule docking results showed that 3l could bind to the LPS binding site of toll-like receptor 4 (TLR4)/MD-2, and 3l was then identified as TLR4/MD-2 inhibitor by co-immunoprecipitation (co-IP) and cellular thermal shift assay (CTESA). Preliminary mechanism studies indicated that 3l could prevent TLR4 from being activated by disrupting TLR4/MD-2 heterodimerization and TLR4 homodimerization, thereby blocking the activation of the NF-κB/MAPK signaling pathway. Furthermore, observation of rat foot swelling, joint pathology and serum inflammatory cytokine levels proved that compound 3l had a significant therapeutic effect on adjuvant-induced arthritis (AIA) in rats in vivo. These results indicated that compound 3l is a potential anti-inflammatory agent, from which more effective anti-inflammatory drugs could be developed.

Keywords: 3l; 8-Quinolinesulfonamide derivatives; Adjuvant induced arthritis; Anti-inflammatory; TLR4/MD-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / therapeutic use*
  • Arthritis / drug therapy*
  • Arthritis / pathology
  • Female
  • Humans
  • Knee Joint / drug effects
  • Knee Joint / pathology
  • Lymphocyte Antigen 96 / antagonists & inhibitors*
  • Lymphocyte Antigen 96 / metabolism
  • Mice
  • Molecular Docking Simulation
  • Protein Binding / drug effects
  • Quinolines / chemical synthesis
  • Quinolines / metabolism
  • Quinolines / therapeutic use*
  • RAW 264.7 Cells
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Sulfonamides / chemical synthesis
  • Sulfonamides / metabolism
  • Sulfonamides / therapeutic use*
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / metabolism

Substances

  • Anti-Inflammatory Agents
  • LY96 protein, human
  • Lymphocyte Antigen 96
  • Quinolines
  • Sulfonamides
  • TLR4 protein, human
  • Tlr4 protein, rat
  • Toll-Like Receptor 4