Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives and Analogs Targeting the NLRP3 Inflammasome

Molecules. 2017 Jan 30;22(2):213. doi: 10.3390/molecules22020213.

Abstract

A series of benzo[d]imidazole analogues of thiabenzole were synthesized and their antiinflammatory activities toward NLRP3 (nucleotide-binding domain leucine-rich repeat containing protein family，pyrin domain-containing 3，also known as cryopyrin or NALP3) inflammasome were evaluated in vitro. Two lead compounds, TBZ-09 and TBZ-21, were identified by antiproduction of IL-1β. In the second round of biological evaluation, based on the lead, 34 more compounds were synthesized and their in vitro anti-inflammatory activities were investigated. Several compounds were identified as anti-inflammatory agents that can reduce IL-1β expression in a dosedependent manner. A preliminary structure-activity relationship is also summarized here.

Keywords: benzimidazole; IL‐1β; NLRP3; anti‐inflammatory; drug discovery.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / pharmacology*
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacology*
  • Humans
  • Inflammasomes / antagonists & inhibitors*
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / immunology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Molecular Structure
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*

Substances

  • Anti-Inflammatory Agents
  • Benzimidazoles
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Adenosine Triphosphate