Structure-Activity Relationships and Anti-inflammatory Activities of N-Carbamothioylformamide Analogues as MIF Tautomerase Inhibitors

J Chem Inf Model. 2015 Sep 28;55(9):1994-2004. doi: 10.1021/acs.jcim.5b00445. Epub 2015 Aug 26.

Abstract

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is an attractive therapeutic target for the treatment of inflammatory diseases. In our previous study, 3-[(biphenyl-4-ylcarbonyl)carbamothioyl]amino benzoic acid (compound 1) was discovered as a potent inhibitor of MIF by docking-based virtual screening and bioassays. Here, a series of analogues of compound 1 derived from similarity search and chemical synthesis were evaluated for their MIF tautomerase activities, and their structure-activity relationships were then analyzed. The most potent inhibitor (compound 5) with an IC50 of 370 nM strongly suppressed lipopolysaccharide (LPS)-induced production of TNF-α and IL-6 in a dose-dependent manner and significantly enhanced the survival rate of mice with LPS-induced endotoxic shock from 0 to 35% at 0.5 mg/kg and to 45% at 1 mg/kg, highlighting the therapeutic potential of the MIF tautomerase inhibition in inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Benzhydryl Compounds / chemistry
  • Binding Sites
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Formamides / chemistry*
  • Formamides / pharmacology*
  • Inhibitory Concentration 50
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Nitric Oxide / chemistry
  • Protein Binding / drug effects
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology

Substances

  • Anti-Inflammatory Agents
  • Benzhydryl Compounds
  • Enzyme Inhibitors
  • Formamides
  • Macrophage Migration-Inhibitory Factors
  • Sulfhydryl Compounds
  • Nitric Oxide
  • Intramolecular Oxidoreductases
  • phenylpyruvate tautomerase
  • diphenylmethane