Phenolic hydrazones are potent inhibitors of macrophage migration inhibitory factor proinflammatory activity and survival improving agents in sepsis

J Med Chem. 2007 Apr 19;50(8):1993-7. doi: 10.1021/jm061477+. Epub 2007 Mar 27.

Abstract

A series of phenolic hydrazones were synthesized and evaluated for their inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity. Compound 7 emerged as a potent inhibitor of MIF with an IC50 of 130 nM. Compound 7 dose-dependently suppressed TNFalpha secretion from lipopolysaccharide stimulated macrophages. The therapeutic importance of the MIF inhibition by 7 is demonstrated by the significant protection from the lethality of sepsis when administration of the compound was initiated in a clinically relevant time frame.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Hydrazones / chemical synthesis*
  • Hydrazones / chemistry
  • Hydrazones / pharmacology
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Phenols / chemical synthesis*
  • Phenols / chemistry
  • Phenols / pharmacology
  • Sepsis / drug therapy*
  • Sepsis / metabolism
  • Sepsis / mortality
  • Structure-Activity Relationship
  • Survival Rate
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors

Substances

  • Hydrazones
  • Lipopolysaccharides
  • Macrophage Migration-Inhibitory Factors
  • Phenols
  • Tumor Necrosis Factor-alpha