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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Hydrazones / chemical synthesis*
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Hydrazones / chemistry
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Hydrazones / pharmacology
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Lipopolysaccharides / pharmacology
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Macrophage Activation
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Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
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Male
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Mice
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Mice, Inbred BALB C
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Phenols / chemical synthesis*
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Phenols / chemistry
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Phenols / pharmacology
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Sepsis / drug therapy*
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Sepsis / metabolism
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Sepsis / mortality
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Structure-Activity Relationship
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Survival Rate
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
Substances
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Hydrazones
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Lipopolysaccharides
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Macrophage Migration-Inhibitory Factors
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Phenols
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Tumor Necrosis Factor-alpha