Phenolic Hydrazones Are Potent Inhibitors of Macrophage Migration Inhibitory Factor Proinflammatory Activity and Survival Improving Agents in Sepsis

Darrin R. Dabideen,† Kai Fan Cheng,† Bayan Aljabari,† Edmund J. Miller,‡ Valentin A. Pavlov,§ and Yousef Al-Abed*†#
Laboratory of Medicinal Chemistry, Laboratory of Cardiopulmonary Research, and Laboratory of Biomedical Sciences, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030, and The New York School of Medicine, New York, New York 10016
J. Med. Chem., 2007, 50 (8), pp 1993–1997
DOI: 10.1021/jm061477+
Publication Date (Web): March 27, 2007
Copyright © 2007 American Chemical Society
†

 Laboratory of Medicinal Chemistry, The Feinstein Institute for Medical Research.

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‡

 Laboratory of Cardiopulmonary Research, The Feinstein Institute for Medical Research.

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§

 Laboratory of Biomedical Sciences, The Feinstein Institute for Medical Research.

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*

 To whom correspondence should be addressed. Phone:  516 562 3406. Fax:  516 562 1022. E-mail:  yalabed@nshs.edu.

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#

 The New York School of Medicine.

Abstract

Abstract Image

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 TNFα 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.

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History

  • Published In Issue April 19, 2007
  • Received December 26, 2006

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