Phenolic hydrazones are potent inhibitors of macrophage migration inhibitory factor proinflammatory activity and survival improving agents in sepsis.
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.
Dabideen
Darrin R
DR
Laboratory of Medicinal Chemistry, 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, USA.
Cheng
Kai Fan
KF
Aljabari
Bayan
B
Miller
Edmund J
EJ
Pavlov
Valentin A
VA
Al-Abed
Yousef
Y
D000818:Animals; D002460:Cell Line; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D006835:Hydrazones; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D010636:Phenols; D014409:Tumor Necrosis Factor-alpha