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PLoS By Category | Recent PLoS Articles
Biochemistry - Chemistry - Immunology - Rheumatology

Discovery of Novel Orally Active Anti-Inflammatory N-Phenylpyrazolyl-N-Glycinyl-Hydrazone Derivatives That Inhibit TNF-a Production
Published: Monday, October 08, 2012
Author: Renata B. Lacerda et al.

by Renata B. Lacerda, Leandro L. da Silva, Cleverton K. F. de Lima, Eduardo Miguez, Ana Luisa P. Miranda, Stefan A. Laufer, Eliezer J. Barreiro, Carlos A. M. Fraga

Herein, we describe the synthesis and pharmacological evaluation of novel N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that were designed as novel prototypes of p38 mitogen-activated protein kinase (MAPK) inhibitors. All of the novel synthesized compounds described in this study were evaluated for their in vitro capacity to inhibit tumor necrosis factor a (TNF-a production in cultured macrophages) and in vitro MAPK p38a inhibition. The two most active anti-TNF-a derivatives, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N’-((4-(2-morpholinoethoxy)naphthalen-1-yl)methylene)acetohydrazide (4a) and (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N’-(4-chlorobenzylidene)acetohydrazide (4f), were evaluated to determine their in vivo anti-hyperalgesic profiles in carrageenan-induced thermal hypernociception model in rats. Both compounds showed anti-inflammatory and antinociceptive properties comparable to SB-203580 used as a standard drug, by oral route at a dose of 100 µmol/kg. This bioprofile is correlated with the ability of NAH derivatives (4a) and (4f) suppressing TNF-a levels in vivo by 57.3 and 55.8%, respectively.
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