Anti-inflammatory Profile of N-Phenylpyrazole Arylhydrazone Derivatives in Rats

Abstract

A series of synthetic N-phenylpyrazole arylhydrazone compounds, rationally designed as mixed-hybrid isosteres of two known inhibitors of prostaglandin synthase and 5-lipoxygenase enzymes, BW-755c and CBS-1108, has been investigated for anti-inflammatory activity in the carrageenan-induced pleurisy model in rats. The compounds have different oxygenated substituent groups in the aryl group of the hydrazone framework to ensure a different range of redox properties. A new arylhydrazone derivative, 2,6-di-tert-butyl-4-(4-nitro-3-methyl-N-phenylpyrazol-5-yl-hydr azonomethyl)phenol, was also synthesized and tested for anti-inflammatory activity. Although all the compounds significantly inhibited (by 30-90%) neutrophil accumulation in the pleural cavity, there was great variability in the anti-oedematogenic effect of the compounds (3-96%). 5-(4'-Hydroxy-3'-methoxybenzylidene)hydrazone-3-methyl-4-nitrop henylpyrazole was the most active compound in this series; it had a remarkable antiinflammatory profile, almost blocking both assays. In contrast, the compound with a 2,6-di-tert-butylated hydroxybenzene ring on the hydrazone group inhibited neutrophil migration only. These results will be useful for further structure-activity relationship studies devoted to improving the dual prostaglandin synthase-5-lipoxygenase activity of these derivatives and determining the minimum structural requirements necessary for this activity.

Maternal Protein Restriction During Early Lactation Induces Changes on Neutrophil Activation and TNF-α Production of Adult Offspring

“…Acute pleurisy was induced as described in earlier works [22]. Briefly, 100 µL of LPS (E. coli-B4; Sigma, St. Louis, MO) (250 ng/cavity), was injected into the thoracic cavity (i.t.)…”

Neutrophil activation by heme: implications for inflammatory processes

“…22 Briefly, hemin was injected into the thoracic cavity of rats (30-300 nmol/cavity) in a volume of 100 L. The animals were killed 4 hours after injection under ether anesthesia, and their thoracic cavities were opened and rinsed with 3 mL PBS containing heparin (10 IU/mL). Total leukocytes in the pleural fluid were determined on Neubauer chambers after dilution in Turk solution (Laborclin, São Paulo, Brazil).…”

A química medicinal de N-acilidrazonas: novos compostos-protótipos de fármacos analgésicos, antiinflamatórios e anti-trombóticos

“…Visando verificar-se a atividade antiinflamatória desejada, especialmente os eventuais efeitos sobre a bioformação de leucotrienos, por inibição da 5-LO, os derivados desta série (11) com o anel fenílico da subunidade c (Esquema 2) dissubstituído por grupos oxigenados (e.g. 11e) 46 Finalmente, vale registrar, ainda, que derivados nos quais a subunidade (c, Esquema 2) era saturada 30 não apresentaram atividade significativa em nenhum dos bioensaios realizados, indicando que nesta série de derivados hidrazônicos (11), as atividades estudadas dependem da presença da sub-unidade aromática ou heteroaromática (c, Esquema 2) na função hidrazônica.…”

“…Ademais, priorizou-se a obtenção de derivados mono-para-substituídos na unidade fenílica da imina, exceto pela presença do substituinte 3,5-di-tert-butil-4-hidroxibenzeno, eleito por suas propriedades redox particulares, 52 identificadas como relevantes para a atividade antiedematogênica medida na pleurisia induzida por carragenina, conforme observado para 11e. 46 11e Uma vez caracterizada estruturalmente, esta série de compostos (23) foi bioensaiada, utilizando-se os mesmos protocolos farmacológicos usados com os derivados hidrazônicos anteriores (11).…”