Pyrazoles modulate the inflammatory process through the inhibition pf COX-2 activity and leucocytes´oxidative burst

• Autor(a) principal: Silva, Jorge Miguel Almeida
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.22/24802
• topic: Inflammation; Cyclooxygenase-2; Oxydative burst; Pyrazoles

The inflammation is a complex process which includes several stages, namely the activity of inducible cyclooxygenase 2 (COX-2), as well as the production of reactive species (RS) during the leukocytes’ oxidative burst. Currently, the anti-inflammatory drugs that inhibit COX-2 are linked with various undesired side effects, therefore, it would be interesting to find selective inhibitors to Cox-2 capable of modulate the RS production. Pyrazoles are aromatic heterocyclic compounds made upo f five-element rings with three carbon atoms and two nitrogen atoms. It is recognised that pyrazoles have a strong anti-inflammatory, antibacterial, antifungal, and anticancer action. In this work, a panel of 28 structurally related pyrazoles were evaluated through the inhibition of: human COX-2 activity; the production of PGE2 using a human blood assay; COX-2 expression in human leukocytes’; human leukocytes’ oxidative burst. Lastly, to assess its selectivity, the compounds were tested in vitro against ovine COX-1. The results revealed that several of the tested pyrazoles had a significant inhibitory Effect on COX-2 activity, and compounds 4 and 11B emerged as the most potent inhibitors, with IC50˂25µM. Regardless, amongst the compounds studied only 1ª was able to inhibit both the COX-2 activity and the PGE2 production. Concerning the COX-2 expression, the compounds 14 and 16 stood out since they were able to significantly inhibit its expression. The pyrazole 11B has also demonstrated a selectivity to COX-2, unliked the compound 14, which showed selectivity to COX-1. A multiple of the studied pyrazoles, namely compound 4, showed a potential suppressive Effect (IC50˂5 µM) against human leukocytes’ oxidative burst. At last, various pyrazoles were able to inhibit both pathways (COX-2 and oxidative burst), particularly the pyrazoles 1B, 4 and 11B. This study provided importante considerations about pyrazoles and their promising modulatory Effect against inflammation, which might contribute for the design and development of new anti-inflammatory molecules.