Browsing by Author "Silva, Jorge Miguel Almeida"
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- Pyrazoles modulate the inflammatory process through the inhibition pf COX-2 activity and leucocytes´oxidative burstPublication . Silva, Jorge Miguel Almeida; Freitas, Marisa; Moreira, FernandoThe 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.
- Revealing the immunomodulatory potential of pyrazoles and exploring structure-activity relationshipsPublication . Silva, Jorge Miguel Almeida; Rocha, S.; Silva, V. L. M.; Silva, A. M. S.; Moreira, Fernando; Fernandes, E.; Freitas, M.Inflammation is a complex and tightly regulated process by a cascade of events that involves the production of prostaglandins (PG) by the inducible isoform cyclooxygenase 2 (COX-2) and the production of reactive pro-oxidant species. Conversely, COX-1, which is consistently present in a variety of tissues, has traditionally been categorized as the primary isoform responsible for maintaining the balance of prostaglandin production. Given the adverse effects associated with currently employed antiinflammatory agents, there is an urgent need to develop novel and efficacious compounds capable of regulating the inflammatory cascade. In this sense, a panel of 28 structurally related pyrazoles were evaluated through the inhibition of human COX-2 and ovine COX-1 activity; the ex vivo production of PGE2 in human whole blood; COX-2 expression in human leukocytes; and human leukocytes’ oxidative burst. The results revealed that some of the tested pyrazoles had a significant inhibitory effect on COX- 2 activity. Pyrazoles 4 and 11B (Fig. 1) stood out as the most potent inhibitors. Pyrazole 11B exhibited greater inhibitory activity against COX-2 than COX-1, while pyrazole 14 displayed selective inhibition of COX-1, with an IC50 value lower than 1 μM. Interestingly, pyrazoles 14 and 16 (Fig. 1) downregulated the COX-2 expression in human leukocytes. Several of the tested pyrazoles, namely compound 4, showed a potential suppressive effect (IC50 5 μM) against human leukocytes’ oxidative burst. In addition, various pyrazoles were able to inhibit both COX-2 activity and oxidative burst, particularly the pyrazoles 1B, 4 and 11B.