Pyrazoles have a multifaceted anti-inflammatory effect targeting prostaglandin E2, cyclooxygenases and leukocytes' oxidative burst

• Type: Article in International Scientific Journal
• Date: 2024

Authors

Rocha, S (Author) Other; Silva, J (Author) Other; Silva, VLM (Author) Other; Silva, AMS (Author) Other; Corvo, ML (Author) Other; Freitas, M (Author) Other; Eduarda Fernandes (Author) FFUP

Journal

Title: International Journal of Biochemistry and Cell Biology

Vol. 172

ISSN: 1357-2725

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

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Other information

Authenticus ID: P-010-GMT

DOI: 10.1016/j.biocel.2024.106599

Abstract (EN): Elevated levels of prostaglandin E2 have been implicated in the pathophysiology of various diseases. Antiinflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, thereby leading to the suppression of prostaglandin E2, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E2 production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E2 levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin E2 in vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structureactivity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E2 levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E2 levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13