Abstract：
Elevated levels of prostaglandin E2 have been implicated in the pathophysiology of various diseases. Anti-inflammatory 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 E2in 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 structure-activity 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.
摘要：
前列腺素E2水平的升高与各种疾病的病理生理学有关。通过抑制环氧合酶酶活性起作用的抗炎药，由此导致前列腺素E2的抑制,由于它们对环加氧酶的非特异性抑制,通常与几种副作用相关。因此,用创新的分子和/或机制靶向抑制前列腺素E2的产生成为治疗炎症相关疾病的一个引人注目的治疗策略.因此,在这项研究中，我们对28种吡唑衍生物进行了系统分析,以探讨其降低前列腺素E2水平的潜在机制.在这种情况下，对这些衍生物的评估扩展到检查它们在体外减少人全血中前列腺素E2的能力，抑制环氧合酶-1和环氧合酶-2酶，调节环氧合酶-2的表达，并抑制人白细胞的氧化爆发。结果使建立了重要的结构-活动关系，阐明他们活动的关键决定因素。特别是,吡唑部分的4-苯乙烯基和氯取代的存在被确定为关键决定因素.吡唑8显示了通过下调环氧合酶-2表达来降低前列腺素E2水平的能力，和吡唑-1,2,3-三唑18作为双重作用剂出现，抑制人白细胞氧化爆发和环氧合酶-2活性。此外，吡唑26显示通过选择性环氧合酶-1抑制有效降低前列腺素E2水平。这些结果强调了吡唑的多方面抗炎潜力，为有利于研究活动的替代和结构框架提供新的见解。
