Aims

This study investigated the antinociceptive and anti-inflammatory effects of new pyrazole compounds LQFM011(5), LQFM043(6) and LQFM044(7) as well as the mechanisms of action and acute in vitro toxicity.

Main methods

The antinociceptive activity was evaluated using the acetic acid-induced abdominal writhing test, formalin-induced pain test and the Randall–Selitto test. The anti-inflammatory activity was evaluated using models of paw oedema and pleurisy induced by carrageenan; cell migration, the levels of tumour necrosis factor α (TNF-α) and myeloperoxidase (MPO) enzyme activity were evaluated. In addition, the ability to inhibit phospholipase A2 (PLA2) in vitro and docking in PLA2 were used. Acute oral systemic toxicity in mice was evaluated through the neutral red uptake assay.

Key findings

The synthesised compounds (5–7), delivered via gavage (p.o.) at 70, 140 or 280 µmol/kg, decreased the number of writhings induced by acetic acid; the three compounds (280 µmol/kg p.o.) reduced the paw licking time in the first and second phase of the formalin test and decreased the nociceptive threshold variation in the Randall–Selitto test. Furthermore, this dose reduced oedema formation, leucocyte migration (specifically through reduction in polymorphonuclear cell movement) and increased mononuclear cells. MPO activity and the levels of pro-inflammatory cytokines TNF-α were decreased. Evaluation of PLA2 inhibition via the docking simulation revealed more interactions of LQFM043R(6) and LQFM044(7), data that corroborated the half-maximal inhibitory concentration (IC₅₀) of PLA2 inhibition in vitro. Therefore, LQFM011(5), LQFM043(6) and LQFM044(7) were classified with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) as category 4.

中文翻译：

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新吡唑化合物的设计，合成和药理评估。

目的

这项研究调查了新型吡唑化合物LQFM011（5），LQFM043（6）和LQFM044（7）的抗伤害感受和抗炎作用，以及其作用机制和急性体外毒性。

主要方法

使用乙酸诱导的腹部扭体试验，福尔马林诱导的疼痛试验和Randall-Selitto试验评估抗伤害感受活性。使用角叉菜胶诱导的爪水肿和胸膜炎模型评估抗炎活性；评估细胞迁移，肿瘤坏死因子α（TNF-α）和髓过氧化物酶（MPO）酶的活性。此外，还具有体外抑制磷脂酶A2（PLA2）并与PLA2对接的能力。通过中性红吸收试验评估小鼠的急性口服全身毒性。

主要发现

合成的化合物（5 - 7），在70，140或280通过管饲法（PO）递送微摩尔/千克，减少乙酸诱导的扭体的数量; 这三种化合物（280 µmol / kg po）在福尔马林测试的第一和第二阶段减少了舔爪时间，并在Randall-Selitto测试中降低了伤害感受性阈值变化。此外，该剂量减少了水肿形成，白细胞迁移（特别是通过减少多形核细胞运动）和增加了单核细胞。MPO活性和促炎细胞因子TNF-α水平降低。通过对接模拟评估PLA2抑制作用，发现LQFM043R（6）和LQFM044（7）有更多的相互作用）的数据证实了体外对PLA2抑制作用的最大抑制浓度（IC ₅₀）的一半。因此，LQFM011（5），LQFM043（6）和LQFM044（7）被归类为全球化学品统一分类和标签制度（GHS）的类别4。