吡唑缀合咪唑并[1,2-a]吡嗪衍生物的合成及其通过减弱NF-κB、氧化应激和细胞凋亡对脓毒症大鼠急性肺损伤的保护作用,Acta Pharmaceutica

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吡唑缀合咪唑并[1,2-a]吡嗪衍生物的合成及其通过减弱NF-κB、氧化应激和细胞凋亡对脓毒症大鼠急性肺损伤的保护作用
Acta Pharmaceutica ( IF 2.1 ) Pub Date : 2023-09-14 , DOI: 10.2478/acph-2023-0031
Binbin Zang ₁ , Lihui Wang ₁

Affiliation

目前的工作是为了阐明吡唑共轭咪唑的药理作用[1,2-A]吡嗪衍生物对抗脓毒症大鼠急性肺损伤及其作用机制。各种吡唑共轭咪唑并[1,2-A]-吡嗪衍生物已通过简单的合成路线合成。它们表现出多种针对 NF-ĸB 的抑制活性我知道了 50范围为 1 至 94 µmol L–1。其中，化合物3h[(4-(4-((4-羟基苯基)磺酰基)苯基)-5-(4-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)(8-(甲氨基)咪唑[1,2-A]pyrazin-2-yl)methanone] 被确定为最有效的 NF-κB 抑制剂我知道了 501.02 µmol·L–1。未发现合成的化合物对正常细胞系 MCF-12A 具有细胞毒性。还在盲肠结扎穿刺 (CLP) 诱导的大鼠脓毒症肺损伤中研究了最有效的 NF-ĸB 抑制剂 3h 的药理活性。诱导肺脓毒症后将化合物3h给予大鼠，并测量各种生化参数。结果表明，化合物 3h 显着降低了肺部炎症和膜通透性，肺组织的 H&E 染色证明了这一点。它大大减少了促炎细胞因子（TNF-α、IL-1B、IL-6）和氧化应激（MPO、MDA、SOD）的产生。在蛋白质印迹和膜联蛋白--PI 测定中分别显示 NF-κB 和细胞凋亡的减弱。化合物3h还减少了肺部支气管肺泡灌洗液的产生，并提供了针对肺损伤的保护作用。我们的研究表明了吡唑共轭咪唑的药理学意义[1,2-A] 吡嗪衍生物3h对抗脓毒症大鼠急性肺损伤。

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Synthesis and protective effect of pyrazole conjugated imidazo[1,2-a]pyrazine derivatives against acute lung injury in sepsis rats via attenuation of NF-κB, oxidative stress, and apoptosis

The current work was conducted to elucidate the pharmacological effect of pyrazole-conjugated imidazo[1,2-a]pyrazine derivatives against acute lung injury in rats in sepsis and their mechanism of action. Various pyrazole-conjugated imidazo[1,2-a]-pyrazine derivatives have been synthesized in a straightforward synthetic route. They exhibited a diverse range of inhibitory activity against NF-ĸB with IC 50 ranging from 1 to 94 µmol L–1. Among them, compound 3h [(4-(4-((4-hydroxyphenyl)sulfonyl) phenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl) (8-(methylamino)imidazo[1,2-a]pyrazin-2-yl)methanone] was identified as the most potent NF-κB inhibitor with IC 50 of 1.02 µmol L–1. None of the synthesized compounds was found cytotoxic to normal cell-line MCF-12A. The pharmacological activity of the most potent NF-ĸB inhibitor 3h was also investigated in cecal ligation and puncture (CLP)-induced sepsis injury of the lung in rats. Compound 3h was administered to rats after induc tion of lung sepsis, and various biochemical parameters were measured. Results suggested that compound 3h significantly reduced lung inflammation and membrane permeability, as evidenced by H&E staining of lung tissues. It substantially reduced the generation of pro-inflammatory cytokines (TNF-α, IL-1B, IL-6) and oxidative stress (MPO, MDA, SOD). It showed attenuation of NF-ĸB and apoptosis in Western blot and annexin--PI assay, resp. Compound 3h also reduced the production of bronchoalveolar lavage fluid from the lung and provided a protective effect against lung injury. Our study showed the pharmacological significance of pyrazole-conjugated imidazo[1,2-a] pyrazine derivative 3h against acute lung injury in sepsis rats.

更新日期：2023-09-14

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