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Synthesis and biological evaluation of 1,2,4-triazole derivatives as potential neuroprotectant against ischemic brain injury.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-08 , DOI: 10.1016/j.ejmech.2020.112114 Liping Liao 1 , Caibao Jiang 1 , Jianwen Chen 1 , Jinguo Shi 1 , Xinhua Li 1 , Yang Wang 1 , Jin Wen 1 , Shujia Zhou 1 , Jie Liang 1 , Yaoqiang Lao 1 , Jingxia Zhang 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-08 , DOI: 10.1016/j.ejmech.2020.112114 Liping Liao 1 , Caibao Jiang 1 , Jianwen Chen 1 , Jinguo Shi 1 , Xinhua Li 1 , Yang Wang 1 , Jin Wen 1 , Shujia Zhou 1 , Jie Liang 1 , Yaoqiang Lao 1 , Jingxia Zhang 1
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A series of 1,2,4-triazole derivatives 1-14 was synthesized to investigate their neuroprotective effects and mechanisms of action. Compounds 5-11 noticeably protected PC12 cells from the cytotoxicity of H2O2 or sodium nitroprusside (SNP). Compound 11 was the most effective derivative. Compound 11 chelated Fe (II) iron, scavenged reactive oxygen species (ROS), and restored the mitochondrial membrane potential (MMP). Moreover, it enhanced the activity of the antioxidant defense system by increasing the serum level of superoxide dismutase (SOD) and promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Compound 11 caused certain improvements in behavior, the cerebral infarction area, and serum levels of biochemical indicators (TNF-α, IL-1β, SOD and MDA) in a rat MCAO model. The lethal dose (LD50) of compound 11 in mice receiving intraperitoneal injections was greater than 400 mg/kg. Meanwhile, pharmacokinetic experiments revealed high bioavailability of this compound after both oral and intravenous administration (F = 60.76%, CL = 0.014 mg/kg/h) and a longer half-life (4.26 and 5.11 h after oral and intravenous administration, respectively). Based on these findings, compound 11 may be a promising neuroprotectant for the treatment of ischemic stroke.
中文翻译：
1,2,4-三唑衍生物作为抗缺血性脑损伤的潜在神经保护剂的合成和生物学评价。
合成了一系列1,2,4-三唑衍生物1-14以研究其神经保护作用和作用机制。化合物 5-11 显着保护 PC12 细胞免受 H2O2 或硝普钠 (SNP) 的细胞毒性。化合物11是最有效的衍生物。化合物 11 螯合 Fe (II) 铁，清除活性氧 (ROS)，并恢复线粒体膜电位 (MMP)。此外，它还通过增加血清超氧化物歧化酶（SOD）水平和促进核因子红细胞2相关因子2（Nrf2）的核转位来增强抗氧化防御系统的活性。化合物11对大鼠MCAO模型的行为、脑梗塞面积和血清生化指标（TNF-α、IL-1β、SOD和MDA）水平产生一定的改善。化合物11对小鼠腹腔注射的致死剂量(LD50)大于400mg/kg。同时，药代动力学实验表明该化合物口服和静脉给药后均具有较高的生物利用度（F = 60.76%，CL = 0.014 mg/kg/h），半衰期较长（口服和静脉给药后分别为4.26和5.11 h） 。基于这些发现，化合物11可能是治疗缺血性中风的有前途的神经保护剂。
更新日期：2020-02-10
中文翻译：
1,2,4-三唑衍生物作为抗缺血性脑损伤的潜在神经保护剂的合成和生物学评价。
合成了一系列1,2,4-三唑衍生物1-14以研究其神经保护作用和作用机制。化合物 5-11 显着保护 PC12 细胞免受 H2O2 或硝普钠 (SNP) 的细胞毒性。化合物11是最有效的衍生物。化合物 11 螯合 Fe (II) 铁，清除活性氧 (ROS)，并恢复线粒体膜电位 (MMP)。此外，它还通过增加血清超氧化物歧化酶（SOD）水平和促进核因子红细胞2相关因子2（Nrf2）的核转位来增强抗氧化防御系统的活性。化合物11对大鼠MCAO模型的行为、脑梗塞面积和血清生化指标（TNF-α、IL-1β、SOD和MDA）水平产生一定的改善。化合物11对小鼠腹腔注射的致死剂量(LD50)大于400mg/kg。同时，药代动力学实验表明该化合物口服和静脉给药后均具有较高的生物利用度（F = 60.76%，CL = 0.014 mg/kg/h），半衰期较长（口服和静脉给药后分别为4.26和5.11 h） 。基于这些发现，化合物11可能是治疗缺血性中风的有前途的神经保护剂。
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