Acute lung injury (ALI) is a disease characterized by pulmonary inflammation, blood barrier functional disorder, and hypoxemia. Herein, a series of 2-aminopyrimidine derivatives were synthesized. Most of them exhibited inhibitory effects on inflammatory cytokines IL-6 and IL-8 in human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Compound A8 displayed an excellent anti-inflammatory activity, achieving inhibition rates of 83% for IL-6 and 85% for IL-8. Besides, A8 has a strong binding affinity to CTSL and a good inhibitory activity on JAKs. Western blot analysis indicated that compound A8 strongly blocked the maturation of CTSL and the phosphorylation of p-38, p-65, and STATs, thereby repressing the activation of the MAPK, NF-κB, and JAK/STAT signaling pathway. Moreover, animal experiments showed that A8 played a protective and therapeutic role in ALI in mice, validating its potential as a treatment for ALI.

中文翻译：

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2-芳基氨基嘧啶衍生物作为双重组织蛋白酶 L 和 JAK 抑制剂治疗急性肺损伤的设计、合成和生物学评价


急性肺损伤 （ALI） 是一种以肺部炎症、血液屏障功能障碍和低氧血症为特征的疾病。在此，合成了一系列 2-氨基嘧啶衍生物。其中大多数对人支气管上皮 （HBE） 细胞中的炎性细胞因子 IL-6 和 IL-8 表现出抑制作用，浓度为 5 μM，无显著细胞毒性。化合物 A8 表现出优异的抗炎活性，对 IL-6 的抑制率为 83%，对 IL-8 的抑制率为 85%。此外，A8 对 CTSL 具有很强的结合亲和力，对 JAKs 具有良好的抑制活性。Western blot 分析表明，化合物 A8 强烈阻断 CTSL 的成熟和 p-38、p-65 和 STAT 的磷酸化，从而抑制 MAPK、NF-κB 和 JAK/STAT 信号通路的激活。此外，动物实验表明 A8 在小鼠的 ALI 中发挥保护和治疗作用，验证了其作为 ALI 治疗的潜力。