Twelve azole derivatives of emodin were designed to possess anti‐inflammatory activity and synthesized via a two‐step sequence composed of the Williamson ether reaction and N‐alkylation. The anti‐inflammatory properties of these compounds were evaluated in RAW264.7 cells by measuring lipopolysaccharide (LPS)‐induced nitric oxide (NO) production. The introduction of imidazole and four carbons into the scaffold of emodin led to the discovery of the potent compound 7e, which showed the best inhibition of NO production among twelve analogs. In our experiential setting, the IC50 of compound 7e in NO production is 1.35 µM, which is lower than that of indomethacin. Mechanically, compound 7e effectively inhibited the protein and messenger RNA expressions of cyclooxygenase‐2 and inducible NO synthase, as well as that of the proinflammatory cytokine interleukin‐6, and the cytokines interleukin‐1β and tumor necrosis factor‐α in the LPS‐stimulated RAW 264.7 macrophages. Compound 7e exerted inhibitory effects on the nuclear factor κB pathway by reducing the LPS‐induced phosphorylation of the inhibitor of NF‐κB and the nuclear translation of p‐p65. These results suggest the potential of compound 7e in improving inflammatory conditions and diseases.

中文翻译：

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带有唑基部分的新型大黄素衍生物的合成和抗炎作用

大黄素的 12 种唑类衍生物被设计为具有抗炎活性，并通过由威廉姆森醚反应和 N-烷基化组成的两步​​序列合成。通过测量脂多糖 (LPS) 诱导的一氧化氮 (NO) 产生，在 RAW264.7 细胞中评估了这些化合物的抗炎特性。将咪唑和四个碳原子引入大黄素支架导致发现了强效化合物 7e，其在 12 种类似物中表现出对 NO 产生的最佳抑制。在我们的实验环境中，化合物 7e 在 NO 生产中的 IC50 为 1.35 µM，低于吲哚美辛。从机制上讲，化合物 7e 有效抑制环加氧酶 2 和诱导型 NO 合酶的蛋白质和信使 RNA 表达，以及 LPS 刺激的 RAW 264.7 巨噬细胞中的促炎细胞因子白细胞介素-6、细胞因子白细胞介素-1β 和肿瘤坏死因子-α。化合物 7e 通过减少 LPS 诱导的 NF-κB 抑制剂磷酸化和 p-p65 的核翻译，对核因子 κB 通路发挥抑制作用。这些结果表明化合物 7e 在改善炎症状况和疾病方面的潜力。