含苯并咪唑结构的薁类衍生物的设计合成及抗炎活性研究

Design, Synthesis and Anti-inflammatory Activity of Azulene Derivatives Containing Benzimidazole Unit

苯并咪唑(BI)结构广泛存在于多种生物活性化合物中, 在药物合成领域受到越来越多的关注. 薁类衍生物是一类可从药用植物中获得的天然产物, 具有抗炎、抗氧化及低毒等特点. 以薁类衍生物与BI为原料, 通过Buchwald- Hartwig偶联得到了14个含苯并咪唑结构的薁类衍生物, 并研究了其抗炎活性和构效关系. 结果表明, 这些化合物能有效抑制脂多糖(LPS)诱导的巨噬细胞中NO的产生, 具有比愈创木薁磺酸钠(GAS-Na)更好的抗炎活性. 其中有三个薁类衍生物具有低毒性和高抗炎效果, 酶联免疫吸附测定法(ELISA)表明其以浓度依赖性的方式抑制LPS诱导的肿瘤坏死因子α (TNF-α)和白细胞介素6 (IL-6)的释放. 研究表明1-愈创木薁-苯并咪唑(GABI-1)具有高抗炎活性(给药浓度为20 μmol/L时的NO抑制率为33.69%)和低细胞毒性, 有望成为新型抗炎药候选分子.

Benzimidazole (BI) unit exists in many bioactive compounds and has attracted more and more attention in the field of drug synthesis. Azulene derivatives are natural products obtained from medicinal plants, which have the characteristics of anti-inflammatory, antioxidant, and low toxicity. Using azulene derivatives and BI as raw materials, fourteen azulene derivatives that contain benzimidazole unit were synthesized by using Buchwald-Hartwig coupling strategy. Then their anti-inflammatory activity and structure-activity relationship were studied. The results showed that these compounds can effectively inhibit the production of NO in lipopolysaccharide (LPS) induced macrophages and have higher anti-inflammatory activity than sodium guaiazulene sulfonate (GAS-Na). Among them, three derivatives were screened with low toxicity and high anti-inflammatory activity, and they can inhibit the release of LPS-induced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in a dose-dependent manner by enzyme-linked immunosorbent assay (ELISA). The results show that 1-guaiaculene benzimidazole (GABI-1) has high anti-inflammatory activity (the inhibitory rate of NO was 33.69% at the doses of 20 μmol/L) and low cytotoxicity, which is expected to become a candidate molecule for new anti-inflammatory drugs.