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

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-alpha (TNF-alpha) 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 mu mol/L) and low cytotoxicity, which is expected to become a candidate molecule for new anti-inflammatory drugs.

Automated summary

Benzimidazole unit and azulene derivatives are important bioactive substances with characteristics of anti-inflammatory and low toxicity. By synthesizing azulene derivatives containing benzimidazole unit, three compounds with high anti-inflammatory activity and low toxicity were identified, which could be potential candidates for new anti-inflammatory drugs.