Design and synthesis optimization of novel diimide indoles derivatives for ameliorating acute lung injury through modulation of NF-κB signaling pathway

• Published in: Bioorganic chemistry 2023-07, Vol.136, p.106557-106557, Article 106557
• Main Authors: Zheng, Zhiwei, Li, Xiaobo, Chen, Pan, Zou, Yu, Shi, Xiaojian, Li, Xiang, Young Kim, Eun, Liao, Jing, Yang, Jun, Chattipakorn, Nipon, Wu, Gaojun, Tang, Qidong, Cho, Won-Jea, Liang, Guang
• Format: Article
• Language: English
• Subjects: Acute lung injury; Acute Lung Injury - chemically induced; Acute Lung Injury - drug therapy; Animals; Anti-inflammation; Anti-Inflammatory Agents - adverse effects; Curcumin - pharmacology; Diimide formation; Diimide indoles derivatives; Interleukin-6 - pharmacology; Lipopolysaccharides - adverse effects; Mice; NF-kappa B - metabolism; Signal Transduction; Stability
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106557

[Display omitted] •A method for synthesizing diimide from carboxylic acid and weak amide was established.•Compound 11f has good structural stability, low toxicity in vitro and in vivo, and the IC50 of anti-inflammatory factors IL-6 reached 1.05 μM.•Compound 11f significantly inhibits inflammation through the NF-κB signaling pathway.•Compound11fcould be a potential anti-inflammatory candidate for ALI therapy. Acute lung injury (ALI) is a common respiratory disease caused by local or systemic inflammatory reaction. Based on the natural 7-chain diaryl anti-inflammatory framework, a series of diimide indoles derivatives were designed by combining curcumin and indole in this study. The synthesis of diimide compounds was extended using dichloromethane (DCM) as solvent and 1,1′-carbonyldiimidazole (CDI) and sodium hydride (NaH) as double activators, and a total of 40 diimide-indole derivatives were obtained. The results of in vitro anti-inflammatory activity showed that most compounds could inhibit the production of interleukin-6 (IL-6) better than curcumin and indomethacin. Among the compounds, the IC50 of compound 11f on IL-6 reached 1.05 μM with no obvious cytotoxic side effects. Mechanistically, compound 11f could block the expression of NF-κB P65 phosphorylation, and nuclear translocation of P65. The acute toxicity tests in-vivo also showed no obvious toxicity in mice after the intragastric administration of 1000 mg/kg. In addition, the compound 11f could significantly inhibit the LPS-induced inflammatory response in mice and reduce the number of neutrophils and wet/dry lung weight ratio, thereby alleviating ALI. These results indicated that the novel diimide indoles were promising anti-inflammatory agents for the treatment of ALI.