As a complex pathogenesis driven by immune inflammatory factors and intestinal microbiota, the treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of these important pathogenic factors to reach a favorable therapeutic effect. In the current study, we discovered a series of imidazo[4,5-c]quinoline derivatives that potently and simultaneously inhibited two primary proinflammatory signaling pathways JAK/STAT and NF-κB. Especially, lead compound 8l showed potent inhibitory activities against interferon-stimulated genes (IC₅₀: 3.3 nM) and NF-κB pathways (IC₅₀: 150.7 nM) and decreased the release of various proinflammatory factors at the nanomolar level, including IL-6, IL-8, IL-1β, TNF-α, IL-12, and IFN-γ. In vivo, 8l produced a strong anti-inflammatory activity in both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute enteritis models and restored the structural composition of gut microbiota. Collectively, this study provided valuable lead compounds for the treatment of IBD and revealed the great anti-inflammatory potential of the simultaneous suppression of JAK/STAT and NF-κB signals.

中文翻译：

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发现新型咪唑并[4,5-c]喹啉衍生物通过抑制多种促炎信号通路和恢复肠道稳态来治疗炎症性肠病 (IBD)

作为由免疫炎症因子和肠道菌群驱动的复杂发病机制，炎症性肠病（IBD）的治疗可能依赖于这些重要致病因素的综合调控才能达到良好的治疗效果。在目前的研究中，我们发现了一系列咪唑并[4,5- c ]喹啉衍生物，它们能够有效地同时抑制两条主要的促炎信号通路 JAK/STAT 和 NF-κB。特别是，先导化合物8l对干扰素刺激的基因 (IC ₅₀ : 3.3 nM) 和 NF-κB 通路 (IC ₅₀: 150.7 nM) 并减少纳摩尔水平的各种促炎因子的释放，包括 IL-6、IL-8、IL-1β、TNF-α、IL-12 和 IFN-γ。在体内，8l在硫酸葡聚糖钠 (DSS) 和 2,4,6-三硝基苯磺酸 (TNBS) 诱导的急性肠炎模型中均产生了强大的抗炎活性，并恢复了肠道微生物群的结构组成。总的来说，这项研究为治疗 IBD 提供了有价值的先导化合物，并揭示了同时抑制 JAK/STAT 和 NF-κB 信号的巨大抗炎潜力。