Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis

Abstract

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-<i>c</i>]quinoline derivatives that potently and simultaneously inhibited two primary proinflammatory signaling pathways JAK/STAT and NF-κB. Especially, lead compound <b>8l</b> 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. <i>In vivo</i>, <b>8l</b> 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.