Discovery of (E)-1,3-Diphenyl-2-Propen-1-One Derivatives as Potent and Orally Active NLRP3 Inflammasome Inhibitors for Colitis

The pyrin domain-containing protein 3 (NLRP3) inflammasome may be a potential target for the treatment of inflammatory bowel disease (IBD), and inhibiting the activation of the NLRP3 inflammasome is of great significance for the treatment of IBD. In this study, 27 novel chalcone derivatives were designed and synthesized. Enzyme-linked immunosorbent assay (ELISA) analysis revealed that most of the compounds inhibited IL-1β secretion, with <b>F14</b> exhibiting the most significant activity, showing IC₅₀ values of 0.74 μM (mouse bone marrow-derived macrophage, BMDM) and 0.88 μM (Tohoku Hospital Pediatrics-1, THP-1), respectively. Flow cytometry and immunofluorescence analysis revealed that <b>F14</b> had no effect on mitochondrial reactive oxygen species (ROS) production or mitochondrial damage, nor did it affect the expression of key protein components of the NLRP3 inflammasome. Western blot and computational docking studies suggested that <b>F14</b> may exert anti-inflammatory activity by targeting NLRP3 to block the oligomerization and speck formation of ASC protein. In vivo studies demonstrated that <b>F14</b> exhibited significant therapeutic effects on dextran sulfate sodium (DSS)-induced acute colitis in mice. Overall, this work provides candidate compounds for the development of NLRP3 inflammasome inhibitors and the treatment of inflammatory diseases caused by NLRP3 inflammasome activation.