Design, synthesis and biological evaluation of novel diphenylamine analogues as NLRP3 inflammasome inhibitors

The aberrant activation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous inflammation-related diseases. Development of NLRP3 inflammasome inhibitors is expected to provide a new strategy for the treatment of these diseases. Herein, a novel series of diphenylamine derivatives were designed based on the lead compounds H20 and H28, and the preliminary structure–activity relationship was studied. The representative compound 19 displayed significantly higher inhibitory activity against NLRP3 inflammasome compared to lead compounds H20 and H28, with an IC₅₀ of 0.34 μM. Mechanistic studies indicated that compound 19 directly targets the NLRP3 protein (K_D: 0.45 μM), blocking the assembly and activation of the NLRP3 inflammasome, leading to anti-inflammatory effects and inhibition of cellular pyroptosis. Our findings indicated that compound 19 is a promising NLRP3 inhibitor and could potentially serve as a lead compound for further optimization.