Design, synthesis, and anti-inflammatory evaluation of novel N-(Benzol[d]oxazol-5-yl)sulfonamides as NLRP3 inflammasome inhibitors.

Aberrant activation of the NLRP3 inflammasome drives the pathogenesis of numerous human inflammatory diseases, highlighting the urgent need for small-molecule inhibitors targeting NLRP3. Building upon the lead compound 15z, we designed and synthesized a novel series of benzoxazole derivatives and conducted preliminary structure-activity relationship (SAR) studies. The representative compound D12 exhibited more potent NLRP3 inflammasome inhibitory activity than compound 15z, with an IC50 value of 94.15 nM. Mechanistic studies revealed that D12 directly targets the NACHT domain of NLRP3 protein (KD = 558.4 nM), effectively blocking inflammasome assembly and activation, thereby exerting anti-inflammatory effects. In vivo study showed that D12 significantly increased the survival time in a murine model of LPS-induced sepsis. Our findings indicate that compound D12 is a promising NLRP3 inhibitor, providing a new approach for the discovery of anti-inflammatory drugs.