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

  • Bioorg Chem. 2026 Aug 5:177:109904. doi: 10.1016/j.bioorg.2026.109904.
Zhendi Shi  1 ,  Leyan Wang  1 ,  Jiayue Huang  1 ,  Tongqiang Xu  2 ,  Yuxin Chen  1 ,  Xiaoyang Li  3 ,  Yuqi Jiang  4
Affiliations
  • 1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
  • 2. Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
  • 3. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China.
  • 4. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China; The Qingdao Key Laboratory of Functional Molecules Synthesis and Application, Ocean University of China, Qingdao 266003, China.
PMID: 42035603 DOI: 10.1016/j.bioorg.2026.109904
Abstract

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.

Keywords
Benzoxazole; NLRP3 inflammasome; NLRP3 inhibitor; Sepsis; Sulfonamides.
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