Two series of novel NLRP3 inflammasome inhibitors are designed, synthesized, and evaluated in an effort to develop diversified analogs based on the N-(phenylcarbamoyl)benzenesulfonamide scaffold. SAR studies reveal that the sulfonylurea linker can tolerate chemical modifications with either simply changing over the position of carbonyl and sulfonyl group or structurally flexibly inserting a cyclopropyl group, leading to identification of several more potent and diversified NLRP3 antagonists (e.g., 9) with low nanomolar inhibitory activities. Further studies indicate that these two series of compounds with low cytotoxicity exhibited weak effects on the generation of NO and TNF-a. The findings may serve as good starting points for the development of more potent NLRP3 inflammasome inhibitors as valuable pharmacological probes or potential drug candidates.

设计，合成和评估了两个系列的新型NLRP3炎性体抑制剂，以努力开发基于N-（苯基氨基甲酰基）苯磺酰胺骨架的多样化类似物。SAR研究表明，磺酰脲连接基可以简单地改变羰基和磺酰基的位置，或者在结构上灵活地插入环丙基，从而可以耐受化学修饰，从而鉴定出了几种更有效和多样化的NLRP3拮抗剂（例如，9）具有低纳摩尔抑制活性。进一步的研究表明，这两种具有低细胞毒性的化合物对NO和TNF-α的产生均表现出微弱的作用。这些发现可作为开发更有效的NLRP3炎性体抑制剂（作为有价值的药理探针或潜在药物候选物）的良好起点。