Structural Insights of Benzenesulfonamide Analogues as NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization

NLRP3 inflammasome plays critical roles in a variety of human diseases and represents a promising drug target. In this study, we established the in vivo functional activities of <b>JC124</b>, a previously identified NLRP3 inflammasome inhibitor from our group, in mouse models of Alzheimer’s disease and acute myocardial infarction. To understand the chemical space of this lead structure, a series of analogues were designed, synthesized, and biologically characterized. The results revealed the critical roles of the two substituents on the benzamide moiety of <b>JC124</b>. On the other hand, modifications on the sulfonamide moiety of <b>JC124</b> are well tolerated. Two new lead compounds, <b>14</b> and <b>17</b>, were identified with improved inhibitory potency (IC₅₀ values of 0.55 ± 0.091 and 0.42 ± 0.080 μM, respectively). Further characterization confirmed their selectivity and in vivo target engagement. Collectively, the results strongly encourage further development of more potent analogues based on this chemical scaffold