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 JC124, 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 JC124. On the other hand, modifications
on the sulfonamide moiety of JC124 are well tolerated.
Two new lead compounds, 14 and 17, 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.