Mafenide derivatives inhibit neuroinflammation in Alzheimer's disease by regulating pyroptosis

The main mechanism of pyroptosis is Caspase‐1–mediated GSDMD cleavage, and GSDMD is also the executive protein of pyroptosis. Our previous study has shown that mafenide can inhibit pyroptosis by inhibiting the GSDMD‐Asp275 site to suppress cleavage. In this study, sulfonamide was used as the parent nucleus structure to synthesize sulfa‐4 and sulfa‐20. Screening of drug activity in the pyroptosis model of BV2 and iBMDM cell lines revealed the efficacy of five compounds were superior to mafenide, which exerted a better inhibitory effect on the occurrence of pyroptosis. For in vivo assay, Sulfa‐4 and Sulfa‐22 were intervened in the neuroinflammation APP/PS1 mice. As a result, the administration of Sulfa‐4 and Sulfa‐22 could significantly inhibit the activation of microglia, decrease the expression of inflammatory factors in the central nervous system and simultaneously suppress the production of p30‐GSDMD as well as the expression of upstream NLRP3 inflammasome and Caspase‐1 protein. Immunoprecipitation and Biotin‐labelled assay confirmed the targeted binding relationship of Sulfa‐4 and Sulfa‐22 with GSDMD protein in the iBMDM model in vitro. In this study, we investigated a new type inhibitor of GSDMD cleavage, which exerted a good inhibitory effect on pyroptosis and provided new references for the development of inflammatory drugs in the future.