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.