Synthesis, biological evaluation and molecular dynamics simulations of new sulfonylurea derivatives bearing biphenyl moieties as potential NLRP3 inhibitors

Here in this work we designed and synthesized a series of new sulfonylurea derivatives bearing biphenyl moieties whose structures were confirmed by ¹H-NMR, ¹³C-NMR, IR and MS. The cytotoxicity of these compounds was first evaluated by MTT assay in J774A.1 cells and then their inhibitory activities against NLRP3 activation were evaluated in vitro in both J774A.1 and RAW264.7 cell lines initiated by LPS and ATP. The results showed that compound 10n (Sodium{(2-(nathphalen-2-yl) phenyl) carbamoyl} ((4-(2-hydroxypropan- 2-yl) furan-2-yl) sulfonyl) amide) had a good in vitro safety profile and a significant inhibitory effect on NLRP3 activation with an IC₅₀ value of 100.7 nM in RAW264.7 cells, which was only slightly weaker than MCC950 with an IC₅₀ value of 49.24 nM. Further computational studies (molecular docking, RMSD, RMSF, binding energy and DCCM analysis) indicated that 10n could be accommodated in the binding site of NLRP3 and strongly interact with NLRP3. Compound 10n has the potential to be further developed as a promising NLRP3 inhibitor.