Click inspired new series of pyridazine-triazole-persulfonimide derivatives as DPP-4 inhibitors with exploratory HepG2 phenotypic screening.

A click-enabled pyridazine-1,2,3-triazole sulfonimide platform yielded two libraries: persulfonimides (7a-7f) and aryl sulfonamides (8a-8d). All synthesized compounds were characterized by 1H and 13C NMR spectroscopy and mass spectrometry. In a fluorometric DPP-4 assay at fixed concentrations, inhibition increased with dose, with the most favorable profiles observed for 7d and 7f and the highest activity at 100 nM for 8c (91.31%) versus sitagliptin. In HepG2 cells. 7f reduced viability to 53% at 50 μM, while 8c showed a dose-dependent effect. Sorafenib was more potent (37.45% viability at 10 μM). AO/EB dual staining confirmed apoptosis induction (7f, 100 μM: 66 ± 5.6%; 8c, 100 μM: 42 ± 3.4%), with sorafenib producing (5 μM; 77 ± 3.06%) apoptosis. Docking supported plausible accommodation of top ligands in the DPP-4 cleft, and QikProp suggested favorable permeability with solubility liabilities for some analogues. Overall, pyridazine-triazole sulfonimides emerge as robust DPP-4 inhibitor chemotypes in fixed-dose screening, while the HepG2 effects are exploratory and justify further target-engagement studies.