Synthesis and biological evaluation of novel 1,2-benzisothiazol-3-one-derived 1,2,3-triazoles as caspase-3 inhibitors

Several series of novel 1,4-disubstituted 1,2,3-triazoles were prepared using the Huisgen cycloaddition reaction and evaluated as inhibitors against caspase-3/-7. The 1,2-benzisothiazol-3-one-derived 1,4-disubstituted 1,2,3-triazoles containing an urea group had dramatically increased inhibitory activity in vitro compared to the others, and the most potent caspase-3 inhibitor was found to be N-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-3-oxobenzoisothiazole-2(3H)-carboxamide 14c with IC50-values of 11.0 ± 1.2 nM. Meanwhile, the compound 14c showed significant protection against apoptosis in human Jurkat T cells, as determined by annexin V-FITC/7-AAD. Moreover, in order to better rationalize the action and the binding mode of these compounds, docking studies were carried out.