Synthesis, biological evaluation and structure–activity relationships for a series of novel nonpeptide small molecule inhibitors of caspase-3 are described. Among the studied compounds, 8-sulfamide derivatives of 1, 3-dioxo-4-methyl-2, 3-dihydro-1H-pyrrolo [3, 4-c] quinolines have been identified as potent inhibitors of caspases-3. The most active compound within this series (8f) inhibited caspase-3 with IC50= 4nM.