Many degenerative diseases caused by uncontrolled cell death can be intervened pharmaceutically through inhibiting caspase-3 activity that leads to cell apoptosis.Here is presented the discovery of rosolic acid and phenolphthalein methyl ester,which both belong to fuchsone derivatives,as novel and potent nonpeptide inhibitors of caspase-3.They show high inhibitory potency against caspase-3 in vitro(IC50=0.28 and 0.13 μmol/L).Molecular modeling study provided further an insight into the interaction of phenolphthalein methyl ester with activated caspase-3.The structures of the present small-molecule caspase-3 inhibitors are different from the structures of known caspase-3 inhibitors,so the inhibitors were likely to provide some information for the discovery of anti-caspase-3 inhibitors.