Crude extracts of Punica granatum fruit peel, its isolates, and semisynthetic analogs were investigated for their Cathepsin D protease reticence. Hexane extract (HE), chloroform extract (CE), and ethyl acetate extract (EAE) exhibited significant inhibition of Cathepsin D activity. The bioactivity-guided isolation of hexane- and chloroform-soluble fractions yielded piperine and ursolic acid as bioactive constituents. Upon semisynthetic modifications of ursolic acid, two of the analogs (7 and 8) exhibited higher inhibition of Cathepsin D activity: IC50 at 12.87 and 9.40 lM, respectively. P. granatum fruit peel extracts may act as breast cancer chemopreventive agent.