Ethacrynic acid (EA) is a glutathione S-transferase P1-1 (GST P1-1) inhibitor with weak antiproliferative ability in tumor cells. By use of the principle of bioisosterism, a series of novel EA oxadiazole analogues were designed and synthesized. The structure-activity relationships of inhibiting GST P1-1 activity and cell proliferation of those EA analogues were investigated in human leukemia HL-60 cells. Our data revealed that those EA oxadiazole analogues had improved antiproliferative activity and most of them had similar or better inhibitory effects on GST P1-1 activity than EA. Compound 6u was one of the potent antiproliferative agents without inhibition of GST P1-1 activity. Compounds 6r and 6s were two potent cell growth inhibitors in several solid tumor cell lines with the concentrations inhibiting half of cell growth of less than 5 microM. Our data suggest that these EA oxadiazole analogues are promising antitumor agents that may act through GST P1-1 inhibition-dependent and/or -independent pathways.