The critical role of nuclear topoisomerase enzymes during cell proliferation process guided topoisomerases to be one of the major targets for anticancer drug development. We have designed and synthesized 22 heteroaromatic ring incorporated chalcone derivatives substituted with epoxide or thioepoxide. Topoisomerase enzyme inhibitory activity and cytotoxic tests were also conducted to evaluate compounds' pharmacological efficacy. In the topoisomerase I inhibitory test, compound 1 was most active one, 24% of inhibition at 20μM, among all the compounds but it was lower than camptothecin. Compounds 9, 11, and 13 inhibited the function of topoisomerase II more strongly than etoposide with almost same magnitude (around 90% and 30% inhibition at 100 and 20μM, respectively) which were higher than those of etoposide (72% and 18% inhibition). In the cytotoxicity test, compound 9 inhibited T47D cancer cell growth with the IC value of 6.61±0.21μM. On the other hand, compound 13 (IC: 4.32±0.18μM) effectively suppressed MDA-MB468 cancer cell growth.