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Background Thiazolidinediones (TZDs), also called glitazones, are five-membered carbon ring molecules commonly used for the management of insulin resistance and type 2 diabetes. Recently, many prospective studies have also documented the impact of these compounds as anti-proliferative agents, though several negative side effects such as hepatotoxicity, water retention and cardiac issues have been reported. In this work, we synthesized twenty-six new TZD analogues where the thiazolidinone moiety is directly connected to an N-heterocyclic ring in order to lower their toxic effects. Methods By adopting a widely applicable synthetic method, twenty-six TZD derivatives were synthesized and tested for their antiproliferative activity in MTT and Wound healing assays with PC3 (prostate cancer) and MCF-7 (breast cancer) cells. Results Three compounds, out of twenty-six, significantly decreased cellular viability and migration, and these effects were even more pronounced when compared with rosiglitazone, a well-known member of the TZD class of antidiabetic agents. As revealed by Western blot analysis, part of this antiproliferative effect was supported by apoptosis studies evaluating BCL-xL and C-PARP protein expression. Conclusion Our data highlight the promising potential of these TZD derivatives as anti-proliferative agents for the treatment of prostate and breast cancer.