Novel Thiazolidine-2,4-dione-trimethoxybenzene-thiazole Hybrids as Human Topoisomerases Inhibitors

Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity and mortality worldwide, mostly as the population ages. Despite the encouraging advances made over the years in chemotherapy, the development of new compounds for cancer treatments is an urgent priority. In recent years, the design and chemical synthesis of several innovative hybrid molecules, which bring different pharmacophores on the same scaffold, have attracted the interest of many researchers. Following this strategy, we designed and synthetized a series of new hybrid compounds that contain three pharmacophores, namely trimethoxybenzene, thiazolidinedione and thiazole, and tested their anticancer properties on two breast cancer (MCF-7 and MDA-MB-231) cell lines and one melanoma (A2058) cell line. The most active compounds were particularly effective against the MCF-7 cells and did not affect the viability of the normal MCF-10A cells. Docking simulations indicated the human Topoisomerases I and II (hTopos I and II) as possible targets of these compounds, the inhibitory activity of which was demonstrated by the mean of direct enzymatic assays. Particularly, compound 7e was proved to inhibit both the hTopo I and II, whereas compounds 7c,d blocked only the hTopo II. Finally, compound 7e was responsible for MCF-7 cell death by apoptosis. The reported results are promising for the further design and synthesis of other analogues potentially active as anticancer tools.

Automated summary

Cancer is a complex disease and developing new compounds for cancer treatments is urgently needed. In recent years, the design and synthesis of innovative hybrid molecules have gained interest, with promising results in inhibiting cancer cells. The tested hybrid compounds containing trimethoxybenzene, thiazolidinedione and thiazole showed good efficacy against breast cancer cells, with compound 7e being the most effective. Docking simulations indicated that these compounds may target human Topoisomerases I and II, and enzymatic assays confirmed their inhibitory activity. Compound 7e was found to induce apoptosis in MCF-7 cells. These findings support further research in designing and synthesizing analogues for anticancer purposes.