Molecular Hybrids of Thiazolidinone: Bridging Redox Modulation and Cancer Therapy

Heterocyclic compounds have shown that they hold significant therapeutic activities, highlighting the importance of discovering and developing novel candidates against cancers, infections, and oxidative stress-associated disorders. In this study, we demonstrated the biological activity of our previously synthesized thiazolidinone derivatives (TZDs-1, 6, and 7). Furthermore, we synthesized and structurally characterized a new derivative (TZD-5) using IR, ¹H NMR, and ¹³C NMR spectroscopy, confirming the presence of its key functional groups, namely, carbonyl and imine. Their antioxidant activity was assessed through the DPPH assay, with TZD-5 showing the most potent effect (IC₅₀ = 24.4 µg/mL), comparable to ascorbic acid, an effect attributed to the methoxy group introduced via N-alkylation. Cytotoxicity was evaluated using the MTS assay on normal (HFF-1) and cancerous (HepG2 and A549) cell lines at two time points: 24- and 48 h exposure. Our findings highlight clear differences in cytotoxicity and selectivity among the tested thiazolidinone derivatives. TZD-1 and TZD-6 demonstrated significant, dose-dependent cytotoxic effects on both cancerous (HepG2 and A549) and normal (HFF-1) cell lines, thus limiting their therapeutic potential due to insufficient selectivity. TZD-5 exhibited moderate selectivity with higher susceptibility for HepG2 cells compared to normal cells. Notably, TZD-7 showed the most favorable cytotoxic profile, demonstrating strong selective cytotoxicity toward cancer cell lines with minimal adverse effects on normal fibroblasts. Overall, the results highlight TZD-5 and TZD-7 as promising candidates for antioxidant and selective anticancer therapies.