Harnessing Fragment Merging and Chain Extension Approaches for Designing Phthalimidoalkyl-Arylidene Thiazolidinedione Hybrids: New Frontiers in Apoptosis-Inducing Cancer Treatment

A series of novel phthalimidoalkyl-arylidene thiazolidinedione hybrids (10a–e and 11a–e) were designed and synthesized by the combination of the bioactive phthalimide and thiazolidinedione pharmacophores and connected via an ethyl or propyl linker. Additionally, selenocyanates (12 and 13) were synthesized via nucleophilic substitution using KSeCN in DMF. The novel phthalimide benzylidene thiazolidinedione hybrids (10a–e and 11a–e) and phthalimide selenocyanates (12 and 13) were examined as apoptotic inducers against 15 cancer cell lines. Compound 10e showed the best mean growth inhibition percentage (GI%) of 64.60% compared with the FDA-approved doxorubicin (Dox). Moreover, the synthesized compounds showed higher therapeutic efficacy against the A549 and MDA-MB-468 cell lines compared with HeLa and FaDu cells. Analogs 10e, 11b, 11d, and 13 displayed the highest cytotoxic potential at the MDA-MB-468 cancer cells with IC₅₀ values of 12.52, 13.16, 12.00, and 14.78 µM, respectively, in comparison to Dox (IC₅₀ = 11.39 µM). Evaluation of the apoptotic and proinflammatory markers after treatment with analog 13 revealed upregulation of the proapoptotic Caspases 3, 8, and 9 and downregulation of the prosurvival proteins BCL-2, MMP2, and MMP9 by 1.27-, 6.71-, 2.00-, 2.26-, 2.31-, and 2.12-fold change, respectively. Furthermore, analog 13 showed the most significant downregulation of COX-2 and IL-1β protein expression, showing 2.08- and 2.34-fold changes, respectively. Finally, the molecular docking study against Caspase 6 demonstrated eligible binding affinities of the examined analogs. Overall, this study demonstrated that the synthesized compounds are promising apoptotic inducers and possess great potential as anticancer drugs.