ABSTRACT:
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 IC
50
values of 12.52, 13.16, 12.00, and 14.78 µM, respectively, in comparison to Dox (IC
50
= 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.
