Cytotoxic activity, caspase-3 mediated apoptosis, and PARP-1 inhibition targeted molecular modeling studies of novel imidazole-fused hydrazones

A series of imidazole-fused hydrazones were designed and synthesized as an outcome of the nucleophilic addition of thiosemicarbazide derivatives to ninhydrin. Compounds were screened in human cancer cell lines, HepG2 (liver hepatocellular carcinoma), DLD-1 (colon cancer), and A549 (lung carcinoma). Some compounds had good antiproliferative activity for example compounds 4c, 4i, and 4 m. Particularly, compounds 4c and 4 m showed the most potent activity in the human colon cancer cell line with IC₅₀ values of 7.01 and 4.97 µM, respectively which is better than the prescribed drug cisplatin. In the experimental study, some of the novel compounds were found to be relatively active on Poly ADP-ribose polymerase 1 (PARP-1). This activity was assessed through immunoblotting assay, molecular docking, and molecular dynamics (MD) simulation. Immunoblotting assay data indicated that some tested compounds significantly induced the PARP-1 cleavage. Besides, qRT-PCR studies showed that selected active compounds significantly increased the mRNA expression level of BAX, whereas they decreased the Bcl-2 expression. The molecular docking revealed that the active compounds could bind to PARP-1. The MD simulation implicated that the active compounds except for 4 h could remain stable inside the binding region of the enzyme during the simulation period.