Comprehensive study of imidazole-based hydrazones: From design, synthesis, and characterization to in vitro and in silico antiproliferative activity analysis

The aim of this study was to synthesize novel imidazole-cored hydrazones and investigate their cytotoxic activities against human breast and lung cancer cell lines using in vitro and in silico techniques. For this purpose, 5 novel compounds (6 and 7a–7d) were synthesized. The structures of the synthesized compounds were confirmed using spectroscopic methods. The cytotoxic effects were evaluated against human lung (A549) and breast (MCF-7) cancer cell lines using the MTT assay. All synthesized compounds had higher cytotoxic activity against MCF-7 cells (IC50 < 9.262 μM) than the control drug cisplatin. However, their cytotoxic activity against A549 cells (IC50 > 2.605 μM) was lower than that of cisplatin. Except for compound 7d in the A549 cell line, the IC50 values for all compounds were below 10 μM. Absorption, distribution, metabolism excretion, and toxicity (ADMET) properties showed that all compounds follow Lipinski’s rule of five except for compounds 7b and 7d because of high molecular weight. The binding properties of the synthesized compounds to cancer-related proteins (PDB IDs: 1M17, 2XIR, 1E8X, and 1MP8) were also investigated using the molecular docking technique. All compounds showed higher binding affinity to these proteins than the standards used for comparison (erlotinib, sorafenib, copanlisib, and ifebemtinib). As the 7c compound had higher cytotoxicity against the MCF-7 cancer cell line than the others and 2XIR-compound complexes had higher docking scores than other proteins, a molecular dynamics (MD) simulation study was performed to support the stability of the 2XIR-7c complex. The MD simulation results showed that the complex was stable during the 100 ns simulation. When all studied parameters were evaluated, compound 7c had the most potential for further drug development.