Benzimidazole-Coordinated Copper(II) Complexes as Effectual Chemotherapeutics against Malignancy

Cancer stands as the second-leading cause of global mortality, persistently representing a peril to human well-being. The challenges of drug insensitivity and resistance significantly impede advancements in cancer treatment, emphasizing the critical importance of developing innovative agents that specifically target malignant cells. Benzimidazole derivatives are a preferred choice in cancer therapy, and a variety of benzimidazole-based molecules have demonstrated incredible potential for anticancer therapeutic objectives. Albeit such advancements, there are certain pragmatic limitations, including low bioavailability, which results in insufficient plasma concentration levels, side effects, and toxicity that need to be addressed. In this quest to overcome the existing hurdles, we elucidate the synthesis, structural characterization, and substantial proliferative activity of two copper-(II) complexes bearing benzimidazole ligands. The ligands, 2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo-[d]-imidazole (L) and 6-methyl-2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo-[d]-imidazole (L') were prepared by the coupling of thiophene-2-carboxaldehyde with o-phenylenediamine and 3,4-diaminotoluene, respectively, in water under an ambient condition. Both L and L' react with Cu-(NO₃)₂·3H₂O in methanol, producing the complexes, [Cu-(L)₂(NO₃)₂] (complex 1) and [Cu₂(L')₂(μ-CH₃O)₂]-(NO₃)₂ (complex 2), respectively. Both complexes exhibited solution-phase stability, as confirmed by mass spectral analysis. X-ray structural analysis divulges the mononuclear and dinuclear nature of complex 1 and complex 2, where Cu-(II) centers adopt a slightly distorted square planar geometry in both complexes. Energy framework analysis suggests the higher stability of complex 2 than complex 1, attributed to the more robust character of the dinuclear copper complex. Molecular docking studies for complex 1 and complex 2 against p53, BAX, BCL2, and PARP proteins suggest stable conformations for both complexes. The cell viability and cytotoxicity of the synthetic compounds were evaluated against mouse cancer cell lines, as well as human breast cancer cell lines. Cell cycle, apoptosis, caspase, and TUNEL assays have been carried out to unveil the cell proliferative screening mechanism for the synthetic compounds. The intercalative binding mode of the complexes for CT-DNA triggers the apoptosis of the tumor cells. Hence, we postulate that these compounds have the potential to broaden the arsenal of effective anticancer therapies.