Re(i)–quinolinate–pyridyl complexes with disubstituted benzimidazole pharmacophores as anticancer agents

Abstract

Five new neutral heteroleptic complexes fac-[Re(CO)₃(QN)(L-X)] (Re–F, Re–Cl, Re–Br, Re–Me, and Re–Np) comprising the fac-[Re(CO)₃]⁺ core, 8-quinolinate (QN), and the 2-(4-pyridyl)-5,6-disubstituted benzimidazole derivative (L-X = 2-(4-pyridyl)-5,6-difluorobenzimidazole (L-F) or 2-(4-pyridyl)-5,6-dichlorobenzimidazole (L-Cl) or 2-(4-pyridyl)-5,6-dibromobenzimidazole (L-Br) or 2-(4-pyridyl)-5,6-dimethylbenzimidazole (L-Me)) or 2-(4-pyridyl)-naphthanoimidazole (L-Np) were prepared from Re₂(CO)₁₀, 8-hydroxyquinoline (H-QN), and L-X via a one-pot approach. These complexes were characterized by ATR-IR, ESI-TOF-MS, NMR, and elemental analysis. Molecular structures of these complexes were determined by single-crystal X-ray diffraction analysis. The cytotoxicity study of the synthesized complexes was performed against cancer cell lines (murine mammary carcinoma 4T1, human lung adenocarcinoma A549, and human cervical carcinoma HeLa) and non-carcinogenic model cell lines (murine fibroblast L929, mouse myoblast C2C12, murine fibroblasts NIH 3T3, and cardiomyoblast H9C2 cells). Notably, complex Re–F, featuring a difluorobenzimidazole motif, exhibited potent anticancer activity with good selectivity towards 4T1 cells, while complex Re–Br, with a dibromobenzimidazole motif, showed better selectivity towards HeLa cells. In vitro studies demonstrated that Re–F and Re–Br induced the generation of reactive oxygen species (ROS), exhibited antiproliferative effects, caused cellular morphological alterations, triggered DNA damage, and induced apoptotic cell death. These complexes exhibited potent tumor growth inhibition against multicellular tumor spheroids. Molecular docking and dynamics studies revealed good binding affinity and interactions of the complexes with B-DNA.