Ruthenium-Arene Complexes with Bis(pyrazol-1-yl)methane Ligands: Structural, DFT Analysis, and Cytotoxicity Studies

A series of four η⁶-arene ruthenium(II) half-sandwich complexes ( RuL1-RuL4 ) with bis(pyrazol-1-yl)methane ligands (dpzm, bdmpzm) were synthesized and characterized by FTIR, NMR, ESI-MS, elemental analysis, and single-crystal X-ray diffraction. The structures confirmed robust piano-stool geometries, with subtle effects of arene identity ( p -cymene vs. toluene) and pyrazole methylation on Ru–N bond distances and chelate angles. DFT calculations (B3LYP/6-31G**//LanL2DZ) reproduced crystallographic metrics within ≤ 2.7% and revealed consistently large HOMO–LUMO gaps (3.97–4.07 eV), indicating high electronic hardness. Methylated complexes showed slightly reduced gaps, yet all remained electronically inert. Cytotoxicity assays across nine cancer cell lines (breast, cervical, pancreatic, rhabdomyosarcoma) at concentrations of 20 µM revealed weak antiproliferative activity (cell viability ≥ 100%), in sharp contrast to related Ru(II) scaffolds. The poor activity correlates with wide band gaps, electronic inertness, and steric shielding that limit ligand exchange and charge-transfer processes. These results underscore the importance of ligand design in tuning biological activity: incorporating π-acceptor or labile functionalities could reduce ΔE, enhance MLCT pathways, and unlock the anticancer potential of this scaffold.