Reversible Coordination Modes in Piperazine‐Based Ru(II)‐ p ‐Cymene Acylthiourea Complexes: Modulating DNA Groove Binding for Selective Antimelanoma Activity

Acylthiourea ligands, featuring hard (N, O) and soft (S) donor atoms, enable diverse coordination modes in half‐sandwich Ru(II)‐ p ‐cymene complexes. Herein, we report the synthesis and full characterization of eight half‐sandwich Ru(II)‐ p ‐cymene complexes, comprising four monodentate ( 1m – 4m ) and four bidentate ( 1b – 4b ) species prepared under distinct synthetic conditions. The structures of the complexes 1m , 2m , 3m , 3b , and 4b were confirmed by single‐crystal X‐ray diffraction, while FT‐IR, UV–vis, ESI‐MS, and 1 H/ 13 C NMR spectroscopy unambiguously distinguish the two binding modes. The reversible coordination mode was monitored by 1 H NMR and UV–vis spectroscopy, with base‐induced deprotonation favoring bidentate binding and HCl addition regenerating the monodentate form. Cytotoxic assays revealed that metal coordination markedly enhanced the antiproliferative activity of the ligands. Most bidentate complexes exhibited higher cytotoxicity than their monodentate analogues. In particular, 2b displayed a sixfold increase in potency (IC 50 = 6.05 μM) compared to 2m (36.4 μM) and showed much lower toxicity toward normal ARPE‐19 cells (IC 50 = 55.0 μM), indicating greater selectivity toward cancer cells. Molecular docking suggests DNA groove binding as the anticancer mechanism, highlighting the role of bidentate coordination, with 2b identified as the most promising Ru(II)‐ p ‐cymene complex.