Ruthenium(II)-arene complexes containing β-diketonates: Leishmanicidal activity evaluated by the combination of experimental data, docking and DFT calculations

In this study, we investigated the leishmanicidal activity of four β-diketones, 4,4,4-trifluoro-1-phenyl-1,3-butanedione (HL₁), 2-thenoyltrifluoroacetone (HL₂), 4,4,4-trifluoro-1-(4-bromophenyl)-1,3-butanedione (HL₃) and 4,4,4-trifluoro-1-(4-fluorophenyl)-1,3-butanedione (HL₄), and their corresponding ruthenium(II) arene complexes with general formula [Ru(ƞ⁶-p-cymene)(L_1–4)Cl] (1–4). The compounds were fully characterized by FTIR, UV–Vis, ¹H and ¹⁹F{¹H} NMR, and elemental analysis, and the crystal structure of the new complex 4 was determined, confirming the expected piano-stool geometry. The β-diketones exhibited good to moderate antileishmanial activity against Leishmania (L.) amazonensis promastigotes, with HL₄ being the most active (IC₅₀ = 9.53 μM). In contrast, coordination to Ru(II) generally reduced biological activity, with complexes 1–4 showing only moderate to low effects (IC₅₀ = 55.8 – 90.5 μM). Cytotoxicity assays on RAW 264.7 macrophages revealed limited selectivity for both ligands and complexes (SI ≤ 2.0). Electronic structure analyses using TD-DFT confirmed the main features of the experimental UV–Vis spectra, identifying intraligand charge transfer (ILCT), ligand-to-ligand charge transfer (LLCT), and metal-to-ligand charge transfer (MCLT) transitions. Frontier orbital analysis indicated that the HOMO is mainly centered on Ru(II) and its coordination sphere, while the LUMO is delocalized on the β-diketonate ligands, consistent with MLCT transitions. Finally, molecular docking and quantum mechanical calculations performed on complex 4 revealed promising binding affinities toward two relevant Leishmania protein targets (1LML and 4KPC), supported by charge transfer interactions within this binding sites. Altogether, while the Ru(II) complexes demonstrated limited in vitro leishmanicidal potency, this work provides valuable insights into the structural and electronic factors influencing activity. These results highlight the potential of rationally modifying β-diketonate ligands and the Ru(II) coordination environment as a strategy to optimize future antileishmanial candidates.