Synthesis and Biological Evaluation of Organoruthenium Complexes with Azole Antifungal Agents. First Crystal Structure of a Tioconazole Metal Complex

Nine organoruthenium complexes with azole antifungal agents (L) clotrimazole (<b>ctz</b>), tioconazole (<b>tcz</b>), and miconazole (<b>mcz</b>) with the general formulas [(η⁶-<i>p</i>-cymene)­RuCl₂(L)], [(η⁶-<i>p</i>-cymene)­RuCl­(L)₂]­Cl, and [(η⁶-<i>p</i>-cymene)­Ru­(L)₃]­(PF₆)₂ were prepared and characterized by NMR, HRMS, IR, UV–vis, and X-ray crystallography. Herein, we report the first crystal structure of a tioconazole metal complex as well as the structure of the tioconazole ligand itself and the bis-clotrimazole complex as a hexafluorophosphate salt. The complexes possess a pseudooctahedral geometry typical for organoruthenium­(II) compounds where half of the coordination sites are occupied by the π-bonded arene ligand <i>p</i>-cymene while the remaining sites are occupied by either the chlorido ligands and/or the azole ligands. The stability of the compounds in dmso solution was studied by NMR spectroscopy. The biological activity of all nine complexes and the ruthenium precursor against the fungus <i>Culvularia lunata</i> was evaluated. The complexes showed antifungal activity at low millimolar concentrations, where the activity decreased with the increasing number of ligands. However at 0.5 mM concentrations all tris-azole complexes statistically significantly reduced the radial growth rate, and also at 0.01 mM concentrations the monoazole complexes showed statistically significant effects. <b>Mcz</b> and its complexes were also tested against the human parasite <i>Schistosoma mansoni</i> and revealed schistocidal activity at 10–100 μg/mL in vitro