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

Abstract

Nine organoruthenium complexes with azole antifungal agents (L) clotrimazole (ctz), tioconazole (tcz), and miconazole (mcz) with the general formulas [(η6-p-cymene)RuCl2(L)], [(η6-p-cymene)RuCl(L)2]Cl, and [(η6-p-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 p-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 Culvularia lunata 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. Mcz and its complexes were also tested against the human parasite Schistosoma mansoni and revealed schistocidal activity at 10–100 μg/mL in vitro.