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 (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.