Antibacterial and Antiparasitic Activity of Manganese(I) Tricarbonyl Complexes with Ketoconazole, Miconazole, and Clotrimazole Ligands

Five
manganese­(I) tricarbonyl complexes of the general formula
[Mn­(CO)3(bpyR,R)­(azole)]­PF6 with
R = H, COOCH3, and azole = ketoconazole (ktz), miconazole
(mcz), and clotrimazole (ctz) were synthesized and fully charaterized,
including X-ray structure analysis for the ctz compound. The antibacterial
activity on a panel of eight Gram-positive and Gram-negative bacterial
strains was determined. While there was no effect on the latter microorganisms,
the ctz complex showed submicromolar activity on Staphylococcus
aureus and S. epidermidis with MIC values
of 0.625 μM. Antiparasitic activity was investigated on Leishmania major and Trypanosoma brucei. Coordination of the organic azole drugs to the Mn­(CO)3 moiety led to complexes with low micromolar IC50 values,
but their potential for antileishmanial therapy is low due to comparable
toxicity on mammalian cell lines 293T and J774.1. In contrast, the
antitrypanosomal activity is much more promising, and the most potent
compound incorparting the ktz ligand has an IC50 value
on T. brucei of 0.7 μM with selectivity on
parasitic over mammalian cells as expressed by a selectivity index
above 10. These results demonstrate that metal coordination of established
drugs can significantly improve their biological activity and expand
their range of medicinal applications.