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Improvement of antifungal activity and therapeutic profile of fluconazole by its complexation with copper(II) and zinc(II) ions. Complex characterization and antimicrobial activity studies
* 1 , 2 , 3 , 4 , 1 , 2 , 3 , 5 , 1
1  University of Kragujevac, Faculty of Science, Department of Chemistry, R. Domanovića 12, 34000 Kragujevac, Serbia
2  University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Vojvode Stepe 444a, 11042 Belgrade, Serbia
3  University of Ljubljana, Faculty of Chemistry and Chemical Technology, Department of Chemistry and Biochemistry, Večna pot 113, SI-1000, Ljubljana, Slovenia
4  University of Kragujevac, Institute for Information Technologies Kragujevac, Department of Science, Jovana Cvijića bb, 34000 Kragujevac, Serbia
5  Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11000 Belgrade, Serbia

Abstract:

Over the last few decades, invasive fungal infections represent a serious problem for modern-day healthcare. Aspergillus, Candida and Cryptococcus species are the most common pathogens causing life-threatening infections. Therapeutic options for the treatment of fungal infections are presently limited to only four classes of compounds and each of these drug classes has significant therapeutic limitations, including serious toxic-side effects, resistance development and limited routes of administration. In order to overcome resistance of the clinically used antifungal triazole agents, we synthesized zinc(II) and copper(II) complexes with fluconazole (flz), {[ZnCl2(flz)2]·2C2H5OH}n (1) and {[CuCl2(flz)2].5H2O}n (2). These complexes were obtained from the reactions between ZnCl2 or CuCl2·2H2O with this antifungal agent in 1 : 2 molar ratio in ethanol at room temperature. The compounds were characterized by elemental analysis, NMR, IR and UV-Vis spectroscopy and mass spectrometry. The crystal structure of complex 1 was determined by a single-crystal X-ray diffraction analysis. The antimicrobial effect of both complexes and fluconazole was evaluated against different Candida species as well as Gram-positive and Gram-negative bacteria by means of minimal inhibitory concentrations (MICs). The obtained results have shown that, in most cases, the coordination of fluconazole to Zn(II) and Cu(II) ions leads to the enhancement of its antifungal activity. Both complexes showed strong inhibitory activity against C. albicans biofilm formation at concentrations lower than MIC values, as well as strong inhibition of C. albicans filamentation.

Keywords: antifungal agents, biofilms, copper(II) complex, fluconazole, zinc(II) complex
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