Silver(I) complexes with voriconazole as promising anti-Candida agents

Recognizing that metal ions play an important role in modifying the pharmacological properties of known organic-based drugs, the present manuscript addresses the complexation of the antifungal agent voriconazole (vcz) with the biologically relevant silver(I) ion as a strategy for the development of new antimycotics. The synthesized silver(I) complexes with vcz were characterized by mass spectrometry, IR, UV-Vis and NMR spectroscopy and single-crystal X-ray diffraction analysis. The crystallographic results showed that complexes {[Ag(vcz)(H₂O)]CH₃SO₃}_n (1), {[Ag(vcz)₂]BF₄}_n (2) and {[Ag(vcz)₂]PF₆}_n (3) have polymeric structures in the solid state, in which silver(I) ions have a distorted tetrahedral geometry. On the other hand, DFT calculations revealed that the investigated silver(I) complexes 1-3 in DMSO exist as linear [Ag(vcz-N2)(vcz-N19)]⁺ (1a), [Ag(vcz-N2)(vcz-N4)]⁺ (2a) and [Ag(vcz-N4)₂]⁺ (3a) species, respectively. The evaluated complexes showed an enhanced anti-Candida activity compared to the parent drug with minimal inhibitory concentration (MIC) values in the range of 0.02-1.05 μM. In comparison with vcz, the corresponding silver(I) complexes showed better activity in prevention hyphae and biofilm formation of C. albicans, indicating that they could be considered as promising agents against Candida that significantly inhibit its virulence. Also, these complexes are much better inhibitors of ergosterol synthesis in the cell membrane of C. albicans at the concentration of 0.5 × MIC. This is also confirmed by a molecular docking, which revealed that complexes 1a - 3a showed better inhibitory activity than vcz against the sterol 14α-demethylase enzyme cytochrome P450 (CYP51B), which plays a crucial role in the formation of ergosterol.