Silver() complexes containing antifungal azoles: significant improvement of the anti- potential of the azole drug after its coordination to the silver() ion

Inspired by the emergence of resistance to currently available antifungal therapy and by the great potential of metal complexes for the treatment of various diseases, we synthesized three new silver( i ) complexes containing clinically used antifungal azoles as ligands, [Ag(ecz) 2 ]SbF 6 ( 1 , ecz is econazole), {[Ag(vcz) 2 ]SbF 6 } n ( 2 , vcz is voriconazole), and [Ag(ctz) 2 ]SbF 6 ( 3 , ctz is clotrimazole), and investigated their antimicrobial properties. The synthesized complexes were characterized by mass spectrometry, IR, UV-vis and 1 H NMR spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction analysis. In the mononuclear complexes 1 and 3 with ecz and ctz, respectively, the silver( i ) ion has the expected linear geometry, in which the azoles are monodentately coordinated to this metal center through the N3 imidazole nitrogen atom. In contrast, the vcz-containing complex 2 has a polymeric structure in the solid state in which the silver( i ) ions are coordinated by four nitrogen atoms in a distorted tetrahedral geometry. DFT calculations were done to predict the most favorable structures of the studied complexes in DMSO solution. All the studied silver( i ) complexes have shown excellent antifungal and good to moderate antibacterial activities with minimal inhibitory concentration (MIC) values in the ranges of 0.01-27.1 and 2.61-47.9 μM on the selected panel of fungi and bacteria, respectively. Importantly, the complexes 1-3 have exhibited a significantly improved antifungal activity compared to the free azoles, with the most pronounced effect observed in the case of complex 2 compared to the parent vcz against Candida glabrata with an increase of activity by five orders of magnitude. Moreover, the silver( i )-azole complexes 2 and 3 significantly inhibited the formation of C. albicans hyphae and biofilms at the subinhibitory concentration of 50% MIC. To investigate the impact of the complex 3 more thoroughly on Candida pathogenesis, its effect on the adherence of C. albicans to A549 cells (human adenocarcinoma alveolar basal epithelial cells), as an initial step of the invasion of host cells, was studied. The clinically used antifungal agents, econazole, voriconazole and clotrimazole, were successfully applied in the synthesis of novel silver( i )-azole complexes with significantly improved anti- Candida activity in respect to the parent organic drugs.