Clinically used antifungal azoles as ligands for gold(III) complexes : the influence of the Au(III) ion on the antimicrobial activity of the complex

Stevanović, Nevena Lj. (author), Kljun, Jakob (author), Aleksić, Ivana (author), Skaro-Bogojevic, Sanja (author), Milivojević, Dušan (author), Veselinovic, Aleksandar (author), Turel, Iztok (author), Djuran, Miloš I. (author), Nikodinović-Runić, Jasmina (author), Glišić, Biljana Đ. (author)

In a search for novel antimicrobial metal-based therapeutic agents, mononuclear gold(III) complexes 1–7 of the general formula [AuCl$_3$(azole)], where azole stands for imidazole (im, 1), 1-isopropylimidazole (ipim, 2), 1-phenylimidazole (phim, 3), clotrimazole (ctz, 4), econazole (ecz, 5), tioconazole (tcz, 6) and voriconazole (vcz, 7) were synthesized, characterized and biologically evaluated. In all complexes, the corresponding azole ligand is monodentately coordinated to the Au(III) via the imidazole or triazole nitrogen atom, while the remaining coordination sites are occupied by chloride anions leading to the square-planar arrangement. In vitro antimicrobial assays showed that the complexation of inactive azoles, imidazole, 1-isopropylimidazole and 1-phenylimidazole, to the Au(III) ion led to complexes 1–3, respectively, with moderate activity against the investigated strains and low cytotoxicity on the human normal lung fibroblast cell line (MRC-5). Moreover, gold(III) complexes 4–7 with clinically used antifungal agents clotrimazole, econazole, tioconazole and voriconazole, respectively, have, in most cases, enhanced antimicrobial effectiveness relative to the corresponding azoles, with the best improvement achieved after complexation of tioconazole (6) and voriconazole (7). The complexes 4–7 and the corresponding antifungal azoles inhibited the growth of dermatophyte Microsporum canis at 50 and 25 μg mL$^{−1}$. Gold(III) complexes 1–3 significantly reduced the amount of ergosterol in the cell membrane of Candida albicans at the subinhibitory concentration of 0.5 × MIC (minimal inhibitory concentration), while the corresponding imidazole ligands did not significantly affect the ergosterol content, indicating that the mechanism of action of the gold(III)–azole complexes is associated with inhibition of ergosterol biosynthesis. Finally, complexes 5 and 6 significantly reduced the production of pyocyanin, a virulence factor in Pseudomonas aeruginosa controlled by quorum sensing, and increased cell survival after exposure to this bacterium. These findings could be of importance for the development of novel gold(III)-based antivirulence therapeutic agents that attenuate virulence without pronounced effect on the growth of the pathogens, offering a lower risk for resistance development.

• Language: English
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: Str. 5322-5334
• Numbering: Vol. 51, iss. 13
• PID: 20.500.12556/RUL-141872
• UDC: 546.593:547.78
• ISSN on article: 1477-9234
• DOI: 10.1039/D2DT00411A
• COBISS.SI-ID: 102922499
• Publication date in RUL: 10.10.2022

Record is a part of a journal

• Title: Dalton transactions
• Shortened title: Dalton trans
• Publisher: Royal Society of Chemistry
• ISSN: 1477-9234
• COBISS.SI-ID: 519833113

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• License: CC BY-NC 3.0, Creative Commons Attribution-NonCommercial 3.0 Unported
• Link: http://creativecommons.org/licenses/by-nc/3.0/
• Description: You are free to reproduce and redistribute the material in any medium or format. You are free to remix, transform, and build upon the material. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

Secondary language

• Language: Slovenian
• Keywords: organokovinski kompleksi, zlato, azoli, protimikrobno delovanje