Mononuclear silver(I) complexes with 1,7-phenanthroline as potent inhibitors of Candida growth

Nada D Savić; Sandra Vojnovic; Biljana Đ Glišić; Aurélien Crochet; Aleksandar Pavic; Goran V Janjić; Marina Pekmezović; Igor M Opsenica; Katharina M Fromm; Jasmina Nikodinovic-Runic; Miloš I Djuran

doi:10.1016/j.ejmech.2018.07.049

Mononuclear silver(I) complexes with 1,7-phenanthroline as potent inhibitors of Candida growth

Eur J Med Chem. 2018 Aug 5:156:760-773. doi: 10.1016/j.ejmech.2018.07.049. Epub 2018 Jul 18.

Affiliations

¹ University of Kragujevac, Faculty of Science, Department of Chemistry, R. Domanovića 12, 34000 Kragujevac, Serbia.
² Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia.
³ Department of Chemistry, University of Fribourg, Chemin du Musée 9, CH-1700 Fribourg, Switzerland.
⁴ Institute of Chemistry, Metallurgy and Technology, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia.
⁵ Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Jena, Germany.
⁶ University of Belgrade-Faculty of Chemistry, Studentski trg 16, 11158 Belgrade, Serbia.
⁷ Department of Chemistry, University of Fribourg, Chemin du Musée 9, CH-1700 Fribourg, Switzerland. Electronic address: katharina.fromm@unifr.ch.
⁸ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia. Electronic address: jasmina.nikodinovic@gmail.com.
⁹ Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11000 Belgrade, Serbia. Electronic address: djuran@kg.ac.rs.

PMID: 30053719
DOI: 10.1016/j.ejmech.2018.07.049

Abstract

Mononuclear silver(I) complexes with 1,7-phenanthroline (1,7-phen), [Ag(NO₃-O,O') (1,7-phen-N7)₂] (1) and [Ag(1,7-phen-N7)₂]X, X = ClO₄^- (2), CF₃SO₃^- (3), BF₄^- (4) and SbF₆^- (5) were synthesized and structurally characterized by NMR (¹H and ¹³C), IR and UV-Vis spectroscopy and ESI mass spectrometry. The crystal structures of 1, 3 and 4 were determined by single-crystal X-ray diffraction analysis. In all these complexes, 1,7-phen coordinates to the Ag(I) ion in a monodentate fashion via the less sterically hindered N7 nitrogen atom. The investigation of the solution stability of 1-5 in DMSO revealed that they are sufficiently stable in this solvent at room temperature. Complexes 1-5 showed selectivity towards Candida spp. in comparison to bacteria, effectively inhibiting the growth of four different Candida species with minimal inhibitory concentrations (MIC) between 1.2 and 11.3 μM. Based on the lowest MIC values and the lowest cytotoxicity against healthy human fibroblasts with selectivity index of more than 30, the antifungal potential was examined in detail for the complex 1. It had the ability to attenuate C. albicans virulence and to reduce epithelial cell damage in the cell infection model. Induction of reactive oxygen species (ROS) response has been detected in C. albicans, with fungal DNA being one of the possible target biomolecules. The toxicity profile of 1 in the zebrafish model (Danio rerio) revealed improved safety and activity in comparison to that of clinically utilized silver(I) sulfadiazine.

Keywords: Antimicrobial activity; Candida; Cytotoxicity; Danio rerio; Silver(I) complexes.

MeSH terms

Animals
Antifungal Agents / chemistry*
Antifungal Agents / pharmacology*
Antifungal Agents / toxicity
Candida / drug effects*
Candida albicans / drug effects
Candidiasis / drug therapy
Coordination Complexes / chemistry
Coordination Complexes / pharmacology
Coordination Complexes / toxicity
Drug Design
Humans
Microbial Sensitivity Tests
Models, Molecular
Phenanthrolines / chemistry*
Phenanthrolines / pharmacology*
Phenanthrolines / toxicity
Silver / chemistry*
Silver / pharmacology*
Silver / toxicity
Zebrafish / embryology

Substances

Antifungal Agents
Coordination Complexes
Phenanthrolines
1,7-phenanthroline
Silver