A comparative antimicrobial and toxicological study of gold(III) and silver(I) complexes with aromatic nitrogen-containing heterocycles: synergistic activity and improved selectivity index of Au(III)/Ag(I) complexes mixture

Five aromatic nitrogen-containing heterocycles, pyridazine (pydz, 1), pyrimidine (pm, 2), pyrazine (pz, 3), quinoxaline (qx, 4) and phenazine (phz, 5) have been used for the synthesis of gold(III) and silver(I) complexes. In contrast to the mononuclear Au1-5 complexes all having square-planar geometry, the corresponding Ag1-5 complexes have been found to be polynuclear and of different geometries. Complexes Au1-5 and Ag1-5, along with K[AuCl4], AgNO3 and N-heterocyclic ligands used for their synthesis, were evaluated by in vitro antimicrobial studies against a panel of microbial strains that lead to many skin and soft tissue, respiratory, wound and nosocomial infections. All tested complexes exhibited excellent to good antibacterial activity with minimal inhibitory (MIC) values in the range of 2.5 to 100 mu g mL(-1) against the investigated strains. The complexes were particularly efficient against pathogenic Pseudomonas aeruginosa (MIC = 2.5-30 mu g mL(-1)) and had a marked ability to disrupt clinically relevant biofilms of strains with high inherent resistance to antibiotics. Moreover, the Au1-4 and Ag1-5 complexes exhibited pronounced ability to competitively intercalate double stranded genomic DNA of P. aeruginosa, which was demonstrated by gel electrophoresis techniques and supported by molecular docking into the DNA major groove. Antiproliferative effect on the normal human lung fibroblast cell line MRC5 has also been evaluated in order to determine therapeutic potential of Au1-5 and Ag1-5 complexes. Since the investigated gold(III) complexes showed much lower negative effects on the viability of the MRC5 cell line than their silver(I) analogues and slightly lower antimicrobial activity against the investigated strains, the combination approach to improve their pharmacological profiles was applied. Synergistic antimicrobial effect and the selectivity index of 10 were achieved for the selected gold(III)/silver(I) complexes mixtures, as well as higher P. aeruginosa PAO1 biofilm disruption activity, and improved toxicity profile towards zebrafish embryos, in comparison to the single complexes. To the best of our knowledge, this is the first report on synergistic activity of gold(III)/silver(I) complexes mixtures and it could have an impact on development of new combination therapy methods for the treatment of multi-resistant bacterial infections

Supplementary data for the article: Savić, N. D.; Milivojevic, D. R.; Glišić, B. D.; Ilic-Tomic, T.; Veselinovic, J.; Pavic, A.; Vasiljevic, B.; Nikodinovic-Runic, J.; Djuran, M. I. A Comparative Antimicrobial and Toxicological Study of Gold(III) and Silver(i) Complexes with Aromatic Nitrogen-Containing Heterocycles: Synergistic Activity and Improved Selectivity Index of Au(III)/Ag(i) Complexes Mixture. RSC Advances 2016, 6 (16), 13193–13206. https://doi.org/10.1039/c5ra26002g

Supplementary material for: [https://doi.org/10.1039/c5ra26002g]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2041

A comparative antimicrobial and toxicological study of gold(III) and silver(I) complexes with aromatic nitrogen-containing heterocycles: synergistic activity and improved selectivity index of Au(III)/Ag(I) complexes mixture

Five aromatic nitrogen-containing heterocycles, pyridazine (pydz, 1), pyrimidine (pm, 2), pyrazine (pz, 3), quinoxaline (qx, 4) and phenazine (phz, 5) have been used for the synthesis of gold(III) and silver(I) complexes. In contrast to the mononuclear Au1-5 complexes all having square-planar geometry, the corresponding Ag1-5 complexes have been found to be polynuclear and of different geometries. Complexes Au1-5 and Ag1-5, along with K[AuCl4], AgNO3 and N-heterocyclic ligands used for their synthesis, were evaluated by in vitro antimicrobial studies against a panel of microbial strains that lead to many skin and soft tissue, respiratory, wound and nosocomial infections. All tested complexes exhibited excellent to good antibacterial activity with minimal inhibitory (MIC) values in the range of 2.5 to 100 mu g mL(-1) against the investigated strains. The complexes were particularly efficient against pathogenic Pseudomonas aeruginosa (MIC = 2.5-30 mu g mL(-1)) and had a marked ability to disrupt clinically relevant biofilms of strains with high inherent resistance to antibiotics. Moreover, the Au1-4 and Ag1-5 complexes exhibited pronounced ability to competitively intercalate double stranded genomic DNA of P. aeruginosa, which was demonstrated by gel electrophoresis techniques and supported by molecular docking into the DNA major groove. Antiproliferative effect on the normal human lung fibroblast cell line MRC5 has also been evaluated in order to determine therapeutic potential of Au1-5 and Ag1-5 complexes. Since the investigated gold(III) complexes showed much lower negative effects on the viability of the MRC5 cell line than their silver(I) analogues and slightly lower antimicrobial activity against the investigated strains, the combination approach to improve their pharmacological profiles was applied. Synergistic antimicrobial effect and the selectivity index of 10 were achieved for the selected gold(III)/silver(I) complexes mixtures, as well as higher P. aeruginosa PAO1 biofilm disruption activity, and improved toxicity profile towards zebrafish embryos, in comparison to the single complexes. To the best of our knowledge, this is the first report on synergistic activity of gold(III)/silver(I) complexes mixtures and it could have an impact on development of new combination therapy methods for the treatment of multi-resistant bacterial infections.Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3334

Supplementary data for the article: Savić, N. D.; Milivojevic, D. R.; Glišić, B. D.; Ilic-Tomic, T.; Veselinovic, J.; Pavic, A.; Vasiljevic, B.; Nikodinovic-Runic, J.; Djuran, M. I. A Comparative Antimicrobial and Toxicological Study of Gold(III) and Silver(i) Complexes with Aromatic Nitrogen-Containing Heterocycles: Synergistic Activity and Improved Selectivity Index of Au(III)/Ag(i) Complexes Mixture. RSC Advances 2016, 6 (16), 13193–13206. https://doi.org/10.1039/c5ra26002g

Supplementary material for: [https://doi.org/10.1039/c5ra26002g]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2041

Myrtus comunis and Eucalyptus camaldulensis cytotoxicity on breast cancer cells

In vitro cytotoxicity of methanol, ethyl acetate, n-buthanol, and water extracts of Myrtus communis L. and Eucalyptus camaldulensis Dehnh. was examined against two human breast cancer cell lines (MCF 7 and MDA-MB-231) using MTT and SRB assays. The results showed significant cytotoxic potential of examined extracts, with IC50 values ranging from 7 to 138 μg/ml for M. communis and 3-250 μg/ml for E. camaldulensis. The two plants generally expressed similar activity, and no significant difference in cell line’s sensitivity towards extracts was observed. The results indicate to M. communis and E. camaldulensis as candidates for thorough chemical analyses for identification of active compounds, and eventually for attention in the process of discovery of new natural products in the control of cancer. [Projekat Ministarstva nauke Republike Srbije, br. 173037 i br. 172058

Dinuclear silver(I) complexes with a pyridine-based macrocyclic type of ligand as antimicrobial agents against clinically relevant species: the influence of the counteranion on the structure diversification of the complexes

New dinuclear silver(i) complexes withN,N ',N '',N '''-tetrakis(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane (tpmc), [Ag-2(NO3)(tpmc)]NO3 center dot 1.7H(2)O (1), [Ag-2(CF3SO3)(2)(tpmc)] (2), and [Ag-2(tpmc)](BF4)(2) (3) were synthesized and characterized by NMR (H-1 and(13)C), IR and UV- Vis spectroscopy, cyclic voltammetry and molar conductivity measurements. The molecular structures of the complexes were determined by single-crystal X-ray diffraction analysis. The spectroscopic and crystallographic data showed that the structure of the complexes strongly depends on the nature of the counteranion of silver(i) salt used for their synthesis. The antimicrobial activity of complexes1-3was examined against Gram-positive and Gram-negative bacteria and different species of unicellular fungus Candida spp. The ability of these complexes to inhibit the formation of Candida biofilms and to eradicate the already formed biofilms was tested in the standard microtiter plate-based assay. In addition, a bioelectrochemical testing of the antimicrobial activity of complex 1 against early biofilm was also performed. The obtained results indicated that complexes 1-3 showed increased activity toward Gram-negative bacteria and Candida spp. and could inhibit the formation of biofilms. In most cases, these complexes had positive selectivity indices and showed similar or even better activity with respect to the clinically used silver(i) sulfadiazine (AgSD). The values of the binding constants for complexes 1-3 to bovine serum albumin (BSA) were found to be high enough to indicate their binding to this biomolecule, but not so high as to prevent their release upon arrival at the target site. Moreover, the positive values of partition coefficients for these complexes indicated their ability to be transported through the cell membrane. Once inside the cell, complexes 1-3 could induce the formation of the reactive oxygen species (ROS) in C. albicanscells and/or interact with DNA. Taken together, silver(i) complexes with the tpmc ligand could be considered as novel antimicrobial compounds with favourable pharmacological properties, being safer than AgSD