Discrete metal-oxo clusters and cluster-based assemblies (namely polyoxometalates and Metal–Organic Frameworks) are promising catalysts for the chemical transformation of various biomolecules, such as proteins, DNA, biomass sugars, and lipids.

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 μg mL⁻¹ against the investigated strains. The complexes were particularly efficient against pathogenic Pseudomonas aeruginosa (MIC = 2.5–30 μg 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.

Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl3(1,7-phen-κN7)] (1) and [AuCl3(4,7-phen-κN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC50 value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89μM, while had low toxicity with LC50 value (the concentration inducing the lethal effect of 50% embryos) of 128μM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.

Aromatic character of nitrogen-containing rings is decreased upon gold( iii ) coordination.

New dinuclear silver(I) complexes with N,N′,N′′,N′′′-tetrakis(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane (tpmc), [Ag₂(NO₃)(tpmc)]NO₃·1.7H₂O (1), [Ag₂(CF₃SO₃)₂(tpmc)] (2), and [Ag₂(tpmc)](BF₄)₂ (3) were synthesized and characterized by NMR (¹H and ¹³C), 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 complexes 1–3 was 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. albicans cells 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.

Gold(III) complexes with different L-histidine-containing dipeptides, [Au(Gly-L-His-N_A,N_P,N3)Cl]Cl·3H₂O (1a), [Au(Gly-L-His-N_A,N_P,N3)Cl]NO₃·1.25H₂O (1b), [Au(L-Ala-L-His-N_A,N_P,N3)Cl][AuCl₄]·H₂O (2a), [Au(L-Ala-L-His-N_A,N_P,N3)Cl]NO₃·2.5H₂O (2b), [Au(L-Val-L-His-N_A,N_P,N3)Cl]Cl·2H₂O (3), [Au(L-Leu-L-His-N_A,N_P,N3)Cl]Cl (4a) and [Au(L-Leu-L-His-N_A,N_P,N3)Cl][AuCl₄]·H₂O (4b), have been synthesized and structurally characterized by spectroscopic (¹H NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. The antimicrobial efficiency of these gold(III) complexes, along with K[AuCl₄] and the corresponding dipeptides, was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and fungi, displaying their moderate inhibiting activity. Moreover, the cytotoxic properties of the investigated complexes were assessed against the normal human lung fibroblast cell line (MRC5) and two human cancer, cervix (HeLa) and lung (A549) cell lines. None of the complexes exerted significant cytotoxic activity; nevertheless complexes that did show selectivity in terms of cancer vs. normal cell lines (2a/b and 4a/b) have been evaluated using zebrafish (Danio rerio) embryos for toxicity and antiangiogenic potential. Although the gold(III) complexes achieved an antiangiogenic effect comparable to the known angiogenic inhibitors auranofin and sunitinib malate at 30-fold higher concentrations, they had no cardiovascular side effects, which commonly accompany auranofin and sunitinib malate treatment. Finally, binding of the gold(III) complexes to the active sites of both human and bacterial (Escherichia coli) thioredoxin reductases (TrxRs) was demonstrated by conducting a molecular docking study, suggesting that the mechanism of biological action of these complexes can be associated with their interaction with the TrxR active site.