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Pyocyanin (PYO) is a green blue pigment that is produced extracellularly by the Gram- negative bacteria Pseudomonas aeruginosa. Its color depends on pH value. It exists in blue zwitterion form at neutral and alkaline conditions, while in an acidic environment, it becomes pink after protonation. PYO has shown the antibacterial activity, as well as the ability to inhibit the growth of fungi like Aspergillus fumigatus and Candida albicans. Moreover, it shows the high cytotoxic effect against the human pancreatic cancer cells by inducing their apoptosis. To evaluate the possible mechanism of antimicrobial activity of PYO, in the present study, we have investigated its interactions with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) by fluorescence emission spectroscopy. The obtained value of binding constant to BSA is relatively high (KA = 5.3 × 10^6 M^-1 s^-1), showing the ability of PYO to bind to this transport protein. We have also used synchronous fluorescence spectroscopy to explore the structural changes in BSA in the presence of the studied biopigment. In contrast with the mentioned results for binding to BSA, PYO has shown a low affinity to ct-DNA, what can be seen from the value of its binding constant (KA = 7.8 × 10^3 M^-1 s^-1).

In the present study, synthesis of silver(I) and gold(III) coordination compounds with 1,6-naphthyridine (1,6-naph), {[Ag(1,6-naph)(H2O)](BF4)}n (1) and [AuCl3(1,6-naph)] (2), was reported. The methods used for the structural characterization of a new compound 1 included IR, NMR (1H and 13C) and UV-Vis spectroscopy, cyclic voltammetry and single-crystal X-ray diffraction analysis. The crystallographic results showed that compound 1 represents silver(I) coordination polymer, in which 1,6-naph ligand acts as a bidentate bridging ligand connecting two Ag(I) ions via its N1 and N6 nitrogen atoms, while the third coordination site of the metal ion is occupied by the water oxygen atom, resulted in a T-shape geometry. Compounds 1 and 2 were evaluated in vitro for antimicrobial activity against five bacterial and two Candida species, while their cytotoxicity was tested on the normal human lung fibroblast cell line (MRC-5). Compound 1 has manifested a remarkable antifungal activity on both tested Candida strains (C. albicans and C. parapsilosis) with minimal inhibitory concentrations (MICs) of 1.43 and 11.38 µM (0.49 and 3.9 µg/mL), respectively, while no significant antimicrobial activity was observed for 2. Moreover, silver(I) coordination polymer 1 inhibits the hyphae formation of C. albicans at subinhibitory concentration. The binding affinity of both compounds 1 and 2 with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied by fluorescence spectroscopy, indicating their ability to interact with these biomolecules, with compound 2 being more reactive.

Prodigiosin (PG) is a red biopigment produced as a secondary metabolite by microorganisms such as Serratia marcescens and Streptomyces. In recent years, this tripyrrole compound has attracted an increasing attention due to its antibacterial, antimalarial, and immunosuppressive activities [1]. It is also known for its antitumor activity, inducing the cell death by apoptosis in different human cancer cell lines [2]. Considering this, in the present study, we investigated the interactions of prodigiosin and its copper(II) complex (CuPG; the structural formula is presented below), whose crystal structure was determined previously [2], with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) by fluorescence emission spectroscopy to clarify their binding affinities toward these biomolecules. The antimicrobial activity of the synthesized CuPG complex and PG ligand was evaluated in vitro against various microorganisms that can lead to many infections. Moreover, CuPG and PG were evaluated in a cell viability assay on a healthy MRC-5 cell line, as well as a panel of MDA-MB-231, A549, A375, and HCT116 cancer cell lines.

Recently, we synthesized silver(I) complex with the antifungal agent itraconazole, which showed improved anti-Candida potential and therapeutic safety in comparison to itraconazole and rescued zebrafish embryos affected by lethal C. albicans infection, when used in safe doses. Inspired by these results, in the present study, three new silver(I) complexes with clinically used azoles, econazole (ecz), clotrimazole (ctz) and voriconazole (vcz), [Ag(ecz)2]SbF6 (Ag1), [Ag(ctz)2]SbF6 (Ag2) and {[Ag(vcz)2]SbF6}n (Ag3) were synthesized and structurally characterized by elemental microanalysis, mass spectrometry, spectroscopy (1H NMR, IR and UV-Vis), cyclic voltammetry, molar conductivity measurements, and single crystal X-ray diffraction analysis. The spectroscopic and crystallographic results revealed that, in the synthesized silver(I) complexes, azole ligands are monodentately coordinated to the Ag(I) ion through the nitrogen atom forming [Ag(azole)2]+ complex cation. The antimicrobial effect of complexes and azole ligands was evaluated against different Candida species, as well as Gram-positive and Gram-negative bacteria. The synthesized complexes Ag1-3 exhibited good to moderate antimicrobial activity being, in most cases, more active than the corresponding azole ligands. Complexes Ag2 and Ag3 also showed strong inhibitory activity against C. albicans biofilm formation and strong inhibition of C. albicans filamentation at subinhibitory concentrations.

In a search for novel antimicrobial metal-based therapeutic agents, mononuclear gold(III) complexes 1-7 of the general formula [AuCl3(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 mu g 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 x 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 q

Two zinc(II) complexes with dimethyl 2,2 '-bipyridine-4,5-dicarboxylate (py-2py) of the general formula [Zn(py-2py)X-2], X = Cl- (1) and Br- (2) were synthesized and characterized by NMR, IR and UV-Vis spectroscopy and single-crystal X-ray diffraction analysis. Complexes 1 and 2 are isostructural and adopt a slightly distorted tetrahedral geometry with values of tetrahedral indices tau(4) and tau'(4) in the range of 0.80-0.85. The complexes were evaluated for their in vitro antimicrobial activity against two bacterial (Pseudomonas aeruginosa and Staphylococcus aureus) and two fungal strains (Candida albicans and Candida parapsilosis), while their cytotoxicity was tested on the normal human lung fibroblast cell line (MRC-5) and the model organism Caenorhabditis elegans. Complex 1 showed moderate activity against both Candida strains. However, this complex was twofold more cytotoxic compared to complex 2. The complexes tested had no effect on the survival rate of C. elegans. Complex 2 showed the ability to inhibit filamentation of C. albicans, while complex 1 was more effective than complex 2 in inhibiting biofilm formation. The interactions of complexes 1 and 2 with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) were studied to evaluate their binding affinity toward these biomolecules.

To investigate how modification in the structure of 1,3-propanediamine chain of 1,3-pdta (1,3-propanediamine-N,N,N′,N′-tetraacetate) ligand affects the structural and biological properties of the corresponding metal complexes, two new octahedral complexes, [Co(H2O)5Co(2,2-diMe-1,3-pdta)]·H2O (1) and [Mg(H2O)5Mg(2,2-diMe-1,3-pdta)]·1.5H2O (2) (2,2-diMe-1,3-pdta = 2,2-dimethyl-1,3-propanediamine-N,N,N′,N′-tetraacetate), were synthesized and characterized by IR spectroscopy and single-crystal X-ray diffraction analysis. Additionally, UV-Vis and NMR spectroscopic methods were applied for the characterization of 1 and 2, respectively. Crystallographic data indicate that these complexes contain 2,2-diMe-1,3-pdta coordinated to the metal ion through 2 N and 4 O atoms forming [M(H2O)5M′(2,2-diMe-1,3-pdta)] complex unit (M, M′ = Co(II), Co(II) (1) and M, M′ = Mg(II), Mg(II) (2)), which is composed of [M′(2,2-diMe-1,3-pdta)]2− and [M(H2O)5O]2+ octahedra bridged by one of the axial carboxylate groups. The antimicrobial activities of 1 and 2 were evaluated against different bacteria and Candida spp., while their cytotoxic effect was tested on the normal human lung fibroblasts (MRC-5). The ability of 1 and 2 to inhibit formation of C. glabrata biofilms was also assessed. The obtained structural parameters and biological properties of the two complexes were compared to Co(II) and Mg(II) complexes with 1,3-pdta ligand.

Hexadentate 2,2-dimethyl-1,3-propanediamine-N,N,N',N'-tetraacetate (2,2-diMe-1,3-pdta) ligand, containing two methyl substituents at the central carbon atom of a 1,3-propanediamine, has been prepared and used for the synthesis of Na[Cr(2,2-diMe-1,3-pdta)].3.75H2O (1) and Na[Co(2,2-diMe-1,3-pdta)].3.88H(2)O (2) complexes. These complexes were characterized by IR and electronic absorption spectroscopy, and single-crystal X-ray diffraction analysis. NMR (H-1 and C-13) spectroscopy was additionally applied for the characterization of complex 2. Crystallographic data indicate that the two investigated crystals are isostructural and contain 2,2-diMe-1,3-pdta ligand coordinated to metal ion through 2N and 4O atoms forming an octahedral complex in which the six-membered 1,3-propanediamine chelate ring adopts a twist-boat conformation. There are four such complex anions in the symmetry independent part of the unit cell. Each complex anion is further connected to the sodium counterion(s) via the bridging carboxylate group(s). Structural changes in 2,2-diMe-1,3-pdta-Cr(III) complex stimulated solely by the presence of alkyl side groups are discussed. The present study shows that in 1,3-pdtatype complexes of Cr(III) and Co(III), the environment at coordination centre can be modified by introducing substitution in one of the carbon atoms of the diamine and the resulting difference in the subunit structure can bring about noticeable change in molecular and crystal structure. The examples illustrate the importance of the steric effect for the fine tuning of the dimensionality of the resulting coordination polymer and the water content. The antimicrobial activity of complexes 1 and 2 was evaluated against different bacterial and Candida spp., while their cytotoxic effects were tested on the normal human lung fibroblast cell line (MRC-5).

The article presents an overview of the results achieved during the last several decades on the synthesis and structural characterization of copper(II) complexes with different aminopolycarboxylates. Considering the structural varieties in designing aminopolycarboxylate ligands and significant stereochemical flexibility of the corresponding copper(II) complexes to adopt a wide range of coordination geometries, this review is mainly focused on the results related to the crystallographic characterization of the synthesized complexes. The ligands used for the synthesis of copper(II) complexes described in this article contain two amine nitrogen atoms and different number of the carboxylate oxygen donor atoms (N2O2, N2O3 and N2O4-type of ligands). Giving the importance to the biological relevance of the Cu(II) ion and broad aspects of potential application of aminopolycarboxylate ligands in human practice, the presented results could have some important implications for coordination chemists dealing with structural properties of aminopolycarboxylate-copper(II) complexes and their potential medicinal and biological applications.

Five novel copper(ii) complexes with pyridine-4,5-dicarboxylate esters as ligands, [Cu(NO3)(py-2tz)(H2O)(3)]NO3 (1), [Cu(NO3)(2)(py-2metz)(H2O)] (2), [Cu(NO3)(2)(py-2py)(H2O)]center dot H2O (3), [CuCl2(py-2tz)](2) (4) and [CuCl2(py-2metz)](n) (5) (py-2tz is dimethyl 2-(thiazol-2-yl)pyridine-4,5-dicarboxylate, py-2metz is dimethyl 2-(4-methylthiazol-2-yl)pyridine-4,5-dicarboxylate and py-2py is dimethyl 2,2 '-bipyridine-4,5-dicarboxylate), were synthesized and structurally characterized by different spectroscopic and electrochemical methods. The structure of these complexes was determined by single-crystal X-ray diffraction analysis, confirming the bidentate coordination mode of the corresponding pyridine-4,5-dicarboxylate ester to the Cu(ii) ion through the nitrogen atoms. The antimicrobial potential of copper(ii) complexes 1-5 was assessed against two bacterial and two Candida species. These complexes showed better growth inhibiting activity against Candida spp. with respect to the tested bacterial species, also being moderately toxic towards normal human lung fibroblast cells (MRC-5). Complexes 1 and 4 showed the greatest ability to inhibit the filamentation of C. albicans, which is an important process during fungal infection, and these two complexes efficiently inhibited the biofilm formation of C. albicans at subinhibitory concentrations. Complex 4 also successfully prevented the adhesion of C. albicans in an in vitro epithelial cell model. The mechanism of the antifungal activity of copper(ii) complexes 1-5 was studied through their interaction with ct-DNA, as one of the possible target biomolecules, by fluorescence spectroscopy and gel electrophoresis. Finally, the ability of these complexes to bind to bovine serum albumin (BSA) was studied by fluorescence emission spectroscopy.

In order to develop a novel antifungal agent, we synthesized and completely structurally characterized the silver(I) complex with the known antimycotic itraconazole (itraco), [Ag(itraco-N)(2)]NO3 center dot H2O (Agitraco). The spectroscopic and crystallographic results revealed that, in this complex, two itraco ligands are monodentately coordinated to the Ag(I) ion via the triazole nitrogen atom forming a cationic [Ag(itraco-N)(2)]+ part, which is neutralized by the nitrate anion. The antifungal effect of silver(I) complex and itraconazole was evaluated against four different Candida species (C. albicans, C. glabrata, C. parapsilosis and C. krusei) by means of minimal inhibitory concentrations (MICs). Agitraco complex shows enhanced antifungal activity than itraco, being 2.3- and 4.5-fold more active against C. albicans and C. glabrata, respectively. The complex was also more efficient in inhibiting yeast to hyphae transition process in C. albicans, which is an important step in its pathogenesis. Part of the improved activity of Agitraco could be attributed to the greater induction of reactive oxygen species in Candida spp. with respect to itraco. The toxicity evaluation in the zebrafish model (Danio rerio) suggests that the Agitraco complex has better therapeutic profile and improved antifungal efficacy with respect to the parent drug, which were also proven in vivo using the zebrafish model of lethal disseminated candidiasis. Interaction of Agitraco with bovine serum albumin (BSA) was investigated with the aim to assess its binding affinity toward this biomolecule.

Candida albicans is a fungal pathogen that accounts for more than a million death annually. Analysis of Candida biofilms and rapid assessment of antifungal therapy is a critical challenge in clinical practice. Current biochemical methods are time-consuming and expensive or require expert interpretation of the results. Hence, there is the need for a rapid anti-fungal and anti-biofilm test. While electroanalysis has been previously adopted to determine antibiotic susceptibility in bacterial biofilms, there are no studies on yeast and fungi. In this work, electroanalysis of C. albicans biofilm and evaluation of anti-biofilm activity of several antifungal compounds using screen-printed carbon electrodes (SPEs) are reported. Results are compared with standard biochemical and microscopic methods. The current output decreases by 47.5%, 73.4%, and 88.5% in biofilms treated with the antifungals fluconazole (Flz), amphotericin B (AmB), and complex Ag3, respectively, indicating the suitability of electrochemical testing for evaluation of anti fungal drugs. Chronoamperometry allows measuring antifungal activity on Candida biofilm as early as 10 h after inoculation, which show promises for the development of bioelectrochemical sensors in clinical settings.

Three new silver(I) complexes [Ag(NO3)(tia)(H2O)](n) (Ag1), [Ag(CF3SO3)(1,8-naph)](n) (Ag2) and [Ag-2(1,8-naph)(2)(H2O)(1.2)](PF6)(2) (Ag3), where tia is thianthrene and 1,8-naph is 1,8-naphthyridine, were synthesized and structurally characterized by different spectroscopic and electrochemical methods and their crystal structures were determined by single-crystal X-ray diffraction analysis. Their antimicrobial potential was evaluated against four bacterial and three Candida species, and the obtained results revealed that these complexes showed significant activity toward the Gram-positive Staphylococcus aureus, Gram-negative Pseudomonas aeruginosa and the investigated Candida species with minimal inhibitory concentration (MIC) values in the range 1.56-7.81 mu g/mL. On the other hand, tia and 1,8-naph ligands were not active against the investigated strains, suggesting that their complexation with Ag(I) ion results in the formation of antimicrobial compounds. Moreover, low toxicity of the complexes was detected by in vivo model Caenorhabditis elegans. The interaction of the complexes with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied to evaluate their binding affinity towards these biomolecules for possible insights into the mode of antimicrobial activity. The binding affinity of Ag1-3 to BSA was higher than that for DNA, indicating that proteins could be more favorable binding sites for these complexes in comparison to the nucleic acids.

Copper(II) and zinc(II) complexes with clinically used antifungal drug fluconazole (fcz), {[CuCl2(fcz)(2)](.)5H(2)O}(n), 1, and {[ZnCl2(fcz)(2)]Greek ano teleia2C(2)H(5)OH}(n), 2, were prepared and characterized by spectroscopic and crystallographic methods. The polymeric structure of the complexes comprises four fluconazole molecules monodentately coordinated via the triazole nitrogen and two chlorido ligands. With respect to fluconazole, complex 2 showed significantly higher antifungal activity against Candida krusei and Candida parapsilosis. All tested compounds reduced the total amount of ergosterol at subinhibitory concentrations, indicating that the mode of activity of fluconazole was retained within the complexes, which was corroborated via molecular docking with cytochrome P450 sterol 14 alpha-demethylase (CYP51) as a target. Electrostatic, steric and internal energy interactions between the complexes and enzyme showed that 2 has higher binding potency to this target. Both complexes showed strong inhibition of C. albicans filamentation and biofilm formation at subinhibitory concentrations, with 2 being able to reduce the adherence of C. albicans to A549 cells in vitro. Complex 2 was able to reduce pyocyanin production in Pseudomonas aeruginosa between 10% and 25% and to inhibit its biofilm formation by 20% in comparison to the untreated control. These results suggest that complex 2 may be further examined in the mixed Candida-P. aeruginosa infections.

New silver(I) complex with thianthrene (tia), [Ag(NO3)(tia)(H2O)]n, was synthesized by the reaction of AgNO3 with an equimolar amount of tia in ethanol/dichloromethane (v/v 1:1) at room temperature, and characterized by NMR, IR and UV-Vis spectroscopy and single-crystal X-ray diffraction analysis. The antimicrobial activity of the synthesized complex was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and Candida spp. This complex showed significant activity toward important human pathogens Gram-positive Staphylococcus aureus and Candida parapsilosis with minimal inhibitory concentrations (MICs) being 3.91 µg/mL. The interaction of [Ag(NO3)(tia)(H2O)]n with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied to evaluate the binding affinity towards these biomolecules for possible insights on the mode of antimicrobial activity. The binding affinity of the investigated complex to BSA is higher than that for DNA, indicating that proteins could be more favorable binding sites for this complex in comparison to the nucleic acids.

Three novel Zn(II) complexes, [ZnCl2(qz)(2)] (1), [ZnCl2(1,5-naph)](n) (2) and [ZnCl2(4,7-phen)(2)] (3), where qz is quinazoline, 1,5-naph is 1,5-naphthyridine and 4,7-phen is 4,7-phenanthroline, were synthesized by the reactions of ZnCl2 and the corresponding N-heterocyclic ligand in 1:2 molar ratio in ethanol at ambient temperature. The characterization of these complexes was done by NMR, IR and UV-Vis spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction analysis. Complexes 1 and 3 are mononuclear species, in which Zn(II) ion is tetrahedrally coordinated by two nitrogen atoms belonging to two qz or 4,7-phen ligands, respectively, and by two chloride anions, while complex 2 is a 1D coordination polymer that contains 1,5-naph as bridging ligand between two metal ions. In agar disc-diffusion assay, complexes 1-3 manifested good inhibitory activity against two investigated Candida strains (C. albicans and C. parapsilosis), while not inducing toxic effects on the healthy human fibroblast cell line (MRC-5). This activity was not fungicidal, as revealed by the broth microdilution assay, however complex 3 showed the ability to modulate Candida hyphae formation, which is an important process during infection and showed significant synergistic effect with clinically used antifungal polyene nystatin.

In a continuing search for a novel metal-containing antimicrobial agents, the present study reports the synthesis, characterization and biological evaluation of two silver(I) complexes with 1,10-phenanthroline-based ligands, [Ag(1,10-phen)(2)]CF3COO center dot H2O (Ag1) and [Ag(CF3COO)(5,6-epoxy-1,10-phen)](2)(Ag2), 1,10-phen is 1, 10-phenanthroline and 5,6-epoxy-1,10-phen is 5,6-epoxy-5,6-dihydro-1,10-phenanthroline. The complexes were characterized by different spectroscopic techniques (IR, H-1 and C-13 NMR and UV-Vis), while the crystal structure of Ag2 complex was determined by a single-crystal X-ray diffraction analysis. The spectroscopic data confirmed that the structure of Ag1 complex, with silver(I) ion tetrahedrally coordinated by two bidentate 1, 10-phen ligands, is in accordance to the previous report (S.E. Paramonov et al., 2003). The crystallographic results showed that in dinuclear Ag2 complex, both Ag(I) ions are coordinated bidentately by 5,6-epoxy-1, 10-phen and monodentately by trifluoroacetate, with presence of the short Ag center dot center dot center dot Ag contact of 2.963 angstrom. Both silver (I) complexes were evaluated in vitro for antimicrobial activity against four bacterial and four Candida species, showing selectivity towards the investigated species of Candida with minimal inhibitory concentrations (MICs) between 0.9 and 12.5 mu M. Moreover, Ag2 complex manifested significant antiproliferative properties in the case of a range of human cell lines, including human breast cancer (MDA-MB 231), which resulted from the presence of epoxy functional group in the ligand. The gel electrophoresis results obtained from the studies of Ag1 and Ag2 interactions with bacteriophage lambda DNA (XDNA) suggested that these complexes did not cause DNA degradation.

New polynuclear manganese(II) and cadmium(II) complexes with 2,2-dimethyl-1,3-propanediamine-N,N, N',N'-tetraacetato ligand (2,2-diMe-1,3-pdta), {Ba[M(2,2-diMe-1,3-pdta)]center dot 3H(2)O}(n) (M = Mn (1) or Cd (2)) were synthesized and characterized by IR spectroscopy and single-crystal X-ray diffraction analysis. In addition, complex 2 was characterized by solution H-1 and C-13 NMR spectroscopy. Crystallographic analysis showed that 2,2-diMe-1,3-pdta ligand is hexadentately coordinated to each M(II) ion through the two nitrogen and four carboxylate oxygen atoms, whereas the one of these oxygen atoms is also involved in coordination to the second M(II) ion of the dinuclear [M-2(2,2-diMe-1,3-pdta)(2)](4-) unit in polymeric structures. Moreover, three of four carboxylic groups of 2,2-diMe-1,3-pdta ligand are additionally bonded to four Ba(II) ions, in three distinctive bridging coordination modes. Each Ba(II) ion is surrounded by ten oxygen atoms, seven belonging to carboxylate groups of 2,2-diMe-1,3-pdta, and three belonging to water molecules. The coordination environment around Mn(II) and Cd(II) ions could be assigned as a face capped octahedron, while coordination polyhedron around Ba(II) ion in these two complexes was described as a distorted sphenocorona. The antimicrobial potential of complexes 1 and 2 and corresponding metal salts used for their synthesis was evaluated against different bacterial and Candida spp. Both complexes showed selective antifungal activity against the tested Candida spp. compared to the bacterial strains, with the minimal inhibitory concentration (MIC) values in the range 3.12 - 12.50 mu M. Moreover, complex 1 caused the slightly decrease of hyphae length, while no significant influence on hyphal length of complex 2 was observed. With aim to assess the therapeutic profile of the complexes, their cytotoxicity was evaluated against the normal human lung fibroblast cell line (MRC-5).

Over the last few decades, invasive fungal infections represent a serious problem for modern-day healthcare. Aspergillus, Candida and Cryptococcus species are the most common pathogens causing life-threatening infections. Therapeutic options for the treatment of fungal infections are presently limited to only four classes of compounds and each of these drug classes has significant therapeutic limitations, including serious toxic-side effects, resistance development and limited routes of administration. In order to overcome resistance of the clinically used antifungal triazole agents, we synthesized zinc(II) and copper(II) complexes with fluconazole (flz), {[ZnCl2(flz)2]·2C2H5OH}n (1) and {[CuCl2(flz)2].5H2O}n (2). These complexes were obtained from the reactions between ZnCl2 or CuCl2·2H2O with this antifungal agent in 1 : 2 molar ratio in ethanol at room temperature. The compounds were characterized by elemental analysis, NMR, IR and UV-Vis spectroscopy and mass spectrometry. The crystal structure of complex 1 was determined by a single-crystal X-ray diffraction analysis. The antimicrobial effect of both complexes and fluconazole was evaluated against different Candida species as well as Gram-positive and Gram-negative bacteria by means of minimal inhibitory concentrations (MICs). The obtained results have shown that, in most cases, the coordination of fluconazole to Zn(II) and Cu(II) ions leads to the enhancement of its antifungal activity. Both complexes showed strong inhibitory activity against C. albicans biofilm formation at concentrations lower than MIC values, as well as strong inhibition of C. albicans filamentation.

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 to

New polynuclear silver(I) complexes with 1,5-naphthyridine (1,5-naph), [Ag(NO3)(1,5-naph)](n) (Ag1), [Ag (CF3COO)(1,5-naph)]n (Ag2) and [Ag(CF3SO3)(1,5-naph)](n) (Ag3) were synthesized by the reaction of the corresponding silver(I) salt and 1,5-naph in ethanol at room temperature. These complexes were characterized by NMR, IR and UV Vis spectroscopy, while their crystal structures were determined by single-crystal X-ray diffraction analysis. In all these complexes, 1,5-naph acts as a bridging ligand between two Ag(I) ions, while the remaining coordination sites are occupied by oxygen atom(s) of the corresponding anion. The antimicrobial efficiency of these silver(I) complexes was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and fungi. The complexes showed good to moderate antibacterial activity with the minimal inhibitory concentration (MIC) values being in the range 2.5-100 mu g/mL (6.5-333.3 mu M), while their antifungal activity against the investigated Candida spp. was significantly higher (MIC = 0.78-6.25 mu g/mL; 2.6-20.8 mu M). Moreover, complexes Ag1 and Ag2 effectively inhibited C. albicans biofilms formation, while Ag1 was also shown to inhibit the formation of mixed C. albicans/Pseudomonas aeruginosa biofilms. Toxicological evaluations on zebrafish (Dario rerio) embryos revealed that all silver(I) complexes could be applied as antifungal agents, whereas Ag3 had the best therapeutic potential showing both the lowest MIC values against the tested Candida strains and the non-toxic in vivo response in the zebrafish embryos at these doses.

1,2-Bis(4-pyridyl)ethane (bpa) and 1,2-bis(4-pyridyl)ethene (bpe) were used for the synthesis of polynuclear silver(I) complexes, {[Ag(bpa)]NO3}(n) (1), {[Ag(bpa)(2)](CF3SO3H2O)-H-.}(n) (2) and {[Ag(bpe)]CF3SO3}(n) (3). In complexes 1-3, the corresponding nitrogen-containing heterocycle acts as a bridging ligand between two Ag(I) ions. In vitro antimicrobial activity of these complexes, along with the ligands used for their synthesis, was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and fungi. The silver(I) complexes 1-3 showed selectivity towards Candida spp. and Gram-negative Escherichia coli in comparison to the other investigated bacterial strains, effectively inhibiting the growth of four different Candida species with minimal inhibitory concentrations (MICs) between 2.5 and 25 mu g/mL and the growth of E. coli, with MIC value being 12.5 mu g/mL. Importantly, complex 2 significantly reduced C. albicans filamentation, an essential process for its pathogenesis. Antiproliferative effect on the normal human lung fibroblast cell line MRC-5 was also evaluated with the aim of determining the therapeutic potential of the complexes 1-3. The interactions of these complexes with calf thymus DNA (ctDNA) and bovine serum albumin (BSA) were studied to evaluate their binding activities towards these biomolecules for possible insights on their mode of action.

Infections of the cow udder leading to mastitis and lower milk quality are one of the biggest problems in the dairy industry worldwide. Unfortunately, therapeutic options for the treatment of cow mastitis are limited as a consequence of the development of pathogens that are resistant to conventionally used antibiotics. In the search for agents that will be active against cow mastitis associated pathogens, in the present study, five new silver(I) complexes with different chelating pyridine-4,5-dicarboxylate types of ligands, [Ag(NO3)(py-2py)](n) (1), [Ag(NO3)(py-2metz)](n) (2), [Ag(CH3CN)(py-2py)]BF4 (3), [Ag(py-2tz)(2)]BF4 (4) and [Ag(py-2metz)(2)]BF4 (5), py-2py is dimethyl 2,2'-bipyridine-4,5-dicarboxylate, py-2metz is dimethyl 2-(4-methylthiazol-2-yl)pyridine-4,5-dicarboxylate and py-2tz is dimethyl 2-(thiazol-2-yl)pyridine-4,5-dicarboxylate, were synthesized, structurally characterized and assessed for in vitro antimicrobial activity using both standard bioassay and clinical isolates from a contaminated milk sample obtained from a cow with mastitis. These complexes showed remarkable activity against the standard panel of microorganisms and a selection of clinical isolates from the milk of the cow diagnosed with mastitis. With the aim of determining the therapeutic potential of silver(I) complexes, their toxicity in vivo against the model organism, Caenorhabditis elegans (C. elegans), was investigated. The complexes that had the best therapeutic profile, 2 and 5, induced bacterial membrane depolarization and the production of reactive oxygen species (ROS) in Candida albicans cells and inhibited the hyphae as well as the biofilm formation. Taken together, the presented data suggest that the silver(I) complexes with pyridine ligands could be considered for the treatment of microbial pathogens, which are causative agents of cow mastitis.

The reactions between equimolar amounts of CuX2 (X = NO3− and CF3SO3−) and two aromatic nitrogen-containing heterocycles differing in the position of nitrogen atoms, 1,7- and 4,7-phenanthroline (1,7- and 4,7-phen), were performed in ethanol/methanol at room temperature. When CuX2 salts were mixed with 4,7-phen, two copper(II) complexes, [Cu(NO3)2(4,7-Hphen)2](NO3)2 (1) and [Cu(CF3SO3)(4,7- phen)2(H2O)2]CF3SO3 (2), were formed. On the other hand, in the reaction of CuX2 salts with 1,7-phen, only 1,7-HphenNO3 (3a/b) and 1,7-HphenCF3SO3 (4) were obtained as the final products. The obtained products 1–4 were characterized by spectroscopic and X-ray diffraction techniques. In the copper(II) complexes 1 and 2, the coordination geometry around the Cu(II) ion is distorted octahedral and square pyramidal, respectively. The antimicrobial potential of the copper(II) complexes 1 and 2 and corresponding compounds used for their synthesis were assessed against four different bacterial species and Candida albicans, displaying moderate growth inhibiting activity. The cytotoxic properties of the investigated complexes were also evaluated against the normal human lung fibroblast cell line (MRC-5) indicating moderate, yet more pronounced cytotoxicity than antimicrobial properties.

Five novel silver(I) complexes with 4,7-phenanthroline (4,7-phen), [Ag(NO 3 -O)(4,7-phen-μ-N4,N7)] n (1), [Ag(ClO 4 -О)(4,7-phen-μ-N4,N7)] n (2), [Ag(CF 3 COO-O)(4,7-phen-μ-N4,N7)] n (3), [Ag 2 (H 2 O) 0.58 (4,7-phen) 3 ](SbF 6 ) 2 (4) and {[Ag 2 (H 2 O)(4,7-phen-μ-N4,N7) 2 ](BF 4 ) 2 } n (5) were synthesized, structurally elucidated and biologically evaluated. These complexes showed selectivity towards Candida spp. in comparison to the tested bacteria and effectively inhibited the growth of four different Candida species, particularly of C. albicans strains, with minimal inhibitory concentrations (MICs) in the range of 2.0–10.0 μM. In order to evaluate the therapeutic potential of 1–5, in vivo toxicity studies were conducted in the zebrafish model. Based on the favorable therapeutic profiles, complexes 1, 3 and 5 were selected for the evaluation of their antifungal efficacy in vivo using the zebrafish model of lethal disseminated candidiasis. Complexes 1 and 3 efficiently controlled and prevented fungal filamentation even at sub-MIC doses, while drastically increased the survival of the infected embryos. Moreover, at the MIC doses, both complexes totally prevented C. albicans filamentation and rescued almost all infected fish of the fatal infection outcome. On the other side, complex 5, which demonstrated the highest antifungal activity in vitro, affected the neutrophils occurrence of the infected host, failed to inhibit the C. albicans cells filamentation and showed a poor potential to cure candidal infection, highlighting the importance of the in vivo activity evaluation early in the therapeutic design and development process. The mechanism of action of the investigated silver(I) complexes was related to the induction of reactive oxygen species (ROS) response in C. albicans, with DNA being one of the possible target biomolecules. © 2019 Elsevier Inc.