Silver N-heterocyclic Carbene Research Articles

Synthesis of aryl linked binuclear silver N-heterocyclic carbene complexes, DNA interaction study and biological potentials

New binuclear N-heterocyclic carbene (NHC) salts and their silver complexes were synthesized and confirmed through multiple spectroscopic techniques and determined their stability in solution form. The synthesized bis Ag(I)–NHC complexes were tested In Vitro against three bacterial strains (Staphylococcus aureus and Staphylococcus pneumonia and Escherichia coli) to measure their antibacterial potential. The antibacterial activity of silver complexes was far better than their respective ligands as well as standard drug silver sulfadiazine. The MIC value of silver complexes was almost in level to broad spectrum standard drug ciprofloxacin and very much better than silver sulfadiazine. The anticancer activity of silver complexes and their salts were measured in dose dependent response against HCT-116 which was in comparable to standard drug 5-Flourouracil. DNA affinity of complexes was found better than cisplatin and almost comparable with its analogue carboplatin.

Macrocycles of Axially Chiral and Racemic N-Heterocyclic Carbene Silver(I), Gold(I) and Palladium(II) Complexes: Synthesis, Characterization and Computational Structures

In this study, Ag(I), Au(I) and Pd(II) bis -N-hetero-cyclic carbene (NHC) complexes derived from axially chiral R-1,1′-binaphthyl-2,2′-diol (R-BINOL) and racemic biphenyl-2,2′-diol scaffolds have been synthe-sized. The metallation of these bis -imidazolium and bis -triazolium types of ligand precursors of R-BINOL and biphenol unit, viz. (1–4)d has been achieved using standard procedure. The {[L(L′-NHC) 2 ]Ag}Cl-type, chiral (1–2)e and racemic (3–4)e complexes have been obtained by the treatment of ligand with Ag 2 O. Similarly, chiral Pd(II) (1f) and Au(I) (1g) complexes have been synthesized and analysed using spectroscopic techniques. The geometry-optimized structures obtained through the density functional theory display good proximity with the reported X-ray structures of similar type of Ag(I), AAu(I) and Pd(II) complexes.

Synthesis and properties of cyclic tetracarbene-based organometallic assemblies

A tubular tetranuclear silver(I) N-heterocyclic carbene (NHC) metallacage [Ag4(1)2](PF6)4 was synthesized by in situ deprotonation of a cyclic tetraimidazolium ligand with Ag2O. The interaction of obtained octacarbene-based metallacage with aromatic molecules, especially 4,4′-biphenyldicarboxaldehyde in solution was studied by NMR technique. The 4,4′-biphenyldicarboxaldehyde appearing to be located outside of the cavity with multiple C–H⋯O interactions was further confirmed by X-ray crystallography. Additionally, the reaction of the metallacage [Ag4(1)2](PF6)4 with [Cp∗IrCl2]2 afforded a dinuclear half-sandwich iridium complex [Cp∗2Ir2(1)](PF6)4 that contains two CNC-pincer-ligated Cp∗Ir fragments. The complex [Cp∗2Ir2(1)](PF6)4 was characterized by NMR spectroscopy, mass spectrometry and X-ray crystallography.

Silver(I) N-Heterocyclic Carbene Complexes Derived from Clotrimazole: Antiproliferative Activity and Interaction with an Artificial Membrane-Based Biosensor

With the aim of combining the potential anticancer properties of both clotrimazole, an imidazole based antifungal agent, and silver(I) N-heterocyclic carbenes, 13 novel silver(I) N-heterocyclic car...

A Novel Ag-N-Heterocyclic Carbene Complex Bearing the Hydroxyethyl Ligand: Synthesis, Characterization, Crystal and Spectral Structures and Bioactivity Properties

In this study, a novel silver N-heterocyclic carbene (Ag-NHC) complex bearing hydroxyethyl substituent has been synthesized from the hydroxyethyl-substituted benzimidazolium salt and silver oxide by using in-situ deprotonation method. A structure of the Ag-NHC complex was characterized by using UV-Vis, FTIR, 1H-NMR and 13C-NMR spectroscopies and elemental analysis techniques. Also, the crystal structure of the novel complex was determined by single-crystal X-ray diffraction method. In this paper, compound 1 showed excellent inhibitory effects against some metabolic enzymes. This complex had Ki of 1.14 0.26 µM against human carbonic anhydrase I (hCA I), 1.88±0.20 µM against human carbonic anhydrase II (hCA I), and 10.75±2.47 µM against α-glycosidase, respectively. On the other hand, the Ki value was found as 25.32±3.76 µM against acetylcholinesterase (AChE) and 41.31±7.42 µM against butyrylcholinesterase (BChE), respectively. These results showed that the complex had drug potency against some diseases related to using metabolic enzymes.

Benzimidazolium-acridine-based silver N-heterocyclic carbene complexes as potential anti-bacterial and anti-cancer drug

A series of N-alkylated benzimidazolium salts based on 9-substituted acridine has been synthesized and subsequently converted into the corresponding Ag(I) carbene complexes. The compounds were characterized by IR, 1H and 13C NMR spectroscopy. Identity and purity were confirmed by HRMS and elemental analysis, respectively. Both, ligands and complexes, were evaluated on their antibacterial and anticancer potential. All complexes exhibited higher activity against both Gram positive and Gram negative bacterial strains than the corresponding ligands. Human cell line experiments indicated low in-vitro cytotoxicity, while some of the complexes showed promising activity against breast cancer cells.

Novel fast-acting pyrazole/pyridine-functionalized N-heterocyclic carbene silver complexes assembled with nanoparticles show enhanced safety and efficacy as anticancer therapeutics.

In this study, we designed and synthesized four novel multi-nuclear silver complexes (1-4) coordinated with pyrazole- or pyridine-functionalized N-heterocyclic carbene (NHC) ligands. The crystal structures of the silver-NHC complexes were confirmed by X-ray diffraction analysis. In vitro assays showed that the silver-NHC complexes effectively killed a broad range of cancer cells after short-term drug exposure, serving as fast-acting cytotoxic agents. Of note, in cisplatin-resistant A549 cancer cells, the silver complexes were not cross-resistant with the clinically used cisplatin agent. Detailed mechanistic studies revealed that complex 2 triggered caspase-independent cell necrosis associated with intracellular reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) depletion. By exploiting a facile nano-assembly process, silver-NHC complexes 1, 2 and 4 were successfully integrated into the hydrophobic cores of amphiphilic matrices (DSPE-PEG2K), enabling systemic injection. The silver complex-loaded nanotherapeutics (1-NPs, 2-NPs, and 4-NPs) showed high safety margins with reduced systemic drug toxicities relative to cisplatin in animals. Furthermore, in a xenograft model of human colorectal cancer, the administration of the nanotherapeutics resulted in a marked inhibition of tumor progression.

Coumarin incorporated 1,2,4–triazole derived silver(I) N–heterocyclic carbene complexes as efficient antioxidant and antihaemolytic agents

Three series of structurally and electronically varied silver complexes of coumarin and allyl substituted N–heterocyclic carbene (NHC) ligands derived from 1,2,4–triazole core have been prepared and characterized. The ionic 1,2,4–triazolium salts have been prepared by successive N–alkylation method using allyl bromide and appropriately substituted 4–bromomethylcoumarin derivatives. Further, in–situ deprotonation method for triazolium salts was followed with different silver sources (silver oxide and silver acetate) and reaction conditions to obtain structurally diverse silver NHC coordination architectures. Furthermore, the structure of 4–bromomethyl–6–chlorocoumarin, a triazolium salt and two silver complexes has been established by single crystal X–ray diffraction technique. The silver NHC complexes displayed a linear coordination geometry with monoclinic crystal system. Supramolecular assembly of the salt and the complexes evidenced moderate π − π stacking interactions between adjacent coumarin rings. Since silver(I) NHC complexes are well known for medicinal properties, present complexes have been studied for their potent antioxidant and antihaemolytic abilities. Bis–NHC coordinated silver hexafluorophosphate complexes displayed DPPH radical scavenging activity with an IC50 value in the range 61 ± 14 to 131 ± 7 μM, while others displayed moderate to poor activity. Similarly, antihaemolytic activity has been carried out at 100 μM concentration, and the complexes exhibited lysis of red blood cells as low as 2.32 ± 0.05%.

Poly(ionic liquid)s-Supported N-Heterocyclic Carbene Silver Complexes for the Cycloaddition of CO2 with Epoxides

A series of poly(ionic liquid)s-supported N-heterocyclic carbene silver complexes (Poly(NHC-Ag/IL)s), poly(ionic liquid)s (PILs) and poly(N-heterocyclic carbene silver complexes) (Poly(NHC-Ag)s) were prepared through radical co-polymerization of N-vinylimidazolium ionic liquids, NHC-Ag monomers and divinylbenzene, respectively. These polymers were applied to catalyze the cycloaddition reaction of carbon dioxide and epoxides without any co-catalyst. Poly(NHC-Ag/IL)s exhibited higher activities than the corresponding PILs and Poly(NHC-Ag)s, which was attributed to the synergistic effect of NHC-Ag and bromide. Furthermore, Poly(NHC-Ag/IL)s could be easily recycled five times without significant loss of catalytic activity. Multi-functional poly(ionic liquid)s-supported N-heterocyclic carbene silver complexes (Poly(NHC-Ag/IL)s) were synthesized by radical co-polymerization of N-vinylimidazolium ionic liquids, NHC-Ag monomers and DVB. Poly(NHC-Ag/IL)s exhibited high activities for cycloaddition reaction of carbon dioxide and epoxides due to their multi-functional groups including Lewis acidic silver and a bromine anion.

Active ruthenium(II)-NHC complexes for alkylation of amines with alcohols using solvent-free conditions

A series of new ruthenium(II) complexes bearing N-heterocyclic carbene ligands with benzylic groups were prepared by transmetallation reactions between silver(I) N-heterocyclic carbene complexes and [RuCl2(p-cymene)]2. All of the obtained complexes were characterized by FT-IR, 1H NMR and 13C NMR spectroscopy, and the molecular structure of compound 3c was also determined by X-ray crystallography. These ruthenium complexes were tested for the alkylation of aromatic amines with a wide range of primary alcohols under solvent-free conditions using the hydrogen borrowing strategy. All of the compounds tested here showed excellent catalytic activity for these reactions and N-monoalkylated products were obtained selectively using 2.5 mol% of the ruthenium complexes.

Synthesis, characterization, in vitro antimicrobial and anticancer studies of new platinum N-heterocyclic carbene (NHC) complexes and unexpected nickel complexes

A series of bidendate pyridine-functionalized metal N-heterocyclic carbene (NHC) complexes with various wingtip substituents (R = methyl, phenyl and tert-butyl) had been prepared from silver oxide-mediated transmetalation method. The basic backbone of the NHC ligands were prepared in two stepwise reactions: reduction of the commercially available 2-benzoylpyridine, followed by halogenation to yield 2-(chloro(phenyl)methyl)pyridine. Subsequent reactions with different imidazoles gave the desired imidazolium salts (or NHC precursors) with different R groups at the N wingtip (R = Me, Ph, t-Bu). Transmetalation of the imidazolium salts into platinum NHC complexes were achieved by using Ag2O mediated method with Pt(cod)Cl2 as the transmetalating agent. On the other hand, nickel NHC complexes were obtained via one pot synthesis method with nickel chloride as the transmetalating agent and reflux in the presence of a base. Following recrystallisation, the molecular structure of Pt NHC complex ( ± )-5a had been successfully elucidated via single crystal X ray diffraction (XRD) analysis. The six-membered ring of the platinum NHC complexes adopted a boat conformation with the phenyl ring arranged at the axial position. Meanwhile, two unexpected nickel complexes, i.e. a simple nickel coordination complex and a nickelate complex, were obtained and studied using XRD. These Pt NHC complexes and unexpected Ni complexes were evaluated for their in vitro antimicrobial and anticancer activities against a panel of pathogenic microorganisms and three selected human cancer cell lines, including breast (MCF7), colon (HCT116) and oral (H103) cancer cells. Generally, the Pt NHC complexes displayed enhanced antimicrobial activities upon coordination to metals, as compared to the corresponding imidazolium salts i.e. NHC precursors, with minimum inhibitory concentration (MIC) values in micromolar (μM) range. A couple of platinum NHC complexes synthesized exhibited antimicrobial activities with MIC as low as 2 μM, which are comparable to silver NHC complexes with renowned antimicrobial profiles. Similarly, upon coordination to the metals, the cytotoxic effects of the platinum NHC complexes increased significantly as compared to the imidazolium salts. Among all, platinum NHC complex (±)-5c displayed significant cytotoxicities towards the cancer cells with IC50 values that are two to three times lower than that of the anticancer drug cisplatin. In summary, evidences for influence of both wingtip substituents and metals on the biological activities of the complexes have been found.

Antibacterial and transfection activities of nebulized formulations incorporating long n-alkyl chain silver N-heterocyclic carbene complexes.

The development of new antibacterial molecules is essential in view of the emergence of pathogenic strains resistant to multiple antibiotics. Among the infectious pathologies, pulmonary infections are particularly difficult to treat due to the complexity of lung anatomy and the presence of natural barriers such as mucus. At present, the aerosol delivery of antibacterial compounds is still poorly employed. Furthermore, the presence of bacteria in lungs negatively affects aerosolized Cystic Fibrosis gene therapy efficiency. A multi-functional formulation (antibacterial and transfection activities) could increase the therapeutic effect. This work reports the synthesis of new N-heterocyclic carbene silver complexes (Ag-NHC) featuring a lipid chain and the evaluation of their antibacterial potency, especially when delivered following aerosolization. When formulated alone in water, these Ag-NHC displayed remarkable antibacterial activities against some Staphyloccocus aureus strains and Pseudomonas aeruginosa clinical strains. Moreover, combined with cationic lipid and DNA (ternary combination), they could be used to deliver therapeutic genes via aerosolization in infected lungs. Altogether, the data reported herein support n-alkyl chain Ag-NHC as a possible alternative to conventional antibiotics for treating respiratory infections and to combat the emergence of multi-resistant bacteria.

Macrometallocycle binuclear NHC silver(I) complex with bridging azobenzene: Synthesis, structure and recognition for hydrogen sulfate

One bis-imidazolium salt 2,2′-di[2’’-(N-methyl-imidazoliumyl)ethoxyl]azobenzene hexafluorophosphate (LH2·(PF6)2) and its macrometallocycle binuclear N-heterocyclic carbene silver(I) complex [(LAg)2](PF6)2 were prepared and characterized. The structure of [(LAg)2](PF6)2 was determined by X-ray single crystal diffraction, 1H NMR and 13C NMR spectroscopy. In complex [(LAg)2](PF6)2, one 34-membered macrometallocycle was formed by two biscarbene ligand L and two silver(I) ions. Additionally, the selective recognition of hydrogen sulfate using [(LAg)2](PF6)2 as a chemosensor was investigated on the basis of fluorescence titrations, ultraviolet titrations, 1H NMR titrations, HRMS and IR spectra. Complex [(LAg)2](PF6)2 was demonstrated to be an effective chemosensor for hydrogen sulfate.

Stepwise Synthesis of Tetra-imidazolium Macrocycles and Their N-Heterocyclic Carbene Metal Complexes.

A modular stepwise synthetic method has been developed for the preperation of tetra-imidazolium macrocycles. Initially a series of three bis(imidazolylmethyl)benzene precursors were alkylated with 1,2-dibromoethane to produce the corresponding bis-bromoethylimidazolium bromide salts. In the second step the bis-bromoethylimidazolium bromide salts were reacted with selected bis(imidazolylmethyl)benzene molecules to produce a series of two symmetrical and three asymmetrical tetra-imidazolium macrocycles. These tetra-imidazolium salts act receptors for anions and 1H-NMR titration studies were used to determine the association constants between two of the macrocycles and the halide anions chloride, bromide and iodide. The tetra-imidazolium salts are precursors for N-heterocyclic carbene (NHC) ligands and the corresponding silver(I), gold(I), and palladium(II) NHC complexes have been prepared. Varied structures were obtained, which depend on the chosen macrocyclic ligand and metal ion and in the case of the coinage metals Ag(I) and Au(I), mono, di, and hexanuclear complexes were formed.

Novel Silver-NHC complexes: Synthesis and anticancer properties

The aim of this study was to present the synthesis, characterization and anticancer activities of two novel benzimidazole-based NHC salts (1a-b) and their silver(I) complexes (2a-b) with methylbenzyl and isopropylbenzyl chains. All compounds were prepared using Schlenk techniques in an inert atmosphere. The carbene complexes were prepared with the interaction of carbene precursors and Ag2O. All new compounds were characterized by elemental analysis, LC-MS, FT-IR, 1H NMR, and 13C NMR spectroscopic techniques. The anticancer activities of the salts and complexes were determined by cell proliferation analysis using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human prostate cancer cells (DU-145) and human breast cancer cells (MCF-7, MDA-MB-231). L-929, mouse adipose tissue fibroblasts were used as model normal cells. The cells were plated at a cell density of 1 × 105 cells in 96-well plates and treated with different concentrations (1–20 μM) of salts and complexes during 24, 48 and 72 h. The MTT assay results indicated that the salts (1a-b) have lower anticancer activity on cancer cells than their silver(I) complexes (2a-b). It was also observed that benzimidazole salts (1a-b) and their Ag-NHC complexes (2a-b) displayed lower anticancer activities on L-929 normal cells than on cancer cells. These results highlight that the anticancer activities of N-heterocyclic carbene-silver complexes vary according to the structure of the silver complex and cell line type.

Synthesis and Characterization of Ag(I) Complexes Derived from New N-Heterocyclic Carbenes

Two new unsymmetrical imidazolium salts viz., [1-(4-ethylphenyl)-3-propyl-1H-imidazole-3-ium bromide] (3) and [1-(2,6-dimethylphenyl)-3-propyl-1H-imidazole-3-ium bromide] (4) have been synthesized via the reaction of propyl bromide with imidazole derivatives, [1-(4-ethylphenyl)-1Himidazole] (1) and [1-(2,6-dimethylphenyl)-1H-imidazole] (2) in absence of solvent. Then two new N-heterocyclic carbene silver complexes (5 and 6) were prepared through the reaction of imidazoluim salts (3 and 4) as a source of N-heterocyclic carbene with Ag2O by in situ method. These complexes can be used in the future as a transfer agent for preparing other transitional metal carbine complexes (NHCs) via transmetallation method. The formation of these compounds was confirmed by spectral analysis.

Ruthenium(II)-NHC-catalyzed (NHC = perhydrobenzimidazol-2-ylidene) alkylation of amines using the hydrogen borrowing methodology under solvent-free conditions

New ruthenium(II) complexes with N-heterocyclic carbene ligand were synthesized by transmetalation reactions between silver(I) N-heterocyclic carbene complexes and [RuCl2(p-cymene)]2. The complexes were characterized by physicochemical and spectroscopic methods. These ruthenium complexes were applied to the N-monoalkylation of aromatic amines with a wide range of primary alcohols under solvent-free conditions using the hydrogen borrowing strategy. The catalytic reactions using all ruthenium complexes resulted in N-monoalkylated products with high selectivities using furfuryl alcohol as the alkylating agent.

Activation of nitriles by silver(I) N-heterocyclic carbenes: An efficient on-water synthesis of primary amides

A first example of silver(I) N-heterocyclic carbene (Ag(I)-NHC) catalyzed on-water synthesis of primary amides by hydration of nitriles under mild reaction conditions is described. This organometallic catalytic system has excellent tolerance for various homo-aromatic, hetero-aromatic and aliphatic nitriles to afford primary amides in good yields in neat water.

Amide bond synthesis via silver(I) N-heterocyclic carbene-catalyzed and tert-butyl hydroperoxide-mediated oxidative coupling of alcohols with amines under base free conditions

We present a base free method for amide bond construction via oxidative coupling of alcohols with amines catalyzed by Silver(I) N-heterocyclic carbenes (Ag(I)-NHCs) and mediated by tert-butyl hydroperoxide (TBHP) in ethanol. The results of controlled experiments suggest that the oxidative coupling proceeds through the formation of aldehyde, then subsequent attack by amine to give hemiaminal, which can then be oxidized to amide.

Ru(ii)-N-heterocyclic carbene complexes: synthesis, characterization, transfer hydrogenation reactions and biological determination.

A series of ruthenium(ii) complexes with N-heterocyclic carbene ligands were successfully synthesized by transmetalation reactions between silver(i) N-heterocyclic carbene complexes and [RuCl2(p-cymene)]2 in dichloromethane under Ar conditions. All new compounds were characterized by spectroscopic and analytical methods. These ruthenium(ii)–NHC complexes were found to be efficient precatalysts for the transfer hydrogenation of ketones by using 2-propanol as the hydrogen source in the presence of KOH as a co-catalyst. The antibacterial activity of ruthenium N-heterocyclic carbene complexes 3a–f was measured by disc diffusion method against Gram positive and Gram-negative bacteria. Compounds 3d exhibited potential antibacterial activity against five bacterial species among the six used as indicator cells. The product 3e inhibits the growth of all the six tested microorganisms. Moreover, the antioxidant activity determination of these complexes 3a–f, using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azinobis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) as reagent, showed that compounds 3b and 3d possess DPPH and ABTS antiradical activities. From a concentration of 1 mg ml−1, these two complexes presented a similar scavenging activity to that of the two used controls gallic acid (GA) and butylated hydroxytoluene (BHT). From a concentration of 10 mg ml−1, the percentage inhibition of complexes 3b and 3d was respectively 70% and 90%. In addition, these two Ru–NHC complexes exhibited antifungal activity against Candida albicans. Investigation of the anti-acetylcholinesterase activity of the studied complexes showed that compounds 3a, 3b, 3d and 3e exhibited good activity at 100 μg ml−1 and product 3d is the most active. In a cytotoxicity study the complexes 3 were evaluated against two human cancer cell lines MDA-MB-231 and MCF-7. Both 3d and 3e complexes were found to be active against the tested cell lines showing comparable activity with examples in the literature.