Silver N-heterocyclic Carbene Complexes Research Articles

New silver N[sbnd]heterocyclic carbenes complexes: Synthesis, molecular docking study and biological activities evaluation as cholinesterase inhibitors and antimicrobials

We focused our study for the conception and the synthesis of a new series of Silver (I) N-heterocyclic carbene complexes which were obtained from the corresponding N-heterocyclic carbene (NHC) precursors and their unsymmetrical benzimidazolium salts. These new Ag-NHC complexes were screened for their antibacterial, antifungal, and anti-cholinesterase activities. The biological activities of synthesized products were compared with standard drugs. N-heterocyclic carbenes 2a-f and complexes 3a-f exhibited moderate antibacterial and antifungal activities. The results proved that the compounds indicated moderate to excellent activity against both AChE and BuChE. It was found that most of the complexes displayed good AChE and BuChE inhibitory activities. In particular, compounds 3c and 3e were the most potent inhibitors in the series with IC50 values of 8.56 ± 1.17 μM and 5.05 ± 0.30 μM against AChE and BChE, respectively. Docking studies revealed that compounds 3c and 3e bind manly to the catalytic anionic site (CAS) of the AChE, and BChE respectively.

Silver (I) N-Heterocyclic Carbene Complexes: A Winning and Broad Spectrum of Antimicrobial Properties.

The evolution of antibacterial resistance has arisen as the main downside in fighting bacterial infections pushing researchers to develop novel, more potent and multimodal alternative drugs.Silver and its complexes have long been used as antimicrobial agents in medicine due to the lack of silver resistance and the effectiveness at low concentration as well as to their low toxicities compared to the most commonly used antibiotics. N-Heterocyclic Carbenes (NHCs) have been extensively employed to coordinate transition metals mainly for catalytic chemistry. However, more recently, NHC ligands have been applied as carrier molecules for metals in anticancer applications. In the present study we selected from literature two NHC-carbene based on acridinescaffoldand detailed nonclassicalpyrazole derived mono NHC-Ag neutral and bis NHC-Ag cationic complexes. Their inhibitor effect on bacterial strains Gram-negative and positivewas evaluated. Imidazolium NHC silver complex containing the acridine chromophore showed effectiveness at extremely low MIC values. Although pyrazole NHC silver complexes are less active than the acridine NHC-silver, they represent the first example of this class of compounds with antimicrobial properties. Moreover all complexesare not toxic and they show not significant activity againstmammalian cells (Hek lines) after 4 and 24 h. Based on our experimental evidence, we are confident that this promising class of complexes could represent a valuable starting point for developing candidates for the treatment of bacterial infections, delivering great effectiveness and avoiding the development of resistance mechanisms.

A green approach for A3-coupling reactions: an experimental and theoretical study on NHC silver and gold catalysts

N-heterocyclic carbene silver and gold complexes active in A3-coupling (aldehyde–alkyne–amine) reactions in green conditions.

An efficient and recyclable AgNO3/ionic liquid system catalyzed atmospheric CO2 utilization: Simultaneous synthesis of 2-oxazolidinones and α-hydroxyl ketones

Oxazolidinones and α-hydroxyl ketones are two series of fine chemicals that have been generally utilized in biological, pharmaceutical, and synthetic chemistry. Herein, a AgNO3/ionic liquid (IL) catalytic system was developed for the simultaneous synthesis of these compounds through the atom-economical three-component reactions of propargyl alcohols, 2-aminoethanols, and CO2. Notably, this system behaved excellent catalytic activity with the lowermost metal loading of 0.25 mol%. Meanwhile, it is the first reported metal-catalyzed system that could efficiently work under atmospheric CO2 pressure and be recycled at least five times. Evaluation of the green metrics proved the AgNO3/IL-catalyzed processes to be relatively more sustainable and greener than the other Ag-catalyzed examples. Further mechanistic investigations revealed the derivative active species of N-heterocyclic carbene (NHC) silver complexes and CO2 adducts generated during the process. Subsequently, their reactivity in this reaction was assessed for the first time, which was finally identified as beneficial for the catalytic activity.

Molecular Docking Analysis of N-Heterocyclic Carbene and Silver N-Heterocyclic Carbene Complexes with Thioredoxin Reductas

Molecular Docking Analysis of N-Heterocyclic Carbene and Silver N-Heterocyclic Carbene Complexes with Thioredoxin Reductas

Molecular docking analysis of N-heterocyclic carbene and silver N-heterocyclic carbene complexes with thioredoxin reductas

Molecular docking analysis of N-heterocyclic carbene and silver N-heterocyclic carbene complexes with thioredoxin reductas

Silver(I) N-heterocyclic carbene complexes: Synthesis, characterization and cytotoxic properties

In this study, sulfonate functionalized N-heterocyclic carbene ligand precursors were obtained from the compounds 1-alkylbenzimidazole, 1,3-propane sultone, and 1,4-butane sultone. These NHC ligand precursors were metallated with Ag2O on moderate conditions to give novel silver-NHC complexes. All new compounds were characterized by by 1H NMR, 13C NMR, FT-IR and elemental analysis techniques. The cytotoxic properties of the silver(I) complexes have been assessed in various human cancer lines, including cisplatin-sensitive and resistant cells. IC50 values of these four complexes were determined by the MTT based assay on three human cell lines brain (SHSY5Y) and liver (HEP3B). These silver N-heterocyclic carbene complexes have been highlighted metal-based cancer therapeutic agents with unique structures and functions. These strategies provide exciting opportunities for discovering new types of metallodrugs.

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.

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.