Silver N-heterocyclic Carbene Complexes Research Articles

Synthesis, Characterization and DNA Binding Study of Silver N-Heterocyclic Carbene Complex [Bis (1,3-Dipentyl-1,3-Dihydro-2-Imidazole-2-Ylidene) Silver (I) hexafluorophosphate (V)] by Surface-Enhanced Raman Spectroscopy (SERS)

The silver organometallic compounds favorably target DNA in cancerous cells and stop their growth by inhibiting DNA replication. Specific properties of these compounds help in their action as drugs and different changes occur in the structure of DNA. In-depth study of the binding mechanism of drugs is of potential use for novel drug synthesis. Surface-enhanced Raman spectroscopy (SERS) coupled with multivariate data analysis was employed to probe the interaction of silver N-heterocyclic carbene complex (drug) with DNA. In this study, silver N-heterocyclic carbene complex was synthesized and various concentrations were exposed to known concentrations of DNA. Silver nanoparticles were used for enhancement of Raman signals, which enabled sensitive detection and characterization of molecular changes occurring during binding process. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were applied to extract meaningful information from the spectral data. Changes in intensity and position of significant SERS signals were noted, which gave an indication of the bonding of the drug with DNA. The results reveal the strong intercalative binding of drug with nitrogenous bases of DNA. PCA and PLS-DA provide evidence for successful DNA-drug interaction.

Silver Organometallics that are Highly Potent Thioredoxin and Glutathione Reductase Inhibitors: Exploring the Correlations of Solution Chemistry with the Strong Antibacterial Effects.

The antibacterial activity of silver species is well-established; however, their mechanism of action has not been adequately explored. Furthermore, issues of low-molecular silver compounds with cytotoxicity, stability, and solubility hamper their progress to drug leads. We have investigated silver N-heterocyclic carbene (NHC) halido complexes [(NHC)AgX, X = Cl, Br, and I] as a promising new type of antibacterial silver organometallics. Spectroscopic studies and conductometry established a higher stability for the complexes with iodide ligands, and nephelometry indicated that the complexes could be administered in solutions with physiological chloride levels. The complexes showed a broad spectrum of strong activity against pathogenic Gram-negative bacteria. However, there was no significant activity against Gram-positive strains. Further studies clarified that tryptone and yeast extract, as components of the culture media, were responsible for this lack of activity. The reduction of biofilm formation and a strong inhibition of both glutathione and thioredoxin reductases with IC50 values in the nanomolar range were confirmed for selected compounds. In addition to their improved physicochemical properties, the compounds with iodide ligands did not display cytotoxic effects, unlike the other silver complexes. In summary, silver NHC complexes with iodide secondary ligands represent a useful scaffold for nontoxic silver organometallics with improved physicochemical properties and a distinct mechanism of action that is based on inhibition of thioredoxin and glutathione reductases.

Synthesis and catalytic activity of silver N-heterocyclic carbene complexes based on bis(3,5-dimethylpyrazol-1-yl)methyl-substituted pyridylimidazole

A series of N-heterocyclic carbene (NHC) silver complexes derived from 6-[bis(3,5-dimethylpyrazol-1-yl)methyl]-2-pyridylimidazole have been synthesized and characterized by physico-chemical and spectroscopic methods, and the structures of four complexes have been confirmed by X-ray structural analyses. The functionalized NHC is a monodentate ligand in (NHC)AgCl through the carbene carbon atom, and a bridging [C,N,N] tridentate ligand in (NHC)2Ag2(BF4)2 and (NHC)2Ag2(PF6)2 through two pyrazolyl nitrogens and the carbene carbon to form a metallomacrocycle, in which a head (carbene)– to tail (nitrogen) coordination mode to two silver atoms is observed. Preliminary catalytic tests show that these newly synthesized Ag–NHC complexes exhibit excellent catalytic activity at a low catalyst loading (0.1–1 mol%) in the aldehyde–amine–alkyne coupling reaction.

Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity.

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

Ethylene polymerization using N-Heterocyclic carbene complexes of silver and aluminum

ABSTRACTVarious transition metal catalysts have been utilized for ethylene polymerization. Silver catalysts have attracted less attention as the catalysts, but are potential for production of high molecular weight polyethylene. Herein, we report that silver complexes with various N-heterocyclic carbene (NHC) ligands in combination with modified methylaluminoxane (MMAO) afford polyethylene with high molecular weight (melting point over 140°C). SEM observation showed that the produced polyethylene has ultra-high molecular weight. NMR investigation of the reaction between the silver complexes with organoaluminums indicate that the NHC ligands transfer from the silver complex to aluminum to produce NHC aluminum complexes. Ph3C[B(C6F5)4] abstract methyl group from the NHC aluminum complex to afford cationic aluminum complex. The NHC aluminum complex promoted ethylene polymerization in the presence of Ph3C[B(C6F5)4] and organoaluminums. NHC ligand also promoted ethylene polymerization in combination with MMAO to produce polyethylene with high melting point (140.7°C). Thus, the aluminum complexes are considered to be the actual active species in silver-catalyzed ethylene polymerization.

Air stable N-heterocyclic carbene silver complexes: synthesis, characterization, and antibacterial activity

A new benzimidazolium salt containing a 2,5-dimethylbenzyl substituent and six N-heterocyclic carbene (NHC) silver complexes were prepared. The complexes were characterized by NMR, FTIR, and LC-MS spectroscopic methods and elemental analyses. They are stable in solution for a week. The antibacterial properties of the Ag(I) complexes against two Gram-positive and two Gram-negative bacteria were investigated. Inhibition zone and minimum inhibitory concentration (MIC) data establish that these NHC-Ag(I) complexes possess antibacterial activities; 2b showed the highest antibacterial activity overall against Gram-positive and Gram-negative bacteria.

Silver N-heterocyclic carbene complexes are potent uncompetitive inhibitors of the papain-like protease with antiviral activity against SARS-CoV-2.

The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite promising results, metal complexes have been relatively unexplored as antiviral agents in general and in particular against SARS-CoV-2. Here we report on silver NHC complexes with chloride or iodide counter ligands that are potent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) but inactive against 3C-like protease (3CLpro) as another SARS-CoV-2 protease. Mechanistic studies on a selected complex confirmed zinc removal from a zinc binding domain of PLpro as relevant factor of their activity. In addition, enzyme kinetic experiments revealed that the complex is an uncompetitive inhibitor and with this rare type of inhibition it offers great pharmacological advantages in terms selectivity. The silver NHC complexes with iodide ligands showed very low or absent host cell toxicity and triggered strong effects on viral replication in cells infected with SARS-CoV-2, making them promising future antiviral drug candidates.

Chemoselective reduction of imines and azobenzenes catalyzed by silver N-heterocyclic carbene complexes

The first example of NHC (N-heterocyclic carbene) ligand-promoted reduction of imines and azobenzenes with a homogeneous silver catalyst is reported.

N-Heterocyclic Carbene Silver Complex Modified Polyacrylonitrile Fiber/MIL-101(Cr) Composite as Efficient Chiral Catalyst for Three-Component Coupling Reaction.

Complex asymmetric synthesis can be realized by the chiral induction of amino acids in nature. It is of great significance to design a new biomimetic catalytic system for asymmetric synthesis. In this context, we report the preparation and characterization of the composite of polyacrylonitrile fiber (PANF) and metal-organic framework to catalyze the chiral synthesis of propargylamines. A confined microenvironment is established with N-heterocyclic carbene (NHC) silver complex-supported PANF and D-proline-encapsulated MIL-101(Cr). This novel supported catalyst demonstrated high activity in addition to excellent stereoselectivity in the three-component reaction between alkynes, aldehydes, and amines (A3). The regeneration can be realized by adsorption of D-proline again when the stereoselectivity decreases after recycle uses. By regulating the confined microenvironment on the composite, the activity and selectivity of the catalytic system are improved with turnover numbers of up to 2800 and 98% ee. The biomimetic catalytic system to A3 coupling reaction is systematically studied, and the synergistic catalytic mechanism between NHC-Ag and D-proline in the confined microenvironment is revealed.

N-Heterocyclic Carbene (NHC) Silver Complexes as Versatile Chemotherapeutic Agents Targeting Human Topoisomerases and Actin.

In recent years, the number of people suffering from cancer has risen rapidly and the World Health Organization and U.S. and European governments have identified this pathology as a priority issue. It is known that most bioactive anticancer molecules do not target a single protein but exert pleiotropic effects, simultaneously affecting multiple pathways. In our study, we designed and synthesized a new series of silver N-heterocyclic carbene (NHC) complexes [(NHC)2 Ag]+ [AgX2 ]- (X=iodide or acetate). The new complexes were active against two human breast cancer cell lines, MCF-7 and MDA-MB-231. These compounds showed multiple target actions as anticancer, by inhibiting in vitro the activity of the human topoisomerases I and II and interfering with the cytoskeleton dynamic, as also confirmed by in silico studies. Moreover, the antimicrobial activity of these silver complexes was studied against Gram-positive/negative bacteria. These dual properties provide a two-tiered approach, making these compounds of interest to be further deepened for the development of new chemotherapeutic agents.

Six Fluorene-Based N-Heterocyclic Carbene Silver(I) Complexes: Structural Study and Recognition for Cu2+

A series of fluorene-bridged bisazolium salts L1H2·X2-L6H2·X2 (X = Br– or PF6–) and six related N-heterocyclic carbene silver(I) complexes [(L1Ag)2](NO3)2 (1), {[L2Ag2(CH3CN)2]2}(PF6)4 (2), [(L3Ag)2(Ag2Br4)]n (3), [(L4Ag) (NO3)]n (4), [L5Ag2Br2]n (5), and [L6(AgCl)2] (6) have been synthesized and characterized. Each cationic moiety of 1 or 2 contained one 28-membered macrometallocycle formed via two silver(I) ions and two biscarbene ligands (L1 for 1 and L2 for 2). 1D coordination polymeric chains of 3–5 were formed by different monomers. The open structure of 6 was formed through one biscarbene ligand L6 and two [AgCl] units, in which two [AgCl] units pointed to opposite directions. Additionally, the recognition performance of 2 to Cu2+ was researched through fluorescence spectra, UV/vis spectra, 1H NMR titrations, HRMS, IR spectra, and the quantum chemical computations. The results showed that 2 can effectually differentiate Cu2+ from other cations.

Pyridine‐functionalized N‐heterocyclic carbene gold(I) binuclear complexes as molecular electrocatalysts for oxygen evolution reactions

N‐heterocyclic carbene (NHC) complexes of gold(I/III) attained immense interest in catalytic organic transformations and as anticancer agents against several types of human cancers; however, their potential as electrocatalysts is scarce. The electrocatalytic oxygen evolution reaction was performed for the first time using pyridine‐functionalized NHC gold(I) binuclear metallacycles (8 and 9) possessing aptly designed ligand field. Complexes were prepared by the transmetallation of corresponding silver(I) NHC complexes, which were prepared by in situ deprotonation of pyridine and aryl substituted 1,2,4‐triazolium hexafluorophosphate salts (6 and 7) with Ag2O under dark. Both triazolium salts and binuclear gold(I) metallacycles were thoroughly characterised by NMR and ATR‐IR spectral and elemental analyses. A bromide salt 4 and a binuclear gold complex 9 were elucidated for structure by single crystal X‐ray diffraction analysis. Complex 9 possesses distorted linear coordination geometry around the gold atoms by the coordination of carbene carbon and pyridine nitrogen atoms bearing close Au–Au interaction (3.251 Å). The binuclear gold complexes 8 and 9 (along with 10 wt% conductive mesoporous carbon) were investigated as molecular electrocatalysts in oxygen evolution reaction (OER), which evidenced an oxygen evolution overpotential of 2.422 and 2.370 V versus reversible hydrogen electrode (RHE), respectively, to attain a current density of 10 mA.cm−2. The Tafel slope values of 40.9 and 30.4 mV dec−1 for 8 and 9, respectively, indicate the reaction mechanism involved and the suitability of these complexes as apt electrocatalysts for OER. The stability of the prepared molecular electrocatalysts was investigated by cyclic voltammetry and chronoamperometry techniques.

Benzimidazole-based N-heterocyclic carbene silver complexes as catalysts for the formation of carbonates from carbon dioxide and epoxides

A series of left-to-right inequivalent 1,3-disubstituted benzimidazolium halide pro-ligands having the general formula [RBNHCCH2OxMe][X] (R = 3-Me-Bn, 3,5-Me2-Bn, 2,4,6-Me3-Bn, 2,3,5,6-Me4-Bn, 2,3,4,5,6-Me5-Bn, 3,4,5-(OMe)3-Bn, or 4-tBu-Bn; X = Cl, Br) were synthesized by the alkylation of 1-((3-methyloxetan-3-yl)methyl)benzimidazole. The corresponding Ag complexes, (RBNHCCH2OxMe)AgX, were prepared following pro-ligand addition to Ag2O. These compounds were characterized using spectroscopic techniques such as FT-IR, NMR spectroscopy, and single-crystal X-ray diffraction. The solid-state structure of (3-Me-BnBNHCCH2OxMe)AgCl revealed a linear monomer while [(2,4,6-Me3-BnBNHCCH2OxMe)AgCl]2 was found to exist as a dimer with pseudo trigonal planar geometry about each metal center. The synthesized (RBNHCCH2OxMe)AgX complexes were found to be efficient for the addition of carbon dioxide to epoxides to yield value-added cyclic carbonates at ambient pressure. Amongst the investigated complexes, the bimetallic complex [(2,4,6-Me3-BnBNHCCH2OxMe)AgCl]2 was found to be the most active for CO2 insertion, exhibiting favorable activity when compared to known NHC complexes.

Synthesis and biological activity of new silver complexes with N-heterocyclic carbene ligands

Silver complexes of N-heterocyclic carbene (NHC) have been synthesized, structured, and tested for antibacterial activity. All of the silver–NHC complexes (10–13) were made by reacting benzimidazolium salts with Ag2O at room temperature in dichloromethane as a solvent. The hypothesized structures are supported by 1H NMR, 13 C NMR, and IR analysis of the novel compounds. In vitro antibacterial efficacy against Gram-positive S. aureus and Gram-negative Bacteria E. coli was tested on a number of novel Ag–NHC complexes.

Activity of Benzimidazole Derivatives and their N-Heterocyclic Carbene Silver Complexes Against Leishmania major Promastigotes and Amastigotes

Little progress was conducted concerning discovering new efficient antileishmanial drugs for many years. Hence, the disease has become a global health problem meanwhile. Benzimidazole derivatives and heavy metal complexes have shown potent antiparasitic activities. The present work is intended to evaluate fourteen synthetic benzimidazolium salts and N-heterocyclic silver carbene complexes against Leishmania major. Promastigotes and amastigotes of L. major were cultured in vitro to evaluate compound-induced inhibitory effects, and isolated mouse macrophages were used for cytotoxicity evaluation. Reactive oxygen species (ROS) formation was detected for all compounds as a possible mode of action. The silver complexes 3d and 3e revealed significant activity against L. major promastigotes with IC50 values of 6.4 and 5.5 µg mL-1, and SI of 1.77 and 2.02, respectively. Both complexes showed higher ROS production in promastigotes than in macrophages. Further in vivo and enzyme inhibition studies are recommended to evaluate the potential of these compounds as new antileishmanial.

Activity analysis of new N-heterocyclic carbenes and silver N-heterocyclic carbene molecules against novel coronavirus by UV-vis, fluorescence spectroscopy and molecular docking

The biggest pandemic that this generation has experienced is still continuing. While researchers concentrated on vaccine studies, development of treatment procedures and anti-viral drugs are other important parts of struggle against Severe Acute Respiratory Syndrome Coronavirus-2. Also, N-heterocyclic carbenes and their metal complexes have been studied recently as pro-drug researches. In this study, complexation and binding behavior of N-heterocyclic carbene precursor and its silver complex with Bovine Serum Albumin were analyzed by UV-vis and fluorescence spectroscopy. The binding constant of the silver N-heterocyclic carbene complex was determined as 1.38(±0.82)×106 M−1, and the number of binding sites was also determined as 1.2. The structural, Frontier orbital, and electronic transition analyses were performed by Density Functional Theory/Time-Dependent Density Functional Theory. In addition, docking of the molecules in two different Severe Acute Respiratory Syndrome Coronavirus-2 crystal structures and also in Bovine Serum Albumin crystal structure were carried out with the molecular docking method, which is accepted as an essential tool in pharmaceutical studies. According to the docking results, the interactions of N-heterocyclic carbene and its silver complex are better than studied antiviral drugs, and silver complex has better results than that of precursor.

Metallodrug Profiling against SARS-CoV-2 Target Proteins Identifies Highly Potent Inhibitors of the S/ACE2 interaction and the Papain-like Protease PLpro.

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS‐CoV‐2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain‐like protease PLpro. In addition to many well‐established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal‐based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS‐CoV‐2 assays confirming activity for gold complexes with N‐heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal‐based SARS‐CoV‐2 antiviral agents.

Dinuclear silver-bis(N-heterocyclic carbene) complexes: Synthesis, catalytic activity in propargylamine formation and computational studies

Preparation of a series of 1,1′-dialkyl-3,3′-(2-methylenepropane-1,3-diyl)dibenzimidazolium salts (alkyl = ethyl, propyl, butyl) (2a-2c) and their dinuclear bis(N-heterocyclic carbene) silver complexes (3a-3c) is reported. The silver complexes were synthesized via in situ deprotonation with Ag2O in 67-74% yields. The structural definitions of the synthesized compounds were performed by 1H NMR, 13C NMR, elemental analysis, FT-IR and also LC-MSMS techniques (only for 3a-3c). The silver complexes were utilized for three-component coupling reactions of aldehydes, amines and alkynes (A3-coupling). It was found that increasing the chain length of the alkyl substituent on the N-heterocyclic carbene ligand led to increase in catalytic performance. 3c showed the highest activity with 81% yield and with TON of 27 for N,N-diethyl-3-phenylprop-2-yn-1-amine formation. Geometry optimization was performed and geometric parameters were calculated for the compounds. The theoretical harmonic vibration frequencies of molecules were computed by DFT/B3LYP methods for their optimized geometries.

Synthesis, characterization and catalytic properties of cationic N-heterocyclic carbene silver complexes.

Three new dibenzimidazolium salts bridged by 2-methylenepropane-1,3-diyl group were synthesized. Their dinuclear N-heterocyclic carbene Ag(I) complexes were prepared by the reactions of these salts with Ag2O. The structures of the synthesized compounds were defined by nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), elemental analysis, and LC-MSMS (for complexes) techniques. Stability of the silver complexes was confirmed by 1H NMR spectroscopy. Catalytic activities of Ag(I) compounds were tested for three-component coupling reaction of some aldehydes, amines, and phenylacetylene.

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.