Pyrazine Functionalized Ag(I) and Au(I)-NHC Complexes are Potential Antibacterial Agents

Abstract

Antimicrobial resistance is an ever-increasing problem throughout the world and has already reached severe proportions. Bacteria can develop ways to render traditional antibiotics ineffective, raising a crucial need to find new antimicrobials with novel mode of action. We demonstrate here a novel class of pyrazine functionalized Ag(I) and Au(I)-NHC complexes as antibacterial agents against human pathogens that are resistant to several antibiotics. Complete synthetic and structural studies of Au(I) and Ag(I) complexes of 2-(1-methylimidazolium) pyrimidinechloride (L-1), 2,6-bis(1-methylimidazol)pyrazinechloride (L-2) and 2,6-bis(1-methyl imidazol) pyrazinehexa-fluorophosphate (L-3) are reported herein. Chloro[2,6-bis(1-methyl imidazol)pyrazine]gold(I), 2b and chloro [2,6-bis(1-methyl imidazol)pyrazine]silver(I), 2a complexes are found to have more potent antimicrobial activity than other synthesized compounds and several conventionally used antibiotics. Complexes 2b and 2a also inhibit the biofilm formation by Gram-positive bacteria, Streptococcus mutans and Gram-negative bacteria, Escherichia coli, causing drastic damage to the bacterial cell wall and increasing membrane permeability. Complexes 2b and 2a strongly binds to both Lys and Dap-Type peptidoglycan layers, which may be the reason for damage to the bacterial cell wall. Theoretical studies of all the complexes reveal that 2b and 2a are more reactive than other complexes, and this may be the cause of differences in antibacterial activity. These findings will pave the way towards developing a new class of antibiotics against different groups of conventional antibiotic-resistant bacteria.

Silver(I), Gold(I) and Gold(III)-N-Heterocyclic carbene complexes of naphthyl substituted annelated ligand: Synthesis, structure and cytotoxicity

“…Over the past couple of decades, a broad range of silver(I) complexes supported by NHCs has been synthesized [25] and applied for biological screening [26]. More recently, Ag(I)eNHC complexes were found to be potent agents against drug-resistant pathogens [27,28] and recent studies by Youngs and others have shown that AgeNHCs are useful in antibacterial and anticancer applications [28].…”

Cytotoxic potency of self-assembled Ruthenium(II)-NHC complexes with pincer type 2, 6-bis(N-methylimidazolylidene/benzimidazolylidene)pyrazine ligands

“…[2][3][4][5][6][7][8][9][10][11][12] Beyond catalysis, M-NHCs recently contributed interesting results as promising antimicrobial and anticancer drugs. [10][11][12][13][14][15] Though initially the imidazoline NHC ligands comprised N-alkylated derivatives, the file is enriched with N-functionalized NHC by pyridine, pyrimidine, pyrazole, oxazole, thiazole, carbazole, etc. [2][3][4][5][6][7][8][9]14,15] Most of N-alkylated NHCs acts as mono dentate ligands, whereas incorporation of wingtip such as pyridine/pyrimidine/oxazole/thiazole in the backbone offers either mono-, bi-, or tridentate NHC depending upon the designing of the ligand and choice of metal.…”

“…[10][11][12][13][14][15] Though initially the imidazoline NHC ligands comprised N-alkylated derivatives, the file is enriched with N-functionalized NHC by pyridine, pyrimidine, pyrazole, oxazole, thiazole, carbazole, etc. [2][3][4][5][6][7][8][9]14,15] Most of N-alkylated NHCs acts as mono dentate ligands, whereas incorporation of wingtip such as pyridine/pyrimidine/oxazole/thiazole in the backbone offers either mono-, bi-, or tridentate NHC depending upon the designing of the ligand and choice of metal. As NHC ligand is a strong σ-donor and weak π-acceptor than phosphine, it is used as an alternative of phosphine in catalysis.…”

“…[18] Recently, pyrazine-bridged imidazoline or benzimidazoline ligands have been synthesized and used in this study. [6][7][8][9][14][15][16][17][18] A steady growth of interest in Ru(II)-NHC anticancer drugs and photoluminescence study of Ru(II)-NHC complexes over the last 20 years is reflected in the accelerating growth of publications. [13,[19][20][21][22][23] Interestingly, Ru anticancer drugs have been growing rapidly since NAMI-A (ImH+)[RuIIICl4(Im) (S-dmso)], where Im = imidazole and S-dmso = S-bound dimethylsulfoxide) or KP1019 (IndH+)-[RuIIICl4(Ind)2], where Ind = indazole, has successfully completed phase-I clinical trials and an array of other Ru complexes have shown promises for future development.…”

“…[13] Nowadays, the emergence of bacterial or fungal pathogens with enhanced antibiotic resistance is a great threat to infection control. Several pyrazine functionalized M-NHC complexes [14] demonstrated the deleterious effects against multidrug-resistant pathogens, and Hindi et al [24] also summarized the antimicrobial activities of several M-NHCs whereas the reports are inadequate of Ru(II)-NHC for their antimicrobial properties along with anticancer activity. Interestingly, the secondary infection through human pathogens remains a major complication in patients with malignant disease, [25] which encouraged us to study both the anticancer and antimicrobial properties of Ru(II)-NHC.…”