Ionic Liquids Containing Silsesquioxane and Cyclic Siloxane Frameworks.

This paper describes the author's recent work on the preparation and properties of thermally stable ionic liquids (ILs) containing siloxane frameworks. Quaternary ammonium and imidazolium salt-type ILs containing random oligosilsesquioxane frameworks were successfully prepared via the hydrolytic condensation of the corresponding organotrialkoxysilanes by using an aqueous superacid bis(trifluoromethanesulfonyl)imide (HNTf2 ) solution as a catalyst and solvent. Imidazolium salt-type ILs containing polyhedral oligomeric silsesquioxane (POSS) frameworks were also prepared through a reaction similar to that described above by using a water/methanol mixed solution of HNTf2 . In addition, amorphous POSSs with two types of ionic groups randomly distributed in the side chain were prepared. These POSSs were ILs exhibiting fluidity at relatively low temperatures. Furthermore, imidazolium and ammonium salt-type ILs containing cyclic oligosiloxane frameworks were prepared through a reaction similar to that of the corresponding organodialkoxysilanes. The thermal decomposition temperatures of the above ILs containing siloxane frameworks were higher than those of general ILs.

Acetylphenyl-substituted imidazolium salts: synthesis, characterization, in silico studies and inhibitory properties against some metabolic enzymes.

Herein, we present how to synthesize thirteen new 1-(4-acetylphenyl)-3-alkylimidazolium salts by reacting 4-(1-H-imidazol-1-yl)acetophenone with a variety of benzyl halides that contain either electron-donating or electron-withdrawing groups. The structures of the new imidazolium salts were conformed using different spectroscopic methods (1H NMR, 13C NMR, 19F NMR, and FTIR) and elemental analysis techniques. Furthermore, these compounds' the carbonic anhydrase (hCAs) and acetylcholinesterase (AChE) enzyme inhibition activities were investigated. They showed a highly potent inhibition effect toward AChE and hCAs with Ki values in the range of 8.30 ± 1.71 to 120.77 ± 8.61 nM for AChE, 16.97 ± 2.04 to 84.45 ± 13.78 nM for hCA I, and 14.09 ± 2.99 to 69.33 ± 17.35 nM for hCA II, respectively. Most of the synthesized imidazolium salts appeared to be more potent than the standard inhibitor of tacrine (TAC) against AChE and Acetazolamide (AZA) against CA. In the meantime, to prospect for potential synthesized imidazolium salt inhibitor(s) against AChE and hCAs, molecular docking and an ADMET-based approach were exerted.

The Influence of the Halide in the Crystal Structures of 1-(2,3,5,6-Tetrafluoro-4-pyridyl)-3-benzylimidazolium Halides.

The crystal structures of 1-(2,3,5,6-tetrafluoro-4-pyridyl)-3-benzylimidazolium chloride (1) and iodide (3) have been determined by single crystal X-ray diffraction. The crystal structure of 1 is similar to that of the bromide salt (2), possessing anion···C5F5N···C6H5 motifs, whilst that of 3 contains columns of alternating iodide anions and parallel tetrafluoropyridyl rings. All three crystal structures possess C(1)−H∙∙∙X− and C(2)−H∙∙∙X− hydrogen bonding. DFT calculations reveal that the strengths of the hydrogen bonding interactions lie in the order C(1)−H···X− > C(3)−H···X− > C(2)−H···X− for the same halide (X−) and Cl− > Br− > I− for each position. It is suggested that salt 3 adopts a different structure to salts 1 and 2 because of the larger size of iodide.

Synthesis, characterization, in vitro SAR study, and preliminary in vivo toxicity evaluation of naphthylmethyl substituted bis-imidazolium salts.

A series of novel bis-imidazolium salts was synthesized, characterized, and evaluated in vitro against a panel of non-small cell lung cancer (NSCLC) cells. Two imidazolium cores were connected with alkyl chains of varying lengths to develop a structure activity relationship (SAR). Increasing the length of the connecting alkyl chain was shown to correlate to an increase in the anti-proliferative activity. The National Cancer Institute's NCI-60 human tumor cell line screen confirmed this trend. The compound containing a decyl linker chain, 10, was chosen for further in vivo toxicity studies with C578BL/6 mice. The compound was well tolerated by the mice and all of the animals survived and gained weight over the course of the study.

Dehydroepiandrosterone derived imidazolium salts and their antimicrobial efficacy.

Hybrid molecules consisting of steroid-imidazolium salts reveal interesting biological properties, especially regarding antimicrobial activities. Novel dehydroepiandrosterone derived imidazolium salts (11 salts) with side chains of different lengths were obtained in an efficient and straightforward synthetic route. Antimicrobial properties of new salts were examined by determining their minimum inhibitory concentrations (MICs). They were studied against several strains of bacteria, including clinical isolates of MRSA, and fungi. New compounds showed high activity against Gram-positive bacteria and Candida albicans as well as good compatibility with the representatives of the host cells when applied at concentrations corresponding to MIC value. The studies indicated high antimicrobial efficacy of imidazolium salts against the above-mentioned microorganisms with low hemolytic activity at a concentration that restricts the growth of the microorganisms. The interference of salts with the immune defense system, the influence on the biological activity of monocytes/macrophages measured by their viability and metabolic activity was also studied. The new compounds have shown immunoprotective properties.

Novel 2-methylimidazolium salts: Synthesis, characterization, molecular docking, and carbonic anhydrase and acetylcholinesterase inhibitory properties.

In this work, structures of different imidazolium compounds were designed and synthesized. These compounds were synthesized from 2-methylimidazole and alkyl/aryl halides. Their structures were characterized by using 1H NMR, 13C NMR, FTIR spectroscopic techniques. All the synthesized compounds were tested for their inhibition activities on different enzymes. Inhibition experiments gave good and moderate results, proving their activities of these compounds as anticholinergics potential. These obtained novel 2-methylimidazolium salts (1a-e and 2a-e) molecules were effective inhibitors of the carbonic anhydrase I and II isozymes (hCA I and II) and acetylcholinesterase (AChE) enzymes with Ki values in the range of 26.45 ± 6.49-77.60 ± 9.53 nM for hCA I, 27.87 ± 5.00-86.61 ± 5.71 nM for hCA II, and 1.15 ± 0.19-8.89 ± 0.49 nM for AChE, respectively. AChE enzyme inhibitors are the most common drugs applied in the therapy of diseases such as senile dementia, Alzheimer's disease, ataxia, Parkinson's disease, and among others.

Synthesis, characterization, in vitro SAR and in vivo evaluation of N,N'bisnaphthylmethyl 2-alkyl substituted imidazolium salts against NSCLC.

Alkyl- and N,N'-bisnaphthyl-substituted imidazolium salts were tested in vitro for their anti-cancer activity against four non-small cell lung cancer cell lines (NCI-H460, NCI-H1975, HCC827, A549). All compounds had potent anticancer activity with 2 having IC50 values in the nanomolar range for three of the four cell lines, a 17-fold increase in activity against NCI-H1975 cells when compared to cisplatin. Compounds 1-4 also showed high anti-cancer activity against nine NSCLC cell lines in the NCI-60 human tumor cell line screen. In vitro studies performed using the Annexin V and JC-1 assays suggested that NCI-H460 cells treated with 2 undergo an apoptotic cell death pathway and that mitochondria could be the cellular target of 2 with the mechanism of action possibly related to a disruption of the mitochondrial membrane potential. The water solubilities of 1-4 was over 4.4mg/mL using 2-hydroxypropyl-ß-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration.

Synthesis, characterization, and in vitro SAR evaluation of N,N'-bis(arylmethyl)-C2-alkyl substituted imidazolium salts.

A series of C2-alkyl substituted N,N'-bis(arylmethyl)imidazolium salts were synthesized, characterized, and tested for their in vitro anti-cancer activity against multiple non-small cell lung cancer cell lines by our group and the National Cancer Institute's-60 human tumor cell line screen to establish a structure-activity relationship. Compounds are related to previously published N,N'-bis(arylmethyl)imidazolium salts but utilize the historical quinoline motif and anion effects to increase the aqueous solubility. Multiple derivatives displayed high anti-cancer activity with IC50 values in the nanomolar to low micromolar range against a panel of non-small cell lung cancer cell lines. Several of these derivatives have high aqueous solubilities with potent anti-proliferative properties and are ideal candidates for future in vivo xenograft studies and have high potential to progress into clinic use.

Biologically Active Heterocyclic Hybrids Based on Quinazolinone, Benzofuran and Imidazolium Moieties: Synthesis, Characterization, Cytotoxic and Antibacterial Evaluation.

Cytotoxic and antimicrobial agents structurally based on quinazolinone, benzofuran and imidazole pharmacophores, have been designed and synthesized. Spectral (IR, 1 H-NMR) and elemental analysis data established the structures of these novel 3-[1-(1-benzofuran-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)ethyl]-1-methyl-1H-imidazol-3-ium chloride hybrid derivatives. All the synthesized compounds were evaluated for in vitro cytotoxicity and antimicrobial activities. Cytotoxic evaluation using MTT assay revealed that compounds 12c, 12g and 12i exhibited significant cytotoxicity with IC50 values 1, 1, and 0.57 µm on this cell line, respectively. Biological activity of the synthesized compounds as antibacterial agent were also evaluated against three Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram-positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast-like fungi (Candida albicans) strains. All compounds 12a - 12i showed slightly higher activity against Gram-positive bacteria than the Gram-negative one. Among the nine new compounds screened, 3-[1-(5-bromo-1-benzofuran-2-yl)-2-(6-chloro-4-oxoquinazolin-3(4H)-yl)ethyl]-1-methyl-1H-imidazol-3-ium chloride (12e) has pronounced higher antimicrobial activity against all tested strains. These results demonstrated potential importance of molecular hybridization in the development of new lead molecules with major cytotoxicity and antimicrobial activity.

Recent Developments in the Medicinal Applications of Silver-NHC Complexes and Imidazolium Salts.

Because of their great structural diversity and multitude of chemical properties, N-heterocyclic carbenes (NHCs) have been utilized in a variety of capacities. Most recently, NHCs have been utilized as carrier molecules for many transition metals in medicinal chemistry. Specifically, Ag(I)-NHCs have been investigated as potent antibacterial agents and chemotherapeutics and have shown great efficacy in both in vitro and in vivo studies. Ag(I)-NHC compounds have been shown to be effective against a wide range of both Gram-positive and Gram-negative bacterial strains. Many compounds have also shown great efficacy as antitumor agents demonstrating comparable or better antitumor activity than standard chemotherapeutics such as cisplatin and 5-fluorouracil. While these compounds have shown great promise, clinical use has remained an unattained goal. Current research has been focused upon synthesis of novel Ag(I)-NHC compounds and further investigations of their antibacterial and antitumor activity. This review will focus on recent advances of Ag(I)-NHCs in medicinal applications.

Detection of oxidized and glycated proteins in clinical samples using mass spectrometry--a user's perspective.

BACKGROUND: Proteins in human tissues and body fluids continually undergo spontaneous oxidation and glycation reactions forming low levels of oxidation and glycation adduct residues. Proteolysis of oxidised and glycated proteins releases oxidised and glycated amino acids which, if they cannot be repaired, are excreted in urine. SCOPE OF REVIEW: In this review we give a brief background to the classification, formation and processing of oxidised and glycated proteins in the clinical setting. We then describe the application of stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC-MS/MS) for measurement of oxidative and glycation damage to proteins in clinical studies, sources of error in pre-analytic processing, corroboration with other techniques - including how this may be improved - and a systems approach to protein damage analysis for improved surety of analyte estimations. MAJOR CONCLUSIONS: Stable isotopic dilution analysis LC-MS/MS provides a robust reference method for measurement of protein oxidation and glycation adducts. Optimised pre-analytic processing of samples and LC-MS/MS analysis procedures are required to achieve this. GENERAL SIGNIFICANCE: Quantitative measurement of protein oxidation and glycation adducts provides information on level of exposure to potentially damaging protein modifications, protein inactivation in ageing and disease, metabolic control, protein turnover, renal function and other aspects of body function. Reliable and clinically assessable analysis is required for translation of measurement to clinical diagnostic use. Stable isotopic dilution analysis LC-MS/MS provides a "gold standard" approach and reference methodology to which other higher throughput methods such as immunoassay and indirect methods are preferably corroborated by researchers and those commercialising diagnostic kits and reagents. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.

Synthesis and characterization of a helicene-based imidazolium salt and its application in organic molecular electronics.

Herein we demonstrate the synthesis of a helicene-based imidazolium salt. The salt was prepared by starting from racemic 2-methyl[6]helicene, which undergoes radical bromination to yield 2-(bromomethyl)[6]helicene. Subsequent treatment with 1-butylimidazole leads to the corresponding salt 1-butyl-3-(2-methyl[6]helicenyl)-imidazolium bromide. The prepared salt was subsequently characterized by using NMR spectroscopy and X-ray analysis, various optical spectrometric techniques, and computational chemistry tools. Finally, the imidazolium salt was immobilized onto a SiO2 substrate as a crystalline or amorphous deposit. The deposited layers were used for the development of organic molecular semiconductor devices and the construction of a fully reversible humidity sensor.

1-n-Hexadecyl-3-methylimidazolium methanesulfonate and chloride salts with effective activities against Candida tropicalis biofilms.

UNLABELLED: Although the use of catheters in critically ill patients is mostly inevitable, this invasive procedure comes together with several health risks. Within this context, the contamination with Candida tropicalis is a primary concern as this highly prevalent pathogenic yeast can develop an extensive polymeric matrix that hinders the drugs' penetration and its effective treatment. This study addresses the potential for the 1-n-hexadecyl-3-methylimidazolium methanesulfonate (C16 MImMeS) and chloride (C16 MImCl) salts for eliminating the viable cells of biofilms of Candida tropicalis, compared to the performance of chlorhexidine (CHX) and fluconazole (FLZ). The minimum concentration required of C16 MImMeS, C16 MImCl, CHX and FLZ for elimination of the biofilm's viable cells (MBEC) was evaluated through microtitre plate biofilm exposure with different concentrations of these substances. These concentrations were determined at 80% of effective activity against the biofilm's viable cells by using the MTT reduction assay. C16 MImMeS and C16 MImCl were able to eliminate the viable cells at much lower concentrations (15·6 and 0·45 µg ml(-1) respectively) than CHX (1250 µg ml(-1) ) and FLZ (resistance of the viable cells). This demonstrates the high potential of these substances for nosocomial infections control. SIGNIFICANCE AND IMPACT OF THE STUDY: The 1-n-hexadecyl-3-methylimidazolium methanesulfonate (C16 MImMeS) and chloride (C16 MImCl) salts are extremely effective in eliminating the viable cells of Candida tropicalis biofilms, which allows the use of much lower concentrations than with the antimicrobial of choice (chlorhexidine) in hospital practices. These findings indicate these imidazolium salts as high-potential candidates for asepsis of medical environments and materials, including implants.

Imidazolium salts as antifungal agents: strong antibiofilm activity against multidrug-resistant Candida tropicalis isolates.

UNLABELLED: The in vitro activity of the imidazolium salt C16 MImCl against planktonic and biofilm cells of multidrug-resistant isolates of Candida tropicalis was evaluated, both in solution and applied on a commercial catheter surface. This was determined by inhibition and susceptibility assays of biofilm and planktonic cells. In both cases, C16 MImCl prevented in vitro biofilm formation of C. tropicalis strains, including multidrug-resistant ones. Outstanding performances were observed, even at extremely low concentrations. Furthermore, this is the first report of the antifungal lock property of C16 MImCl, using a tracheal catheter as the test specimen to mimic a clinical in vivo condition. As such, C16 MImCl has been identified as a promising antimicotic pharmaceutical candidate for the treatment of candidiasis infections. SIGNIFICANCE AND IMPACT OF THE STUDY: The imidazolium salt 1-n-hexadecyl-3-methylimidazolium chloride (C16 MImCl) strongly prevents, in concentrations as low as 0·028 µg ml(-1) , the biofilm formation of multidrug-resistant Candida tropicalis isolates, either in solution or applied on the surface of commercial catheters. This presents an effective antimicotic candidate and alternative for invasive clinical procedure toolset asepsis.

Anti-tumor activity of lipophilic imidazolium salts on select NSCLC cell lines.

The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-smallcell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.

Efficient synthetic protocols for the preparation of common N-heterocyclic carbene precursors.

The one-pot condensation of glyoxal, two equivalents of cyclohexylamine, and paraformaldehyde in the presence of aqueous HBF4 provided a straightforward access to 1,3-dicyclohexylimidazolium tetrafluoroborate (ICy·HBF4). 1,3-Dibenzylimidazolium tetrafluoroborate (IBn·HBF4) was obtained along the same lines. To synthesize 1,3-diarylmidazolium salts, it was necessary to isolate the intermediate N,N'-diarylethylenediimines prior to their cyclization. Although this additional step required more time and reagents, it led to a much more efficient overall process. It also proved very convenient to carry out the synthesis of imidazolinium salts in parallel to their imidazolium counterparts via the reduction of the diimines into diammonium salts. The critical assembly of the C(2) precarbenic unit was best achieved with paraformaldehyde and chlorotrimethylsilane in the case of imidazolium derivatives, whereas the use of triethyl orthoformate under microwave irradiation was most appropriate for the fast and efficient synthesis of imidazolinium salts. This strategy was applied to the synthesis of six common N-heterocyclic carbene precursors, namely, 1,3-dimesitylimidazolium chloride (IMes·HCl), 1,3-dimesitylimidazolium tetrafluoroborate (IMes·HBF4), 1,3-dimesitylimidazolinium chloride (SIMes·HCl), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IDip·HCl or IPr·HCl), 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (SIDip·HCl or SIPr·HCl), and 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazolium chloride (IDip*·HCl or IPr*·HCl).

Small cyclen-imidazolium-containing molecules and their interactions with DNA.

Three small organic molecules containing different numbers of cyclen and imidazolium units were synthesized. Their interactions with plasmid DNA and their potential for gene delivery vectors were investigated. Agarose gel retardation and ethidium bromide exclusion assays revealed that these molecules can effectively condense DNA, and compounds with higher molecular weights are needed to lower w/w ratio for full condensation. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) indicated that these compounds may form nanosized spherical particles with DNA. Furthermore, the complex formed from 10, i.e., 10/DNA, can partially release DNA from compact state at a relatively higher concentration of NaCl (200 mM). In the presence of the lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 10 could transfer plasmid DNA into BEL-7402 cells. In addition, these compounds exhibited much lower cytotoxicity than PEI 25 kDa.

Efficient synthesis of novel 1,10 phenanthroline-substituted imidazolium salts: Exploring their anticancer applications.

This study reports a new series of 1,10-phenanthroline-substituted imidazolium salts (1a-f), examining their design, synthesis, structure and anticancer activities. The structures of these salts (1a-f) were characterized using 1H, 13C NMR, elemental analysis, mass spectrometry and Fourier transform infrared (FT-IR) spectroscopies. The salts' cytotoxic activities were tested against cancer cell lines, specifically MCF-7, MDA-MB-231 and non-tumorigenic MCF-10A mammary cells. The study compared the impact of aliphatic and benzylic groups in the salts' structure on their anticancer activity. Screening results revealed that compound 1c, in particular, showed promising inhibitory activity against the growth of MDA-MB-231 breast cancer cells, with an IC50 value of 12.8 ± 1.2 µM, indicating its potential as a chemotherapeutic agent. Cell apoptosis analysis demonstrated a tendency for compound 1c to induce early apoptosis in breast cancer cells. The stability/aquation of compound 1c was investigated using 1H NMR spectroscopy and its binding modes with DNA were explored via UV-Vis spectroscopy. Additionally, the study investigated the interaction residues and docking scores of compound 1c and the reference drug doxorubicin against Bax and Bcl-2 proteins using molecular docking.

Bis[1,3-bis-(2,4,6-tri-methyl-phen-yl)imidazolium] bis(µ-cis-1,2-di-phenyl-ethene-1,2-di-thiol-ato-κ2S,S':κS)bis-[(cis-1,2-di-phenyl-ethene-1,2-di-thiol-ato-κ2S,S')iron(III)] di-methyl-formamide disolvate.

The mol-ecular structure of the solvated title salt, (C21H25N2)2[Fe2(C14H10S2)4]·2C3H7NO reveals that the anion is situated on a crystallographic inversion center in the triclinic space group P . The title compound crystallizes utilizing a network of weak π-stacking inter-actions of phenyl rings pertaining to the di-thiol-ene unit. Moreover, the acidic imidazolium H atoms [N-C(H)-N] display non-classical hydrogen-bonding inter-actions of the C-H⋯O type to the oxygen atoms of the N,N-dimethyl formamide solvent, and hydrogen atoms on the backbone of imidazolium rings display weak C-H⋯S inter-actions with the di-thiol-ene sulfur atoms.

Synthesis and evaluation of water-soluble imidazolium salt chitin with broad-spectrum antimicrobial activity and excellent biocompatibility for infected wound healing.

Infections caused by bacteria have long constituted a major threat to human health and the economy. Therefore, there is an urgent need to design broad-spectrum antibacterial materials possessing good biocompatibility to treat such infections. Herein, inspired by the good biocompatibility of chitin and antibacterial properties of imidazolium salts, a polysaccharide-based material, imidazolium salt chitin (IMSC), was homogeneously prepared using a facile method with epichlorohydrin as a chemical crosslinker to combine chitin with imidazole to enhance Staphylococcus aureus (S. aureus)-infected wound healing. The characteristics, antimicrobial properties, and biosafety of IMSC were evaluated. The results demonstrated successful grafting of imidazole onto chitin. Furthermore, IMSC exhibited good water solubility, broad-spectrum antimicrobial activity, hemocompatibility, and biocompatibility. Moreover, IMSC enabled complete healing of S. aureus-infected wound in Sprague-Dawley rats within 15 days of application, thus demonstrating that IMSC could reduce wound inflammation and remarkably accelerate wound healing owing to its efficient antibacterial activity and ability to promote collagen deposition in and around the wound area. Therefore, this study provides a promising and potential therapeutic strategy for infected wound healing by synthesizing a water-soluble and broad-spectrum antimicrobial material exhibiting good biocompatibility.