Use of ionic liquids in amidation reactions for proteolysis targeting chimera synthesis.

Selective degradation of disease-causing proteins using proteolysis targeting chimeras (PROTACs) has gained great attention, thanks to its several advantages over traditional therapeutic modalities. Despite the advances made so far, the structural chemical complexity of PROTACs poses challenges in their synthetic approaches. PROTACs are typically prepared through a convergent approach, first synthesizing two fragments separately (target protein and E3 ligase ligands) and then coupling them to produce a fully assembled PROTAC. The amidation reaction represents the most common coupling exploited in PROTACs synthesis. Unfortunately, the overall isolated yields of such synthetic procedures are usually low due to one or more purification steps to obtain the final PROTAC with acceptable purity. In this work, we focused our attention on the optimization of the final amidation step for the synthesis of an anti-SARS-CoV-2 PROTAC by investigating different amidation coupling reagents and a range of alternative solvents, including ionic liquids (ILs). Among the ILs screened, [OMIM][ClO4] emerged as a successful replacement for the commonly used DMF within the HATU-mediated amidation reaction, thus allowing the synthesis of the target PROTAC under mild and sustainable conditions in very high isolated yields. With the optimised conditions in hand, we explored the scalability of the synthetic approach and the substrate scope of the reaction by employing different E3 ligase ligand (VHL and CRBN)-based intermediates containing linkers of different lengths and compositions or by using different target protein ligands. Interestingly, in all cases, we obtained high isolated yields and complete conversion in short reaction times.

Anti-proliferative, Morphological and Molecular Docking Studies of New Thiophene Derivatives and their Strategy in Ionic Liquids Immobilized Reactions.

BACKGROUND: A number of research were conducted on the pyran and thiophene derivatives, which were attributed to have a wide range of biological activities, including anti-plasmodial, as well as acting as caspase, hepatitis C and cancer inhibitors. OBJECTIVE: The multicomponent reactions of the 5-acetyl-2-amino-4-(phenylamino)-thiophene-3-carbonitrile produced biologically active target molecules like pyran and their fused derivatives. Comparison between regular catalytic multi-component reactions and solvent-free ionic liquids immobilized multicomponent was studied. METHODS: The multicomponent reactions in this work were carried out not only under the reflux conditions using triethylamine as a catalyst but also in solvent-free ionic liquids immobilized magnetic nanoparticles (MNPs) catalysts. RESULTS: Through this work, thirty-one new compounds were synthesized and characterized and were evaluated toward the six cancer cell lines, namely A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460. The most active compounds were further screened toward seventeen cancer cell lines classified according to the disease. In addition, the effect of compound 11e on the A549 cell line was selected to make further morphological changes in the cell line. The Molecular docking studies of 11e and 11f were carried and promising results were obtained. CONCLUSION: The synthesis of heterocyclic compounds derived from thiophene derivatives has been receiving significant attention. After a detailed optimizing study, it has been found that the solvent-free ionic liquids immobilized multi-component syntheses afforded a high yield of compounds, opening a greener procedure for this synthetically relevant transformation. Many of the synthesized compounds can be considered anticancer agents, enhancing further studies.

Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies.

Thyroid diseases affect a considerable portion of the population, with hypothyroidism being one of the most commonly reported thyroid diseases. Levothyroxine (T4) is clinically used to treat hypothyroidism and suppress thyroid stimulating hormone secretion in other thyroid diseases. In this work, an attempt to improve T4 solubility is made through the synthesis of ionic liquids (ILs) based on this drug. In this context, [Na][T4] was combined with choline [Ch]+ and 1-(2-hydroxyethyl)-3-methylimidazolium [C2OHMiM] + cations in order to prepare the desired T4-ILs. All compounds were characterized by NMR, ATR-FTIR, elemental analysis, and DSC, aiming to check their chemical structure, purities, and thermal properties. The serum, water, and PBS solubilities of the T4-ILs were compared to [Na][T4], as well as the permeability assays. It is important to note an improved adsorption capacity, in which no significant cytotoxicity was observed against L929 cells. [C2OHMiM][T4] seems to be a good alternative to the commercial levothyroxine sodium salt with promising bioavailability.

Synthesis of Purine-Based Ionic Liquids and Their Applications.

Bio-based ionic liquids (ILs) are being increasingly sought after, as they are more sustainable and eco-friendly. Purines are the most widely distributed, naturally occurring N-heterocycles, but their low water-solubility limits their application. In this work, four purines (theobromine, theophylline, xanthine, and uric acid) were combined with the cation tetrabutylammonium to synthesize bio-based ILs. The physico-chemical properties of the purine-based ILs were characterized, including their melting and decomposition temperatures and water-solubility. The ecotoxicity against the microalgae Raphidocelis subcapitata was also determined. The ILs show good thermal stability (>457 K) and an aqueous solubility enhancement ranging from 53- to 870-fold, in comparison to their respective purine percursors, unlocking new prospects for their application where aqueous solutions are demanded. The ecotoxicity of these ILs seems to be dominated by the cation, and it is similar to chloride-based IL, emphasizing that the use of natural anions does not necessarily translate to more benign ILs. The application of the novel ILs in the formation of aqueous biphasic systems (ABS), and as solubility enhancers, was also evaluated. The ILs were able to form ABS with sodium sulfate and tripotassium citrate salts. The development of thermoresponsive ABS, using sodium sulfate as a salting-out agent, was accomplished, with the ILs having different thermosensitivities. In addition, the purine-based ILs acted as solubility enhancers of ferulic acid in aqueous solution.

Lubrication by Adsorption Films of Hydrophilic Amine-based Protic Ionic Liquids: Effect of Anion Species.

In this study, we synthesize hydrophilic amine-based protic ionic liquids (PILs) with hydroxy groups in a cation and different anions. Subsequently, we evaluate the kinetic friction coefficients of iron oxide in aqueous solutions of the PILs under different sliding conditions. Ditriethanolamine malate, triethanolamine lactate, triethanolamine methoxyacetate, and triethanolamine acetate are used as PIL samples in this study. Among them, ditriethanolamine malate exhibits the lowest kinetic friction coefficient. As the number of sliding cycles increases, the excellent lubrication capability remains. Subsequently, we characterize the adsorption of the PILs on an iron oxide surface to investigate the lubrication behavior on the basis of quartz crystal microbalance with dissipation monitoring and force curve data. We expect hydrophilic PILs to be excellent water-soluble lubricants and additives for use in metal surface treatments.

Poly(ionic liquid)-Based Efficient and Robust Antiseptic Spray.

Exploring efficient and robust antibacterial materials is crucially important for human health and ecological security. Compared with intrinsically antibacterial materials, materials modified with antibacterial agents either by chemical or physical modification can simultaneously maintain basic functions and antibacterial properties. In particular, physical modification with antiseptic sprays is quite suitable for large-size objects in our daily life but restricted by high volatility of the antibacterial agents or poor adhesion strength between the antibacterial agents and the targeted objects. In this paper, we report a poly(ionic liquid) (PIL-Cn)-based efficient and robust antiseptic spray that exhibits long-term antibacterial properties against both Gram-positive and Gram-negative bacteria on diverse substrates, including glass, PE, and cotton. It is believed that this work will provide an alternative for current antiseptic sprays for usage in our daily life and hospitals.

Synthesis of Ammonium-Based Ionic Liquids for the Extraction Process of a Natural Pigment (Betanin).

The use of new synthesized ammonium-based ionic liquids was explored as an alternative to the current process implemented in the betanin extraction from red beet juice, resulting in high yields: 70% and 82%. Betanin is a vegetal pigment that has been applied to a large variety of products in the food industry, which is important, for it can work as a substitute for the red synthetic dyes used nowadays. Additionally, the use of the kosmotropic salt sodium acetate was explored in order to separate the complex formed by the ionic liquid and pigment of interest in a process that combined two techniques: ATPS (aqueous two-phase system) and SOES (salting-out extraction system). The results reveal that the studied techniques could work as a novel process for the extraction of betanin from red beet juice employing ionic liquids, which have not been tested for this purpose in other research.

The room-temperature, ambient-pressure conversion of CO2 into value-added pharmaceutical products quinazoline-2,4(1H,3H)-diones.

As global warming due to CO2 emissions has become a widely recognized concern, CO2 capture, sequestration, neutralization, and conversion have become possible solutions to address this concern. Among these approaches, the conversion of CO2 into fuels or value-added products has attracted considerable attention. In this work, we report the high-efficiency conversion of CO2 to important industrial raw materials for pharmaceutical compounds, quinazoline-2,4(1H,3H)-diones, via reactions with 2-aminobenzonitriles at room temperature and under ambient pressure, with high conversion yields (91.5-99.3%). 1,8-Diazabicyclo-[5.4.0]-undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), and cholinium (Ch) ammonium-based ionic liquids (ILs) are employed as catalysts during the process. Cations with a pKa value near 11.9 and anions with a pKa value range of 10 to 15 are necessary for the reaction. The experimental results indicate that the ionic liquid pair [HDBU+][3-Cl-PhO-] has high efficiency under very mild conditions, obtaining high product yields of 91.5% at 25 °C and 1 atm and 99.3% at 30 °C and 1 atm. More importantly, the catalysts retain high efficiency and activity after 5 consecutive cycles. To gain insightful understanding of the reaction, density functional theory (DFT) calculations were conducted to study the reaction mechanism. The computational results indicate that the catalytic process contains three stages: cyano activation, intramolecular rearrangement, and intramolecular cyclization. Of these, the rate-determining step is cyano activation, which shows an energy barrier of 24.5 kcal mol-1. Tuning the types of ions in ILs can effectively reduce this energy barrier and allow high efficiencies.

Antimicrobial properties of novel ionic liquids derived from imidazolium cation with phenolic functional groups.

Bacterial infections are nowadays among the major threats to public health worldwide. Thus, there is an urgent and increased need for new antimicrobial agents. As a result, the exploration of the antimicrobial properties of different substances including ionic liquids (ILs) has recently attracted great attention. The present work is aimed at evaluating how the addition of halogens and hydrophobic substituents on alkylimidazolium units of ILs as well as the increase in their chain lengths affects the antimicrobial properties of such ILs. After their synthesis, the antibacterial activities of these compounds against Pseudomona aeruginosa, Escherichia coli, and Staphylococcus aureus are determined by measuring their minimal inhibitory concentrations (MICs). Key features in ILs-membrane interactions are also studied using long-term all-atom molecular dynamics simulations (MDs). The results show that these ILs have good antibacterial activity against S. aureus, E. coli, and P. aeruginosa, with MIC values range from <7.81 to 62.50 µM. The antimicrobial property of tert-butyl N-methylphenolimidazolium salts (denoted as 8b and 8c) is particularly better with MIC values of < 7.81 µM. The antibacterial efficacy is also found to depend on the alkyl chain length and substituents on the phenolic ring. Finally, MDs done for ILs in a phosphatidylcholine (POPC) bilayer show key features in the mechanism of IL-induced membrane disruption, where the ILs are inserted as clusters into one side of the bilayer until saturation is reached. This insertion increases "leaflet strain" up to critical threshold, likely triggering the morphological disruption of the membranes in the microbes.

Ionic Network Based on Dynamic Ionic Liquids for Electronic Tattoo Application.

Electronic tattoos as an emerging epidermal electronic are alluring in the field of wearable electronics for their lightweight and noninvasive properties. However, the combination of flexibility, skin biocompatibility, adhesion, repairability, and erasability remains a challenge for fabricating electronic tattoos. Hence, a dynamic ionic liquid is prepared which is ideally suited for making an electronic tattoo with these challenging features at the same time. Such an intrinsically flexible electronic tattoo can be firmly attached to human skin with negligible irritation. More importantly, the existence of dynamic covalent chemistry provides the electronic tattoo with healing and erasable abilities under mild redox conditions. Owing to the high ionic conductivity of ionic liquids, the electronic tattoo exhibits excellent sensing performance in response to the temperature variation and tensile strain, which can intelligently monitor body temperature, pulse, and movement. As an extension of the application, a specially designed quadrilateral electronic tattoo can sense and distinguish multiple signals simultaneously. This concept of electronic tattoo based on the dynamic ionic liquid shows great potentials in the applications of intelligent wearable electronics.

Synthesis of Recyclable Magnetic Cellulose Nanofibers from Ionic Liquids for Practical Applications in Separation Science.

The present study focused on coupling cellulose nanofibers (alternative materials for plastics and metals) with a magnetic ionic liquid (synthesized by a microwave-assisted method) through mixing to yield magnetic cellulose nanofibers (MCNFs) that can be recycled by attracting them to a magnet. Accordingly, two types of ionic liquids were synthesized: (a) 1-butyl-3-methylimidazolium tetrachloroferrate(III) {[bmim] FeCl4} and (b) 1-glycidyl-3-methylimidazolium tetrachloroferrate {[glmi]FeCl4}, which were characterized by the fast atom bombardment mass spectrometry (FAB-MS) technique. Impregnation of the cellulose nanofibers with the {[bmim]FeCl4} ionic liquid caused the latter to be physically adsorbed onto the nanofibers to produce {MCNF@{[bmim]FeCl4}, whereas the corresponding {[glmi]FeCl4} ionic liquid was chemically bonded to the cellulose nanofibers to yield magnetic {MCNF@[glmi]FeCl4} nanofibers. Under the experimental conditions used, the corresponding magnetic moments were 0.222 A m2 kg-1 for {MCNF@ {[bmim]FeCl4} and 0.095 A m2 kg-1 for {MCNF@[glmi]FeCl4}.

Use of Silicone Membrane Permeation to Assess Thermodynamic Activities of Ionic Liquids and Their Component Cation and Anion.

Ionic liquid (IL) was prepared by mixing lidocaine and ibuprofen as a cation and anion, respectively, at various ratios. We determined the permeation of both compounds from the IL through a silicone membrane selected as a model biological membrane, and mathematically analyzed the permeation data from the viewpoint of the thermodynamic activities of lidocaine, ibuprofen, and the IL. As a result, IL and ibuprofen diffusely permeated through the membrane in the case of applying IL preparations with a molar fraction of ibuprofen of 0.5 or higher. The IL was thought to separate into lidocaine and ibuprofen in the receiver. On the other hand, when applying IL preparations with a molar fraction of lidocaine of 0.5 or higher, IL and lidocaine permeated. The permeation rate of IL itself was maximized when the applied IL was prepared using equimolar amounts of lidocaine and ibuprofen, and it decreased when the fraction of lidocaine or ibuprofen increased by more than 0.5. Their membrane permeation rates increased with an increase in their activity, and no more increase was found when the drugs were saturated in the IL. These membrane permeation profiles reflected well the mathematically calculated ones according to the concept of activity.

Unique and generic structural features of cholinium amino acid-based biocompatible ionic liquids.

Cholinium amino acid-based (Ch-AA) biocompatible ionic liquids (bio-ILs) are synthesized from renewable components and are efficiently used for biomass processing. However, their microscopic structural features that lead to their application as biomass solvents remain undetermined. Herein, we use atomistic simulations to investigate the structures of six different Ch-AA bio-ILs up to the nanometer length scale and demonstrate that, depending on the anion side chain structure, the respective IL exhibits structural ordering at different length scales. All the six Ch-AA bio-ILs investigated here show a generic feature of having a strong hydrogen bonding network between the hydroxyl group of the cholinium cation and the carboxyl group of the amino acid anions. We illustrate that each of these bio-ILs also displays a unique feature. Distinctive intermediate range structural ordering leads to heterogeneity in methioninate- and phenylalaninate-based ILs caused by the anion side chain segregation. Intermediate range ordering is not observed in glutaminate- and glutamate-based ILs because significant anion side chain and backbone interactions hinder the formation of side chain clusters. Interestingly, for the cysteinate-based IL, the side chains do not interact with the backbones and the intermediate range ordering is not observed because of a shorter anionic side chain.

Helicity: A Non-Conventional Stereogenic Element for Designing Inherently Chiral Ionic Liquids for Electrochemical Enantiodifferentiation.

Configurationally stable 5-aza[6]helicene (1) was envisaged as a promising scaffold for non-conventional ionic liquids (IL)s. It was prepared, purified, and separated into enantiomers by preparative HPLC on a chiral stationary phase. Enantiomerically pure quaternary salts of 1 with appropriate counterions were prepared and fully characterized. N-octyl-5-aza[6]helicenium bis triflimidate (2) was tested in very small quantities as a selector in achiral IL media to perform preliminary electrochemical enantiodifferentiation experiments on the antipodes of two different chiral probes. The new organic salt exhibited outstanding enantioselection performance with respect to these probes, thus opening the way to applications in the enantioselective electroanalysis of relevant bioactive molecules.

Structure-Activity Relationship Modeling and Experimental Validation of the Imidazolium and Pyridinium Based Ionic Liquids as Potential Antibacterials of MDR Acinetobacter Baumannii and Staphylococcus Aureus.

Online Chemical Modeling Environment (OCHEM) was used for QSAR analysis of a set of ionic liquids (ILs) tested against multi-drug resistant (MDR) clinical isolate Acinetobacter baumannii and Staphylococcus aureus strains. The predictive accuracy of regression models has coefficient of determination q2 = 0.66 - 0.79 with cross-validation and independent test sets. The models were used to screen a virtual chemical library of ILs, which was designed with targeted activity against MDR Acinetobacter baumannii and Staphylococcus aureus strains. Seven most promising ILs were selected, synthesized, and tested. Three ILs showed high activity against both these MDR clinical isolates.

Green Solvents Combined with Bioactive Compounds as Delivery Systems: Present Status and Future Trends.

Green solvents such as ionic liquids (ILs) unlock possibilities for developing innovative biomedical and pharmaceutical solutions. ILs are the most investigated solvents for compound extractions, as reaction media and/or catalysts, and a desired eco-friendly solvent to process biomacromolecules for biomaterial production. Investigations demonstrate that the tunable nature and physicochemical features of ILs are also beneficial for building up delivery systems through their combination with bioactive compounds. Bioactive compounds from synthetic origins, like ibuprofen, ketoprofen, and natural sources such as curcumin, flavonoids, and polyphenols are essential starting points as preventive and therapeutic agents for treating diseases. Therefore, the association of those compounds with ILs opens up windows of opportunities in this research field. This Review assesses some of the main and important recent information and the current challenges concerning delivery platforms based on ILs combined with bioactive compounds of both natural and synthetic origins. Moreover, the chemistry, bioavailability, and biological functions of the main bioactive compounds used in the ILs-based delivery platforms are described. These data are presented and are discussed, together with the main delivery routes of the systems.

Antibacterial, Antifungal and Ecotoxic Effects of Ammonium and Imidazolium Ionic Liquids Synthesized in Microwaves.

Ionic liquids are increasingly used for their superior properties. Four water-immiscible ionic liquids (butyltriethylammonium bis(trifluoromethylsulfonyl)imide, octyltriethylammonium bis(trifluoromethylsulfonyl)imide, dodecyltriethylammonium bis(trifluoromethylsulfonyl)imide, butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) and their water miscible precursors (bromides) were synthesized in a microwave reactor and by conventional heating. The best conditions for microwave-assisted synthesis concerning the yield and the purity of the product are proposed. The heating in the microwave reactor significantly shortened the reaction time. Biocide and ecotoxic effects of synthesized ionic liquids and their precursors were investigated. All tested compounds had at least a little effect on the growth or living of microorganisms (bacteria or mold). The precursor dodecyltriethylammonium bromide was found to be the strongest biocide, but posed a risk to the aquatic environment due to its relatively high EC50 value in the test with Vibrio fischeri. We assumed that apart from the alkyl chain length, the solubility in water, duration of action, or type of anion can influence the final biocide and ecotoxic effect.

Combinatorial discovery of thermoresponsive cycloammonium ionic liquids.

This work demonstrated, for the first time, the combinatorial discovery and rational identification of small-molecule cycloammonium-based thermoresponsive ionic liquids that exhibit LCST phase transition and carry attractive Tc values in water.

Lipid based biocompatible ionic liquids: synthesis, characterization and biocompatibility evaluation.

We report a new series of lipid-based biocompatible ionic liquids (LBILs) consisting of the long-chain phosphonium compound 1,2-dimyristoyl-sn-glycero-3-ethyl-phosphatidylcholine as the cation and the long-chain fatty acids stearic acid, oleic acid, or linoleic acid as anions. These materials were found to be completely miscible with many polar and nonpolar organic solvents as well as dispersible in water. These LBILs also exhibited excellent biocompatibility with an artificial three-dimensional human epidermis model.

Delivery of ionizable hydrophilic drugs based on pharmaceutical formulation of ion pairs and ionic liquids.

New therapeutics such as antisense oligonucleotides, small interfering RNA and peptide-drug conjugates are taking great relevance in the pharmaceutical industry due to their specificity of action and their improved safety profile. However, they could present bioavailability issues due to their hydrophilic nature, such as BCS class III drugs. Therefore, the formation of ion pairs of these type of molecules allows modifying their physicochemical characteristics such as polarity and lipophilicity leading to improved permeability. By carrying out a tailored synthesis, it is possible to obtain complexes with greater stability and better performance in vitro and in vivo, where their correlation with physicochemical properties continues to be a growing field of research. Moreover, ionic liquids (IL), which are substances that melt below 100 °C, have enabled modifying various drug properties, showing promising results in vitro-in vivo, especially when they are included in suitable drug delivery systems, such as nanoparticles, microparticles, self-emulsifying drug delivery systems, and transdermal patches, among others. The drug-IL is formed from the therapeutic agent and a counterion, mainly by ionic interactions, and resulting in a wide variety of derivatives with different properties. However, the pharmaceutical field is limited to the use of some excipients or GRAS (generally recognized as safe) substances, so the search for new counterions is of great interest. In this article, we have compiled key indexes that can be obtained from databases to guide the search for suitable counterions, together with different drug delivery system strategies to choose the most appropriate formulation according to the non-parenteral route of administration selected. Intellectual property advancements in the field are also presented and analyzed.