A Combined Experimental/Computational Study of Dicationic Ionic Liquids with Bromide and Tungstate Anions.

A panel of dicationic ionic liquids (DILs) with different rigid xylyl (ortho, meta, para) spacers and different anions (bromide and tungstate) has been synthetised and characterised through different experimental and computational techniques. Differences and analogies between the systems are analysed using information derived from their DFT structures, semiempirical dynamics, thermal behaviour, and catalytic properties versus the well-known reaction of CO2 added to epichlorohydrin. A comparison between the proposed systems and some analogues that present non-rigid spacers shows the key effect displayed by structure rigidity on their characteristics. The results show an interesting correlation between structure, flexibility, properties, and catalytic activity.

A Specific Interaction between Ionic Liquids' Cations and Reichardt's Dye.

Solvatochromic probes are often used to understand solvation environments at the molecular scale. In the case of ionic liquids constituted by an anion and a cation, which are designed and paired in order to obtain a low melting point and other desirable physicochemical properties, these two indivisible components can interact in a very different way with the probe. This is the case with one of the most common probes: Reichardt's Dye. In the cases where the positive charge of the cation is delocalized on an aromatic ring such as imidazolium, the antibonding orbitals of the positively charged aromatic system are very similar in nature and energy to the LUMO of Reichardt's Dye. This leads to an interesting, specific cation-probe interaction that can be used to elucidate the nature of the ionic liquids' cations. Parallel computational and experimental investigations have been conducted to elucidate the nature of this interaction with respect to the molecular structure of the cation.

Expanding the Chemical Space of Benzimidazole Dicationic Ionic Liquids.

Benzimidazole dicationic ionic liquids (BDILs) have not yet been widely explored in spite of their potential. Therefore, two structurally related families of BDILs, paired with either bromide or bistriflimide anions and bearing alkyl spacers ranging from C3 to C6, have been prepared. Their thermal properties have been studied by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), while their electrical properties have been assessed by cyclic voltammetry (CV). TG analysis confirmed the higher stability of the bistriflimide BDILs over the bromide BDILs, with minor variation within the two families. Conversely, DSC and CV allowed for ascertaining the role played by the spacer length. In particular, the thermal behavior changed dramatically among the members of the bistriflimide family, and all three possible thermal behavior types of ILs were observed. Furthermore, cyclic voltammetry showed different electrochemical window (C3(C1BenzIm)2/2Tf2N < C4(C1BenzIm)2/2Tf2N, C5(C1BenzIm)2/2Tf2N < C6(C1BenzIm)2/2Tf2N) as well as a reduction peak potential, shape, and intensity as a function of the spacer length. The results obtained highlight the benefit of accessing a more structurally diverse pool of compounds offered by dicationic ILs when compared to the parent monocationic ILs. In particular, gains are to be found in the ease of fine-tuning their properties, which translates in facilitating further investigations toward BDILs as designer solvents and catalysts.

Oxy-imino saccharidic derivatives as a new structural class of aldose reductase inhibitors endowed with anti-oxidant activity.

Aldose reductase is a key enzyme in the development of long term diabetic complications and its inhibition represents a viable therapeutic solution for people affected by these pathologies. Therefore, the search for effective aldose reductase inhibitors is a timely and pressing challenge. Herein we describe the access to a novel class of oxyimino derivatives, obtained by reaction of a 1,5-dicarbonyl substrate with O-(arylmethyl)hydroxylamines. The synthesised compounds proved to be active against the target enzyme. The best performing inhibitor, compound (Z)-8, proved also to reduce both cell death and the apoptotic process when tested in an in vitro model of diabetic retinopathy made of photoreceptor-like 661w cell line exposed to high-glucose medium, counteracting oxidative stress triggered by hyperglycaemic conditions.

Antiangiogenic Activity of Compounds Isolated from Anarrhinum pedatum.

Ten new iridoid glycosides (1-10) and two new monoterpenoids (11 and 12), together with nine known compounds (13-21), were isolated from the n-butanol extract of the aerial parts of Anarrhinum pedatum. The structural characterization of all compounds was performed by spectroscopic analysis, including 1D and 2D NMR and HRESIMS experiments. The isolates were assayed for their antiangiogenic activity by two in vivo models, using zebrafish embryos and chicken chorioallantoic membranes (CAMs). The results showed that among the new compounds 6'- O-menthiafoloylmussaenosidic acid-11-(5- O-ß-d-fructopyranosyl) ester (9) exhibited the most potent antiangiogenic activity in both the zebrafish embryos and CAM assays, reducing the growth of blood vessels. Antiangiogenic effects were also observed for the known compounds 6- O-nerol-8-oyl-antirrinoside (13), antirrinoside (14), 6- O- trans- and cis- p-coumaroyl antirrinoside (15), and (6 S)-2 E-2,6-dimethyl-6-hydroxyocta-2,7-dienoic acid ß-glucopyranosyl ester (18).

Synthesis and investigation of polyhydroxylated pyrrolidine derivatives as novel chemotypes showing dual activity as glucosidase and aldose reductase inhibitors.

Diabetes is a multi-factorial disorder that should be treated with multi-effective compounds. Here we describe the access to polyhydroxylated pyrrolidines, belonging to the d-gluco and d-galacto series, through aminocyclization reactions of two differentially protected d-xylo-hexos-4-ulose derivatives. The prepared compounds proved to inhibit both alpha-glucosidase, responsible for the emergence of hyperglycemic spikes, and aldose reductase, accountable for the development of abnormalities in diabetic tissues. Accordingly, they show the dual inhibitory profile deemed as ideal for diabetes treatment. Significantly, compound 17b reduced the process of cell death and restored the physiological levels of oxidative stress when tested in the photoreceptor-like 661w cell line, thus proving to be effective in an in vitro model of diabetic retinopathy.

Unexpected Intrinsic Lability of Thiol-Functionalized Carboxylate Imidazolium Ionic Liquids.

New thiol-functionalized carboxylate ionic liquids (ILs), varying both for the cation and for the anion structures, have been prepared as new potential redox switching systems by reacting either 3-mercapto propionic acid (3-MPA) or N-acetyl-cysteine (NAC) with commercially available methyl carbonate ILs. Different ratios of thiol/disulfide ILs were obtained depending both on the acid employed in the neutralization reaction and on the reaction conditions used. Surprisingly, the imidazolium ILs displayed limited thermal stability which resulted in the formation of an imidazole 2-thione and a new sulfide ionic liquid. Conversely, the formation of the imidazole 2-thione was not observed when phosphonium disulfide ILs were heated, thus confirming the involvement of the imidazolium ring in an unexpected side reaction. An insight into the mechanism of the decomposition has been provided by means of DFT calculations.

Selectively Charged and Zwitterionic Analogues of the Smallest Immunogenic Structure of Streptococcus Pneumoniae Type 14.

Zwitterionic polysaccharides (ZPs) have been shown in recent years to display peculiar immunological properties, thus attracting the interest of the carbohydrate research community. To fully elucidate the mechanisms underlying these properties and exploit the potential of this kind of structures, in depth studies are still required. In this context, the preparation of two cationic, an anionic, as well as two zwitterionic tetrasaccharide analogues of the smallest immunogenic structure of Streptococcus pneumoniae type 14 (SP14) capsular polysaccharide are presented. By exploiting a block strategy, the negative charge has been installed on the non-reducing end of the lactose unit of the tetrasaccharide and the positive charge either on the non-reducing end of the lactosamine moiety or on an external linker. These structures have then been tested by competitive ELISA, showing that the structural variations we made do not modify the affinity of the neutral compound to binding to a specific antibody. However, lower efficacies than the natural SP14 compound were observed. The results obtained, although promising, point to the need to further elongate the polysaccharide structure, which is likely too short to cover the entire epitopes.

Synthesis and Biological Evaluation of New Glycoconjugated LDH Inhibitors as Anticancer Agents.

Conjugation of known biologically active molecules to carbohydrate frameworks represents a valuable option for the preparation of hybrid, structurally-related families of compounds with the aim of modulating their biological response. Therefore, we present here a study on the preparation of d-galacto, d-manno, d-gluco, and d-lactose glycoconjugates of an established N-hydroxyindole-based (NHI) inhibitor of lactated dehydrogenase (LDH). Structural variations involved the sugar stereochemistry and size as well as the anchoring point of the NHI on the carbohydrate frame (either C-1 or C-6). In the case of the galactose anomeric glycoconjugate (C-1), intriguing solvent-dependent effects were observed in the glycosylation stereochemical outcome. The biological activity of the deprotected glycoconjugates in contrasting lactate formation and cancer cell proliferation are described.

Matrix metalloproteinase-12 inhibitors: synthesis, structure-activity relationships and intestinal absorption of novel sugar-based biphenylsulfonamide carboxylates.

MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar-based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives to characterize the structure-activity relationship (SAR) within this class of glycoconjugate inhibitors. All the new derivatives were tested on human recombinant MMP-12 and MMP-9 in order to evaluate their affinity and the selectivity for the target enzyme. Among them, the four most promising compounds were selected to assess their intestinal permeability using an ex vivo everted gut sac model. Given the high polarity and structural similarity to glucose, compound 3 was demonstrated to cross the intestinal membrane by using the facilitative GLUT2 transport.

Useful access to enantiomerically pure protected inositols from carbohydrates: the aldohexos-5-uloses route.

The intramolecular aldol condensation of aldohexos-5-ulose derivatives of the D-xylo and L-ribo stereoseries has been studied. Only one of the four possible inososes was isolated from both stereoseries in reasonable yields (30-38%). The results obtained, together with the previous findings for the L-arabino and L-lyxo stereoseries, allowed for the rationalisation of a mechanism of the reaction based on open-transition-state models and electron-withdrawing inductive effects. Complementary reductions of the intermediate inososes were possible by changing the reaction conditions, and two isomeric inositol derivatives were obtained with complete stereoselection from each inosose. The presented approach permits us to control the configuration of three out of the six stereocentres of the inositol frame and gives access to seven of the nine inositols. Noteworthy, for the D-xylo derivative, the two-step sequence (condensation followed by reduction with NaBH(OAc)3) represents the biomimetic synthesis of myo-inositol. Furthermore, the sugar-based pathway leads directly to enantiomerically pure selectively protected inositols and does not require any desymmetrisation procedure which is needed when myo-inositol and other achiral precursors are employed as starting materials. As an example of application of the method, the indirect selective protection of secondary inositols' hydroxy functions, by placing specific protecting groups on the aldohexos-5-ulose precursor has been presented.

Prevalence of oxetanose forms in the tautomeric equilibrium of ß-hydroxy-1,5-dicarbonyl monosaccharides.

The synthesis of 4-deoxy- and 4-deoxy-4-C-methylhexos-5-uloses, starting from 4-deoxyhex-4-enopyranosides, and a nuclear magnetic resonance (NMR) study of their isomeric composition are reported. The NMR spectra show that the two δ-dicarbonyl sugars exist as two anomeric α- and ß-oxetanosyl forms, derived from the hemiacetalization of the C-3 hydroxyl group with the aldehydic carbon. The observed tautomeric equilibria have been rationalized with computational calculations. Interestingly, this is the first time that dicarbonyl derivatives are mostly present in their oxetanose forms, offering a new entry into this very interesting type of scaffold.

Betaine mediated enhancement of thermal stability and acidity tolerance of vanadium(V) solutions.

A panel of novel vanadium(IV)-betaine complexes has been synthesized according to new and efficient methodologies and characterized through both spectroscopic techniques and thermal analyses. Vanadium(IV)-betaine solutions have been electrochemically oxidized and the effect of betaine ligands on the thermal and pH stability of vanadium(V) solutions has been evaluated under different temperature and acidity conditions. The obtained results displayed a remarkable effect for both of the examined parameters, achieving the preparation of aqueous vanadium(V) solutions displaying long term stability at more than 55 °C under mild acidic conditions. The species formed in the betaine rich vanadium(V) solutions have been sprectroscopically identified in relationship with the acidity of the solution, and the obtained results were confirmed through computational techniques. Vanadium-betaine based solutions have been finally tested in a lab-scale redox flow battery setup, providing preliminary insight into the possible use of this type of electrolyte in VRFBs.

Challenging DESs and ILs in the valorization of food waste: a case study.

In this study, the efficacy of two of the best performing green solvents for the fractionation of lignocellulosic biomass, cholinium arginate (ChArg) as biobased ionic liquid (Bio-IL) and ChCl:lactic acid (ChCl:LA, 1:10) as natural deep eutectic solvent (NADES), was investigated and compared in the pretreatment of an agri-food industry waste, apple fibers (90°C for 1 h). For the sake of comparison, 1-butyl-3-methylimidazolium acetate (BMIM OAc) as one of the best IL able to dissolve cellulose was also used. After the pretreatment, two fractions were obtained in each case. The results gathered through FTIR and TG analyses of the two materials and the subsequent DNS assay performed after enzymatic treatment led to identify ChArg as the best medium to delignify and remove waxes, present on the starting apple fibers, thus producing a material substantially enriched in cellulose (CRM). Conversely, ChCl:LA did not provide satisfactorily results using these mild conditions, while BMIM OAc showed intermediate performance probably on account of the reduced crystallinity of cellulose after the dissolution-regeneration process. To corroborate the obtained data, FTIR and TG analyses were also performed on the residues collected after the enzymatic hydrolysis. At the end of the pretreatment, ChArg was also quantitatively recovered without significant alterations.

The Structure-Property Relationship of Pyrrolidinium and Piperidinium-Based Bromide Organic Materials.

Two couples of dicationic ionic liquids, featuring pyrrolidinium and piperidinium cations and different linker chains, were prepared and characterized. 1,1'-(propane-1,3-diyl)bis(1-methylpyrrolidinium) bromide, 1,1'-(octane-1,8-diyl)bis(1-methylpyrrolidinium) bromide, 1,1'-(propane-1,3-diyl)bis(1-methylpiperidinium) bromide, and 1,1'-(octane-1,8-diyl)bis(1-methylpiperidinium) bromide were synthesized in quantitative yields and high purity and thermally characterized through TGA and DSC analysis. In this study, we propose a preliminary comparative evaluation of the effect of the linker chain length and of the size of the aliphatic ammonium ring on the thermal and solubility properties of bromide dicationic ionic liquids.

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide.

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of ß-N-acetyl-D-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors.

Variously substituted 2-oxopyridine derivatives: Extending the structure-activity relationships for allosteric modulation of the cannabinoid CB2 receptor.

We previously reported the 2-oxopyridine-3-carboxamide derivative EC21a as the first small synthetic CB2R positive allosteric modulator which displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Herein, we extended the structure-activity relationships of EC21a through structural modifications regarding the p-fluoro benzyl moiety at position 1 and the amide group in position 3 of the central core. The characterization in vitro was assessed through radioligand binding experiments and functional assays (GTPγS, cAMP, ßarrestin2). Among the new compounds, the derivatives A1 (SV-10a) and A5 (SB-13a) characterized respectively by fluorine atom or by chlorine atom in ortho position of the benzylic group at position 1 and by a cycloheptane-carboxamide at position 3 of the central core, showed positive allosteric behavior on CB2R. They enhanced the efficacy of CP55,940 in [35S]GTPγS assay, and modulated CP55,940-dependent ßarrestin2 recruitment and cAMP inhibition. The obtained results extend our knowledge of the structural requirements for interaction with the allosteric site of CB2R.

Deoxynojirimycin and its hexosaminyl derivatives bind to natural killer cell receptors rNKR-P1A and hCD69.

Deoxynojirimycin (1) and two new related 4-O-hexosaminyl-containing disaccharide mimics, beta-d-TalNAc-(1-->4)-DNJ (4) and beta-d-ManNAc-(1-->4)-DNJ (5), have been studied as agonists of natural killer (NK) cell receptors. As a positive and unexpected result, DNJ (1) displayed a remarkable activation effect towards both NKR-P1A (rat) and CD69 (human) receptors, and a quite similar activity was found for 4 and 5. The synthesis of the two disaccharide mimics is based on an approach that avoids the glycosylation step using known intermediates arising from lactose. The key stage of the synthesis involves the construction of the DNJ unit through an initial C-5 oxidation of the reducing d-glucopyranosyl unit followed by a stereoselective double-reductive aminocyclization of the 1,5-dicarbonyl disaccharide intermediates.

Developments in Carbohydrate-Based Metzincin Inhibitors.

Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models.

Synergistic activity between colistin and the ionic liquids 1-methyl-3-dodecylimidazolium bromide, 1-dodecyl-1-methylpyrrolidinium bromide, or 1-dodecyl-1-methylpiperidinium bromide against Gram-negative bacteria.

OBJECTIVES: Ionic liquids have shown potential for applications as antimicrobials. Their antimicrobial activity has been shown to be higher against Gram-positive than Gram-negative bacteria, suggesting a protective role for the outer membrane of Gram-negative microorganisms. Colistin is a last-resort antibiotic often used for treating infections caused by multi-drug resistant Gram-negative bacteria. Colistin interacts with the bacterial lipopolysaccharide, thus altering the structure and increasing the permeability of the outer membrane. The aim of this study was to investigate the interaction between colistin and the ionic liquids 1-methyl-3-dodecylimidazolium bromide, 1-dodecyl-1-methylpyrrolidinium bromide, and 1-dodecyl-1-methylpiperidinium bromide against Gram-negative bacteria of clinical importance such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. METHODS: The interaction between colistin and ionic liquids against Gram-negative bacteria was evaluated by the checkerboard assay. Bacterial killing assays against P. aeruginosa were carried out to assess whether the synergistic combinations were bactericidal. RESULTS: The results of checkerboard assays showed that all three ionic liquids interacted synergistically with colistin against K. pneumoniae, P. aeruginosa, and A. baumannii but not against E. coli, which was more sensitive to all three ionic liquids compared with the other tested species. The synergistic combinations showed no haemolytic activity. Bacterial killing assays showed that the synergistic effect between colistin and each one of the three tested ionic liquids against P. aeruginosa was bactericidal. CONCLUSION: Overall, the results obtained suggest that colistin and ionic liquids might be used in combination for possible applications to combat infections caused by multi-drug resistant Gram-negative bacteria.