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The well-known health beneficial properties of beer are mainly due to phenolic antioxidants. Citrus-flavored beers represent a growing side-market in the beer industry, sparingly investigated to date. The phenolic profile of commercial radler beers (R1, R2) was investigated to evaluate the impact of the lemon juice added to beer in the industrial production. Results were compared to those obtained for opportunely chosen commercial beer (B) and lemonade (L). The study was carried out by an HPLC-MS/MS with an electrospray ionization source in selected ion recording mode, analyzing in a single chromatographic run 26 compounds belonging to the different phenolic classes of hydroxybenzoic, hydroxycinnamic and caffeoylquinic acids, flavonoids and prenylflavonoids. Different phenolic profiles were found for R1 and R2, mainly ascribed to different malt/hop/recipe used for the beer. High to very high level of hesperidin were found in the radlers, so that a major impact on phenolic antioxidants of the radlers was due to the lemon. Similarly, a major impact of the lemon aromas was found, D-limonene being the dominant peak resulting from the GC-MS analysis of the volatile fraction of the radlers. Graphical Abstract

Abstract Differential scanning calorimetry (DSC) was used as an efficient and rapid tool in studying the conformational transitions between the folded and unfolded structures of cellulolytic enzymes. The thermal properties of two crude hydrolytic enzyme cocktails containing extracellular cellulases from Trichoderma longibrachiatum DIBAF-10 were analyzed and compared with three commercial cellulase preparations. Differences in the thermal behavior of fungal cellulases in the liquid phase, freeze-dried state, liquid formulations in sodium citrate buffer (pH 4.8), and contact with cellulose, carboxymethyl cellulose, and cellobiose were evaluated. DSC profiles of cellulases from the DIBAF-10 strain provided important thermodynamic information about the thermal stability of the included proteins. Crude enzyme cocktails underwent a reproducible and irreversible exothermic aggregation phenomenon at 52.45 ± 0.90 °C like commercial β-glucosidase. Freeze-dried and resuspended in a sodium citrate buffer, cellulases from T. longibrachiatum showed an endothermic peak dependent on buffer and enzyme concentration. In the enzyme-substrates systems, a shift of the same peak was recorded for all substrates tested. The thermal analysis of freeze-dried cellulase samples in the range of 20–150 °C gave information on the denaturation process. In conclusion, we demonstrated that DSC is a cost-effective tool for obtaining "conformational fingerprinting" of crude fungal cellulase preparations. Graphical abstract

A new series of pyrimidine and pyridine diamines was designed as dual binding site inhibitors of cholinesterases (ChEs), characterized by two small aromatic moieties separated by a diaminoalkyl flexible linker. Many compounds are mixed or uncompetitive acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with compound 9 being the most active on Electrophorus electricus AChE (EeAChE) (Ki = 0.312 μM) and compound 22 on equine BChE (eqBChE) (Ki = 0.099 μM). Molecular docking and molecular dynamic studies confirmed the interaction mode of our compounds with the enzymatic active site. UV-vis spectroscopic studies showed that these compounds can form complexes with Cu2+ and Fe3+ and that compounds 18, 20, and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce Aβ42 and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 μM on Aβ42 and tau, respectively). Moreover, the most active compounds showed low cytotoxicity on a human brain cell line and they were predicted as BBB-permeable.

Thiophene derivatives, either “small molecules,” oligomers, or polymers, play a role of primary importance among organic semiconductors, therefore, they have numerous and different technological applications in the field of Organic Electronics. For this reason, thiophene-based materials are found in devices, such as Organic Light-Emitting Diodes (OLEDs), Organic Field-Effect Transistors (OFETs), organic solar cells (OSCs), organic photodetectors, etc. Oligothiophenes and polythiophenes have common excellent charge transport properties and synthetic procedures that are now well established. Furthermore, oligothiophenes do not possess the intrinsic disadvantages of polythiophenes, such as the lack of welldefined structures and the inevitable presence of impurities. Electrochemistry can give a significant contribution to the field of oligothiophenes not only by allowing the determination of the Highest-Occupied Molecular Orbital (HOMO) and the Lowest-Unoccupied Molecular Orbital (LUMO) energy levels by the means of Cyclic Voltammetry (CV), but also through rendering oligothiophenes syntheses more expeditiously in comparison with the classical organic ones. This review outlines the application of electrochemistry techniques in the synthesis of oligothiophene derivatives.

The anodic oxidation of 1-butyl-3-methylimidazolium tetrafluoroborate (BMIm-BF4) efficiently generates BF3 from BF4-. This Lewis acid, strongly bound to the ionic liquids, can be efficiently used in classical BF3-catalyzed reactions. We demonstrated the BF3/BMIm-BF4 reactivity in four reactions, namely, a domino Friedel-Crafts/lactonization of phenols, the Povarov reaction, the Friedel-Crafts benzylation of anisole, and the multicomponent synthesis of tetrahydro-11H-benzo[a]xanthen-11-ones. In comparison with literature data using BF3-Et2O in organic solvents, in all the presented cases, analogous or improved results were obtained. Moreover, the noteworthy advantages of the developed method are the in situ generation of BF3 (no storing necessity) in the required amount, using only the electron as redox reagent, and the recycling of BMIm-BF4 for multiple subsequent runs.

Beer antioxidants originate mainly from malts, classified as colored, caramel, and roasted, according to the malting process. This study aimed to characterize, in terms of phenolic antioxidants, three types of Pale Ale craft beers brewed using increasing percentage of dark malt (0, 5, and 15% Caraamber malt, called PA100, PA95, PA85, respectively) and to evaluate the impact of dealcoholization by osmotic distillation (OD) on the same antioxidants. All the alcoholic (PA, 6.2-6.8 vol %) and low alcoholic (LA-PA, 1 vol %) beers were analyzed by HPLC-ESI-MS/MS, total phenolic content (TPC), and antioxidant activity (AA): similar phenolic profiles were evidenced and 43 compounds identified or tentatively identified. Some differences were found among PA100, PA95, and PA85: PA85 was richer in free phenolic compounds (10.55 mg/L) and had a higher TPC (463.7 GAE mg/L) and AA (852.1 TE mg/L). LA-PA beers showed the same phenolic profile and similar TPC and AA compared to PA beers; however, there were some differences regarding LA-PA85 (5.91 mg/L). Dealcoholization by OD seemed to weakly affect the phenolic fraction. ESI-MS/MS infusion experiments evidenced oligosaccharides, small organic acids, and amino acids, whose presence was confirmed and quantitated by NMR: besides ethanol and other alcohols, weak to strong loss of low-molecular-weight metabolites was evidenced in LA-PA beers.

Organic electrochemistry is a technique that allows for the heterogeneous redox reactions avoiding both the use of stoichiometric amounts of redox reagents and the resulting formation of stoichiometric by-products. In fact, the redox reagent in these reactions is the electron, which is naturally eco-friendly and produces no side compounds. It is therefore quite obvious that electrochemistry can be classified as a “green” technology. The use of this methodology in the synthesis of β-lactams is not a novelty, but the growing interest in this class of biologically active compounds, due to the discovery of new fields of application (after a moment of decrease in interest due to antibiotic resistance) has been a stimulus for the search for more efficient electrochemical ways to synthesize and transform β-lactams. Thus, this review deals with the twenty-first-century applications of electroorganic technique to the chemistry of β-lactams, by analyzing first the syntheses classified by the type of reactions (cyclization, cycloaddition, etc.) and then by manipulating the β-lactam structure, using it as a synthon. Lastly, the importance of this technique is demonstrated by a study of a pilot plant scale reduction of a cephalosporanic acid derivative to a commercially important antibiotic.

Agropyron repens (L.) P. Beauv. (couch grass) is a world-wide infesting rhizomatous plant with pharmacological applications. Chemical research is focused on its allelopathic and anti-inflammatory components, which are mainly present in the essential oil. Conversely, the aqueous extracts have been sparingly investigated, although the herbal tea is by far the most used formulation. To fill the gap, the metabolic profile of Agropyron repens rhizome herbal tea was investigated by electrospray ionization (ESI) tandem–mass spectrometry (MS/MS); the phenolic profile was investigated by HPLC-PDA-ESI-MS/MS. ESI-MS fingerprinting was provided, evidencing diagnostic ions for saccharides, organic acids and amino acids. The HPLC-PDA-ESI-MS/MS analysis evidenced at least 20 characteristic phenolic compounds, the most representative being caffeoyl and feruloyl quinic esters, followed by coumaric, caffeic and ferulic acids, and hesperidin among flavonoids. In addition, the essential amino acid tryptophan was identified for the first time. The results suggest new perspectives of applications for Agropyron repens rhizome.

Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aβ42 and tau and to be able to chelate Cu2+ and Fe3+ ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line.

Made available in DSpace on 2022-05-01T15:30:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Fungal diseases affect more than 1 billion people worldwide. The constant global changes, the advent of new pandemics, and chronic diseases favor the diffusion of fungal pathogens such as Candida, Cryptococcus, Aspergillus, Trichophyton, Histoplasma capsulatum, and Paracoccidioides brasiliensis. In this work, a series of nitrofuran derivatives were synthesized and tested against different fungal species; most of them showed inhibitory activity, fungicide, and fungistatic profile. The minimal inhibitory concentration (MIC90) values for the most potent compounds range from 0.48 μg/mL against H. capsulatum (compound 11) and P. brasiliensis (compounds 3 and 9) to 0.98 μg/mL against Trichophyton rubrum and T. mentagrophytes (compounds 8, 9, 12, 13 and 8, 12, 13, respectively), and 3.9 μg/mL against Candida and Cryptococcus neoformans strains (compounds 1 and 5, respectively). In addition, all compounds showed low toxicity when tested in vitro on lung cell lines (A549 and MRC-5) and in vivo in Caenorhabditis elegans larvae. Many of them showed high selectivity index values. Thus, these studied nitrofuran derivatives proved to be potent against different fungal species, characterized by low toxicity and high selectivity; for these reasons, they may become promising compounds for the treatment of mycoses. School of Pharmaceutical Science Universidade Estadual Paulista, SP Department of Scienze di Base e Applicate per l’Ingegneria Sapienza University of Rome, Via Castro Laurenziano 7 Department of Environmental Biology Sapienza University of Rome, Piazzale Aldo Moro 5 Department of Chimica e Tecnologia del Farmaco Sapienza University of Rome, Piazzale Aldo Moro Department of Chemistry and Technology of Drug Instituto Pasteur Fondazione Cenci Bolognetti Sapienza University of Rome, Piazzale Aldo Moro 5 School of Pharmaceutical Science Universidade Estadual Paulista, SP CAPES: 001 CNPq: 134559/2018-5 CNPq: 142049/2019-0 FAPESP: 16/11836-0 FAPESP: 2017/18388-6 FAPESP: 2019/22188-8 FAPESP: 2020/15586-4 CAPES: 88887.500765/2020-00

Antioxidants play a central role in the development and production of food, cosmetics, and pharmaceuticals, to reduce oxidative processes in the human body. Among them, phenolic antioxidants are considered even more efficient than other antioxidants. They are divided into natural and synthetic. The natural antioxidants are generally found in plants and their synthetic counterparts are generally added as preventing agents of lipid oxidation during the processing and storage of fats, oils, and lipid-containing foods: All of them can exhibit different effects on human health, which are not always beneficial. Because of their relevant bioactivity and importance in several sectors, such as agro-food, pharmaceutical, and cosmetic, it is crucial to have fast and reliable analysis Rmethods available. In this review, different examples of gold nanomaterial-based electrochemical (bio)sensors used for the rapid and selective detection of phenolic compounds are analyzed and discussed, evidencing the important role of gold nanomaterials, and including systems with or without specific recognition elements, such as biomolecules, enzymes, etc. Moreover, a selection of gold nanomaterials involved in the designing of this kind of (bio)sensor is reported and critically analyzed. Finally, advantages, limitations, and potentialities for practical applications of gold nanomaterial-based electrochemical (bio)sensors for detecting phenolic antioxidants are discussed.

The Wieland–Miescher ketone, Hajos–Parrish–Eder–Sauer–Wiechert ketone, and their analogues are bicyclic diketones essential as building blocks for the synthesis of several natural and bioactive molecules. For this reason, since 1971, when Hajos and Parrish and Eder, Sauer, and Wiechert reported the stereoselective synthesis of these compounds promoted by L-proline, numerous methodologies and organocatalysts have been studied over the years with the aim of identifying increasingly efficient asymmetrical syntheses of these bicyclic ketones. This review will outline the methodological and stereochemical features of the organocatalytic stereoselective synthesis of these bicyclic scaffolds based on the different organocatalysts employed from 1971 until today. Particular emphasis will be given to the structural features of the catalysts and to the reaction conditions.

Histoplasma capsulatum is a fungus that causes histoplasmosis. The increased evolution of microbial resistance and the adverse effects of current antifungals help new drugs to emerge. In this work, fifty-four nitrofurans and indoles were tested against the H. capsulatum EH-315 strain. Compounds with a minimum inhibitory concentration (MIC90) equal to or lower than 7.81 µg/mL were selected to evaluate their MIC90 on ATCC G217-B strain and their minimum fungicide concentration (MFC) on both strains. The quantification of membrane ergosterol, cell wall integrity, the production of reactive oxygen species, and the induction of death by necrosis–apoptosis was performed to investigate the mechanism of action of compounds 7, 11, and 32. These compounds could reduce the extracted sterol and induce necrotic cell death, similarly to itraconazole. Moreover, 7 and 11 damaged the cell wall, causing flaws in the contour (11), or changing the size and shape of the fungal cell wall (7). Furthermore, 7 and 32 induced reactive oxygen species (ROS) formation higher than 11 and control. Finally, the cytotoxicity was measured in two models of cell culture, i.e., monolayers (cells are flat) and a three-dimensional (3D) model, where they present a spheroidal conformation. Cytotoxicity assays in the 3D model showed a lower toxicity in the compounds than those performed on cell monolayers. Overall, these results suggest that derivatives of nitrofurans and indoles are promising compounds for the treatment of histoplasmosis.

Imidazolium-based dicationic ionic liquids (DILs) are gaining considerable space in the field of organocatalysis mainly due to the opportunities in offering new possible applicable structural variations. In addition to the well-known variables which made the ionic liquids (ILs) famous as the type of cation and anion used, the nature of the molecular spacer moiety turns out a further possibility to improve some physicochemical properties, for example, solubility, acidity, electrochemical behavior, and so on. For this reason, this class of ionic liquids has been considered as possible competitors to their corresponding monocationic salts in replacing common catalysts in organic synthesis, particularly in cases in which their bidentate nature could positively affect the catalytic activity. This mini-review is intended to highlight the progress carried out in the last six years in the field of organocatalysis, including DILs as such and as hybrids with polymers, nanomaterials, and composites.

The occurrence of N-heterocyclic carbenes in imidazolium-based ionic liquids has long been discussed, but no spectroscopic evidence has been reported yet due to their transient nature. The insertion of an ionizable acid group into the cation scaffold of an ionic liquid which acts as a charge tag allows for the direct detection of free carbenes by mass spectrometry.Three different Brønsted acidic ionic liquids were synthesized: 1-methyl-3-carboxymethylimidazolium chloride (MAICl), 1-methyl-3-carboxymethylimidazolium acetate (MAIAc) and the corresponding 2-(3-methyl-1H-imidazol-3-ium-1-yl)acetate zwitterion (MAI - H). The speciation of these compounds was then analysed by electrospray ionization ion-trap mass spectrometry in the negative ion mode.The C2-H deprotonation of the imidazolium cation leading to the formation of the corresponding carbene is highly affected by the basic properties of the counter-anion. In the case of MAICl and MAI - H ionic liquids, no charged species corresponding to the free N-heterocyclic carbene was detected. On the contrary, in the presence of a sufficiently basic anion, such as acetate of MAIAc ionic liquid, an intense signal related to the free carbenic species was observed without the addition of an external base.In situ formation of free N-heterocyclic carbenes from Brønsted acidic ionic liquids was demonstrated, highlighting the crucial role of anion basicity in promoting the C2-H proton abstraction from imidazolium cations with a carboxylic side chain.

A new series of pyrimidine and pyridine diamines was designed as dual binding site inhibitors of cholinesterases (ChEs), characterized by two small aromatic moieties separated by a diaminoalkyl flexible linker. Many compounds are mixed or uncompetitive acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with compound 9 being the most active on Electrophorus electricus AChE (EeAChE) (Ki = 0.312 μM) and compound 22 on equine BChE (eqBChE) (Ki = 0.099 μM). Molecular docking and molecular dynamic studies confirmed the interaction mode of our compounds with the enzymatic active site. UV–vis spectroscopic studies showed that these compounds can form complexes with Cu2+ and Fe3+ and that compounds 18, 20, and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce Aβ42 and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 μM on Aβ42 and tau, respectively). Moreover, the most active compounds showed low cytotoxicity on a human brain cell line and they were predicted as BBB-permeable.

The ability to obtain Fe is critical for pathogens to multiply in their host. For this reason, there is significant interest in the identification of compounds that might interfere with Fe management in bacteria. Here we have tested the response of two Gram-negative pathogens, Salmonella enterica serovar Typhimurium (STM) and Pseudomonas aeruginosa (PAO1), to deferiprone (DFP), a chelating agent already in use for the treatment of thalassemia, and to some DFP derivatives designed to increase its lipophilicity. Our results indicate that DFP effectively inhibits the growth of PAO1, but not STM. Similarly, Fe-dependent genes of the two microorganisms respond differently to this agent. DFP is, however, capable of inhibiting an STM strain unable to synthesize enterochelin, while its effect on PAO1 is not related to the capability to produce siderophores. Using a fluorescent derivative of DFP we have shown that this chelator can penetrate very quickly into PAO1, but not into STM, suggesting that a selective receptor exists in Pseudomonas. Some of the tested derivatives have shown a greater ability to interfere with Fe homeostasis in STM compared to DFP, whereas most, although not all, were less active than DFP against PAO1, possibly due to interference of the added chemical tails with the receptor-mediated recognition process. The results reported in this work indicate that DFP can have different effects on distinct microorganisms, but that it is possible to obtain derivatives with a broader antimicrobial action.

Chirality is undoubtedly a fundamental property of nature since the different interactions of optically active molecules in a chiral environment are essential for numerous applications. Thus, in the field of asymmetric synthesis, the search for efficient, sustainable, cost-effective and recyclable chiral catalysts is still the main challenge in organic chemistry. The field of carbon dots (CDs) has experienced tremendous development in the last 15 years, including their applications as achiral catalysts. Thus, understanding the implications of chirality in CDs chemistry could be of utmost importance to achieving sustainable and biocompatible chiral nanocatalysts. An efficient and cost-effective electrochemical synthetic methodology for the synthesis of L-Proline-based chiral carbon dots (CCDs) and EtOH-derived L-Proline-based chiral carbon dots (CCDs) is herein reported. The electrochemical set-up and reaction conditions have been thoroughly optimised and their effects on CCDs size, photoluminescence, as well as catalytic activity have been investigated. The obtained CCDs have been successfully employed to catalyze an asymmetric aldol reaction, showing excellent results in terms of yield, diastereo- and enantioselectivity. Moreover, the sustainable nature of the CCDs was demonstrated by recycling the catalysts for up to 3 cycles without any loss of reactivity or stereoselectivity.

Introduction - AD, the most common form of dementia, has a multifactorial etiology, and the current therapy (AChEIs and memantine) is unable to interrupt its progress and fatal outcome. This is reflected in the research programs that are oriented toward the development of new therapeutics able to operate on multiple targets involved in the disease progression.Areas covered - The patents from 2016 to present regarding the use of AChEIs in AD, concerns the development of new AChEIs, multitarget or multifunctional ligands, or the associations of currently used AChEIs with other compounds acting on different targets involved in the AD.Expert opinion - The development of new multitarget AChEIs promises to identify compounds with great therapeutic potential but requires more time and effort in order to obtain drugs with the optimal pharmacodynamic profile. Otherwise, the research on new combinations of existing drugs, with known pharmacodynamic and ADME profile, could shorten the time and reduce the costs to develop a new therapeutic treatment for AD. From the analyzed data, it seems more likely that a response to the urgent need to develop effective treatments for AD therapy could come more quickly from studies on drug combinations than from the development of new AChEIs.

In the last twenty years, N-heterocyclic carbenes (NHCs) have been extensively studied for their application as organocatalysts in stereoselective synthesis as well as ligands for transition metals-promoted synthetic methodologies. Derived mainly from azolium salts, NHCs have demonstrated exceptional versatility in their generation usually performed by deprotonation or reduction (chemical or electrochemical). In particular, the generation of NHC under electrochemical conditions, starting from azolium-based ionic liquids, has proven to be a successful green approach and demonstrated wide applicability in organic synthesis. In this Personal Account, the application of electrogenerated NHCs in organic synthesis will be discussed, with a particular attention to the different reactivity in ionic liquids compared to classical organic solvents.

Candida albicans, in specific conditions, is responsible of severe invasive systemic candidiasis that are related to its ability to produce biofilm on biological and artificial surfaces. Many studies reported the role of iron in fungal growth and virulence and the ability of metal chelating agents to interfere with C. albicans metabolism, virulence and biofilm formation. Here we report the activity of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone (deferiprone) derivatives against C. albicans planktonic cells and biofilm. Some of the studied compounds (2b and 3b) were able to chelate Fe(III) and Cu(II), and showed an interesting activity on planktonic cells (MIC50 of 32 μg/mL and 16 μg/mL respectively) and on biofilm formation (BMIC50 of 32 μg/mL and 16 μg/mL respectively) in cultured ATCC 10,231C. albicans; this activity was reduced, in a concentration dependent way, by the addition of Fe(III) and Cu(II) to the culture media. Furthermore, the most active compound 3b showed a low toxicity on Galleria mellonella larvae.

The creation of carbon–carbon bonds is still a highly required topic in organic chemistry for the capacity to give a wide variety of new products of industrial value. Accordingly, the Knoevenagel condensation between activated methylene compounds and aldehydes is one of the most known carbon coupling reactions. In this work, the catalytic activity of imidazolium-based ionic liquids (1-butyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium chloride, 1-methyl-3-carboxymethylimidazolium chloride) was studied under solvent-free conditions and compared with that of sodium salts (sodium chloride, sodium acetate). Mass spectrometric techniques were used to monitor the formation of the reaction products and to detect the key intermediates of the process. Based on the catalyst employed different reaction mechanisms were highlighted, thus laying the foundation for the design of more specific and efficient catalysts.

Candida albicans biofilm represents a major clinical problem due to its intrinsic tolerance to anti-fungal compounds and it has been highly related to infections in catheterized patients. Few compounds are described as able to inhibit biofilm formation or to interfere with preformed biofilm of C. albicans. Here we report the in vitro evaluation of anti-biofilm activity on C. albicans ATCC 10231 of a series of new and already known amine and amide indole derivatives. Among the studied compounds, fifteen resulted active on C. albicans ATCC 10231 biofilm, with BMIC50 ≤ 16 μg/mL. Three of them (7, 23 and 33) showed a selectivity towards mature biofilm and the most active of them was the compound 23 (BMIC50 = 4 μg/mL). On the other hands, two different compounds (21 and 22) were selective towards biofilm formation with BMIC50 values of 8 μg/mL. Otherwise, compounds 16 and 17 resulted active on biofilm formation, with BMIC50 of 8 μg/mL and 2 μg/mL respectively, and on mature biofilm with BMIC50 of 2 μg/mL. These two last compounds also showed an interesting activity towards the planktonic cells of C. albicans. A selection of the more active compounds was also evaluated on different C. albicans strains (PMC1042, PMC1083 and ATCC 10261), showing a comparable or higher anti-biofilm activity, especially on mature biofilm. In vivo toxicity studies using the Galleria mellonella larvae, were finally carried out on more active indole derivatives, showing that they are poorly toxic even at the highest concentrations tested (500–1000 μg/mL).

The anodic oxidation of tetrafluoroborate anion yields the Lewis acid BF3. If this reaction is carried out in an imidazolium ionic liquid, a quite stable system containing BF3 is obtained, whose reactivity is similar to the one of BF3·Et2O, but less harmful. The two reagents’ stabilities were compared by computational analysis, strongly suggesting a higher stability for BF3/BMIm-BF4 system. The effect of substituents on the imidazolium ring and of the electrochemical configuration on BF3 reactivity were studied in a model reaction, styrene oxide isomerization. The experimental conditions were defined for the selective formation of phenylacetaldehyde or of 2-benzyl-4-phenyl-1,3-dioxolane. Moreover, the formation of N-heterocyclic carbene-BF3 adduct was confirmed when carrying out the electrolysis in an undivided cell. Electrogenerated BF3/BMIm-BF4 system demonstrated to be a valid alternative to commercial BF3·Et2O.

Controlled potential electrolyses of caffeine (CAF) were carried out at a Pt electrode in undried acetonitrile (ACN) and ACN-H2O and the products of the anodic oxidation were analyzed by HPLC-PDA-ESI-MS/MS. A higher current efficiency occurred in ACN-H2O, but an analogous chromatographic outline was found in both media, evidencing a reactive pathway of the electrogenerated radical cation CAF&bull, + with water, added or in trace, as nucleophile. No dimeric forms were evidenced, excluding any coupling reactions. Neither was 1,3,7-trimethyluric acid found, reported in the literature as the main oxidative route for CAF in water. Four main chromatographic peaks were evidenced, assigned to four proposed structures on the base of chromatographic and spectral data: a 4,5-diol derivative and an oxazolidin-2-one derivative were assigned as principal oxidation products, supporting a mechanism proposed in a previous work for the primary anodic oxidation of the methylxanthines olefinic C4 = C5 bond. Two highly polar degradation products were also tentatively assigned, that seemed generating along two different pathways, one opening the imidazolic moiety and another one opening the purinic one.

In order to obtain multi-functional molecules for Alzheimer’s disease, a series of deferiprone derivatives has been synthesized and evaluated in vitro with the hypothesis that they can restore the cholinergic tone and attenuate the dyshomeostasis of the metals mainly involved in the pathology. These compounds were designed as dual binding site AChE inhibitors: they possess an arylalkylamine moiety connected via an alkyl chain to a 3-hydroxy-4-pyridone fragment, to allow the simultaneous interaction with catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme. Deferiprone moiety and 2-aminopyridine, 2-aminopyrimidine or 2,4-diaminopyrimidine groups have been incorporated into these compounds, in order to obtain molecules potentially able to chelate bio-metals colocalized in Aβ plaques and involved in the generation of radical species. Synthesized compounds were tested by enzymatic inhibition studies towards EeAChE and eqBChE using Ellman’s method. The most potent EeAChE inhibitor is compound 5a, with a Ki of 788 ± 51 nM, while the most potent eqBChE inhibitors are compounds 12 and 19, with Ki values of 182 ± 18 nM and 258 ± 25 nM respectively. Selected compounds, among the most potent cholinesterases inhibitors, were able to form complex with iron and in some cases with copper and zinc. Moreover, these compounds were characterized by low toxicity on U-87 MG Cell Line from human brain (glioblastoma astrocytoma).

Background: Tegaserod (Zelnorm®) is a 5-hydroxytryptamine (serotonin) type 4 receptor agonist for the treatment of hypomotility disorders of the lower gastrointestinal tract associated with the irritable bowel syndrome with constipation (IBS-C). Objective: The authors provide the reader with a better understanding on tegaserod mechanism of action, on its pharmacodynamics and pharmacokinetic properties, on safety and tolerability, with a summary of the key published clinical trials conducted in patients with irritable bowel syndrome (IBS). Its effects on colon inflammation have also been described. Results: Tegaserod was withdrawn in 2007 due to increased risks of cardiovascular adverse effects. The manufacturer denied this, because pre-existing cardiovascular disease or risk factors were attributed to all affected patients. Thus, no causal relationship between tegaserod use and cardiovascular events was clearly shown. A matched case-control study of tegaserod-treated with untreated patients found no association between tegaserod and adverse cardiovascular outcomes. Despite its adverse effects, tegaserod resulted to be effective in treating chronic constipation in adult women aged < 65 years with IBS-C, while the safety and effectiveness of tegaserod in men with IBS-C have not been established. Conclusion: Tegaserod was resubmitted to the Food and Drug Administration in 2018 for use in a low-risk population. Moreover, tegaserod has also been shown to improve symptoms, enhance gastric accommodation and significantly attenuate visceral pain arising from the colon in functional dyspepsia patients. Treatment with tegaserod seems also to exert a protective effect in inflamed colons, reducing the severity of colitis in animal models.

Heparanase is the sole mammalian enzyme capable of cleaving glycosaminoglycan heparan sulfate side chains of heparan sulfate proteoglycans. Its altered activity is intimately associated with tumor growth, angiogenesis, and metastasis. Thus, its implication in cancer progression makes it an attractive target in anticancer therapy. Herein, we describe the design, synthesis, and biological evaluation of new benzazoles as heparanase inhibitors. Most of the designed derivatives were active at micromolar or submicromolar concentration, and the most promising compounds are fluorinated and/or amino acids derivatives 13a, 14d, and 15 that showed IC50 0.16-0.82 μM. Molecular docking studies were performed to rationalize their interaction with the enzyme catalytic site. Importantly, invasion assay confirmed the antimetastatic potential of compounds 14d and 15. Consistently with its ability to inhibit heparanase, compound 15 proved to decrease expression of genes encoding for proangiogenic factors such as MMP-9, VEGF, and FGFs in tumor cells.

Heparanase is the only mammalian endo-β-d-glucuronidase involved in a variety of major diseases. The up-regulation of heparanase expression increases tumor size, angiogenesis, and metastasis, representing a validated target in the anti-cancer field. To date, only a few small-molecule inhibitors have been described, but none have gotten through pre-clinical development. Previously, we explored 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives as anti-heparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Herein, we report an extended investigation of new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivatives, proving that symmetrical compounds are more effective than asymmetrical analogues, with the most-potent compound, 7g, being active at nanomolar concentration against heparanase. Molecular docking studies were performed on the best-acting compounds 5c and 7g to rationalize their interaction with the enzyme. Moreover, invasion assay confirmed the anti-metastatic potential of compounds 5c, 7a, and 7g, proving the inhibition of the expression of proangiogenic factors in tumor cells.

A new series of pyridine derivatives with carbamic or amidic function has been designed and synthesized to act as cholinesterase inhibitors. The synthesized compounds were tested toward EeAChE and hAChE and toward eqBChE and hBChE. The carbamate 8 was the most potent hAChE inhibitor (IC50= 0.153 ± 0.016 μM) while the carbamate 11 was the most potent inhibitor of hBChE (IC50= 0.828 ± 0.067 μM). A molecular docking study indicated that the carbamate 8 was able to bind AChE by interacting with both CAS and PAS, in agreement with the mixed inhibition mechanism. Furthermore, the carbamates 8, 9 and 11 were able to inhibit Aβ42self-aggregation and possessed quite low toxicity against human astrocytoma T67 and HeLa cell lines, being the carbamate 8 the less toxic compound on both cell lines.

The contamination with water of the cathodic ACN-Et4NBF4 solution gave us the opportunity to investigate alkyl isocyanate reactivity toward electrogenerated anions. The cathodic reduction of a ACN-Et4NBF4 solution led to the formation of both hydroxide and cyanomethyl anions. The reaction of the catholyte with cyclohexylisocyanate led to the exclusive formation of acetamidated product, with no traces of cyanomethylated one. On the contrary, when reacting with benzaldehyde only the cyanomethylated was isolated. Considering that the acetamidated product of benzaldehyde is reported to be unstable (thus its formation cannot be excluded), various experiments were carried out in order to understand the anomalous reactivity of cyclohexylisocyanate. Moreover, computational analysis allowed to state the higher stability of acetamidated product with respect to the cyanomethylated one. The possibility of a concerted reaction, instead of acetamide anion formation prior to the reaction, is still an open question.

We discovered novel and selective sulfonamides/amides acting as inhibitors of the α-carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae (VchCA). This Gram-negative bacterium is the causative agent of cholera and colonises the upper small intestine where sodium bicarbonate is present at a high concentration. The secondary sulfonamides and amides investigated here were potent, low nanomolar VchCA inhibitors whereas their inhibition of the human cytosolic isoforms CA I and II was in the micromolar range or higher. The molecules represent an interesting lead for antibacterial agents with a possibly new mechanism of action, although their CA inhibition mechanism is unknown for the moment.