An enhanced stereoselective synthesis of α,ß-unsaturated esters through the Horner-Wadsworth-Emmons reaction in deep eutectic solvents.

A new scalable synthesis of (E)-α,ß-unsaturated esters has been developed using protic, non-toxic, and biodegradable deep eutectic solvents through the Horner-Wadsworth-Emmons reaction between triethyl phosphonates and (hetero)aromatic carbonyl compounds, encompassing electron-withdrawing and electron-donating groups. Stereoselective preparation of disubstituted or trisubstituted ethyl cinnamate derivatives is achieved in the presence of LiOH, K2CO3, or DBU as bases, at room temperature and under air. Demonstrated with the synthesis of (E)-ethyl 3-(4-bromophenyl)acrylate, the same eutectic mixture (choline chloride/urea) proved to be reusable for three consecutive runs. Gram-scale reactions (10 mmol) can be carried out without the formation of side products, thereby ensuring high atom economy and an EcoScale score of 71.

A Sustainable Synthetic Approach to Tacrine and Cholinesterase Inhibitors in Deep Eutectic Solvents under Aerobic Conditions.

An enhanced, sustainable, and efficient method for synthesizing tacrine, achieving a 98% yield, has been developed by replacing volatile organic compounds with more eco-friendly solvents such as deep eutectic solvent (DESs). The optimized protocol scales easily to 3 g of substrate without yield loss and extends successfully to tacrine derivatives with reduced hepatotoxicity. Particularly notable is the synthesis of novel triazole-based derivatives, yielding 90-95%, by integrating an in situ preparation of aryl azides in DESs with N-propargyl-substituted tacrine derivatives. Quantitative metrics validate the green aspects of the reported drug development processes.

Introducing Water and Deep Eutectic Solvents in Organosodium Chemistry: Chemoselective Nucleophilic Functionalizations in Air.

Advancing the development of perfecting the use of polar organometallics in bio-inspired solvents, we report on the effective generation in batch of organosodium compounds, by the oxidative addition of a C-Cl bond to sodium, a halogen/sodium exchange, or by direct sodiation, when using sodium bricks or neopentylsodium in hexane as sodium sources. C(sp3 )-, C(sp2 )-, and C(sp)-hybridized alkyl and (hetero)aryl sodiated species have been chemoselectively trapped (in competition with protonolysis), with a variety of electrophiles when working "on water", or in biodegradable choline chloride/urea or L-proline/glycerol eutectic mixtures, under hydrous conditions and at room temperature. Additional benefits include a very short reaction time (20 s), a wide substrate scope, and good to excellent yields (up to 98 %) of the desired adducts. The practicality of the proposed protocol was demonstrated by setting up a sodium-mediated multigram-scale synthesis of the anticholinergic drug orphenadrine.

Membrane electrical properties of mouse hippocampal CA1 pyramidal neurons during strong inputs.

In this work, we highlight an electrophysiological feature often observed in recordings from mouse CA1 pyramidal cells that has so far been ignored by experimentalists and modelers. It consists of a large and dynamic increase in the depolarization baseline (i.e., the minimum value of the membrane potential between successive action potentials during a sustained input) in response to strong somatic current injections. Such an increase can directly affect neurotransmitter release properties and, more generally, the efficacy of synaptic transmission. However, it cannot be explained by any currently available conductance-based computational model. Here we present a model addressing this issue, demonstrating that experimental recordings can be reproduced by assuming that an input current modifies, in a time-dependent manner, the electrical and permeability properties of the neuron membrane by shifting the ionic reversal potentials and channel kinetics. For this reason, we propose that any detailed model of ion channel kinetics for neurons exhibiting this characteristic should be adapted to correctly represent the response and the synaptic integration process during strong and sustained inputs.

HippoUnit: A software tool for the automated testing and systematic comparison of detailed models of hippocampal neurons based on electrophysiological data.

Anatomically and biophysically detailed data-driven neuronal models have become widely used tools for understanding and predicting the behavior and function of neurons. Due to the increasing availability of experimental data from anatomical and electrophysiological measurements as well as the growing number of computational and software tools that enable accurate neuronal modeling, there are now a large number of different models of many cell types available in the literature. These models were usually built to capture a few important or interesting properties of the given neuron type, and it is often unknown how they would behave outside their original context. In addition, there is currently no simple way of quantitatively comparing different models regarding how closely they match specific experimental observations. This limits the evaluation, re-use and further development of the existing models. Further, the development of new models could also be significantly facilitated by the ability to rapidly test the behavior of model candidates against the relevant collection of experimental data. We address these problems for the representative case of the CA1 pyramidal cell of the rat hippocampus by developing an open-source Python test suite, which makes it possible to automatically and systematically test multiple properties of models by making quantitative comparisons between the models and electrophysiological data. The tests cover various aspects of somatic behavior, and signal propagation and integration in apical dendrites. To demonstrate the utility of our approach, we applied our tests to compare the behavior of several different rat hippocampal CA1 pyramidal cell models from the ModelDB database against electrophysiological data available in the literature, and evaluated how well these models match experimental observations in different domains. We also show how we employed the test suite to aid the development of models within the European Human Brain Project (HBP), and describe the integration of the tests into the validation framework developed in the HBP, with the aim of facilitating more reproducible and transparent model building in the neuroscience community.

Green Solvents for Eco-Friendly Synthesis of Dimethindene: A Forward-Looking Approach.

Dimethindene is a selective histamine H1 antagonist and is commercially available as a racemate. Upon analyzing the synthetic pathways currently available for the industrial preparation of dimethindene, we set up a sustainable approach for the synthesis of this drug, switching from petroleum-based volatile organic compounds (VOCs) to eco-friendly solvents, such as 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether (CPME) belonging to classes 3 and 2, respectively. Beyond decreasing the environmental impact of the synthesis (E-factor: 24.1-54.9 with VOCs; 12.2-22.1 with 2-MeTHF or CPME), this switch also improved the overall yield of the process (from 10% with VOCs to 21-22% with 2-MeTHF or CPME) and remarkably simplified the manual operations, working under milder conditions. Typical metrics applied at the first and second pass, according to the CHEM21 metrics toolkit, were also calculated for the whole synthetic procedure of dimethindene, and the results were compared with those of the classical procedure.

Advances in deep eutectic solvents and water: applications in metal- and biocatalyzed processes, in the synthesis of APIs, and other biologically active compounds.

Owing to a growing awareness towards environmental impact, the search for "greener", safer, and cost-effective solvents able to replace petroleum-derived solvents has never been greater today. In this context, the use of environmentally responsible solvents like water and the so-called deep eutectic solvents (DESs), constructed from bio-based compounds, has recently experienced important growth in several fields of sciences. This short review highlights the key features of the chemistry of water and (hydrated) DESs when applied to metal- and biocatalyzed transformations as well as to the synthesis of active pharmaceutical ingredients (APIs) and other biologically relevant compounds by providing, through discussion of all relevant literature over the past five years, a comparison of the outcomes of the reactions when carried out in one or the other solvent.

Copper-catalyzed Goldberg-type C-N coupling in deep eutectic solvents (DESs) and water under aerobic conditions.

An efficient and selective N-functionalization of amides is first reported via a CuI-catalyzed Goldberg-type C-N coupling reaction between aryl iodides and primary/secondary amides run either in Deep Eutectic Solvents (DESs) or water as sustainable reaction media, under mild and bench-type reaction conditions (absence of protecting atmosphere). Higher activities were observed in an aqueous medium, though the employment of DESs expanded and improved the scope of the reaction to include also aliphatic amides. Additional valuable features of the reported protocol include: (i) the possibility to scale up the reaction without any erosion of the yield/reaction time; (ii) the recyclability of both the catalyst and the eutectic solvent up to 4 consecutive runs; and (iii) the feasibility of the proposed catalytic system for the synthesis of biologically active molecules.

A Zinc-Mediated Deprotective Annulation Approach to New Polycyclic Heterocycles.

A straightforward approach to new polycyclic heterocycles, 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones, is presented. It is based on the ZnCl2-promoted deprotective 6-endo-dig heterocyclization of N-Boc-2-alkynylbenzimidazoles under mild conditions (CH2Cl2, 40 °C for 3 h). The zinc center plays a dual role, as it promotes Boc deprotection (with formation of the tert-butyl carbocation, which can be trapped by substrates bearing a nucleophilic group) and activates the triple bond toward intramolecular nucleophilic attack by the carbamate group. The structure of representative products has been confirmed by X-ray diffraction analysis.

Scalable Negishi Coupling between Organozinc Compounds and (Hetero)Aryl Bromides under Aerobic Conditions when using Bulk Water or Deep Eutectic Solvents with no Additional Ligands.

Pd-catalyzed Negishi cross-coupling reactions between organozinc compounds and (hetero)aryl bromides have been reported when using bulk water as the reaction medium in the presence of NaCl or the biodegradable choline chloride/urea eutectic mixture. Both C(sp3 )-C(sp2 ) and C(sp2 )-C(sp2 ) couplings have been found to proceed smoothly, with high chemoselectivity, under mild conditions (room temperature or 60 °C) in air, and in competition with protonolysis. Additional benefits include very short reaction times (20 s), good to excellent yields (up to 98 %), wide substrate scope, and the tolerance of a variety of functional groups. The proposed novel protocol is scalable, and the practicability of the method is further highlighted by an easy recycling of both the catalyst and the eutectic mixture or water.

Boosting Conjugate Addition to Nitroolefins Using Lithium Tetraorganozincates: Synthetic Strategies and Structural Insights.

We report the first transition metal catalyst- and ligand-free conjugate addition of lithium tetraorganozincates (R4 ZnLi2 ) to nitroolefins. Displaying enhanced nucleophilicity combined with unique chemoselectivity and functional group tolerance, homoleptic aliphatic and aromatic R4 ZnLi2 provide access to valuable nitroalkanes in up to 98 % yield under mild conditions (0 °C) and short reaction time (30 min). This is particularly remarkable when employing ß-nitroacrylates and ß-nitroenones, where despite the presence of other electrophilic groups, selective 1,4 addition to the C=C is preferred. Structural and spectroscopic studies confirmed the formation of tetraorganozincate species in solution, the nature of which has been a long debated issue, and allowed to unveil the key role played by donor additives on the aggregation and structure of these reagents. Thus, while chelating N,N,N',N'-tetramethylethylenediamine (TMEDA) and (R,R)-N,N,N',N'-tetramethyl-1,2-diaminocyclohexane (TMCDA) favour the formation of contacted-ion pair zincates, macrocyclic Lewis donor 12-crown-4 triggers an immediate disproportionation process of Et4 ZnLi2 into equimolar amounts of solvent-separated Et3 ZnLi and EtLi.

Regiodivergent synthesis of functionalized pyrimidines and imidazoles through phenacyl azides in deep eutectic solvents.

We report that phenacyl azides are key compounds for a regiodivergent synthesis of valuable, functionalized imidazole (32-98% yield) and pyrimidine derivatives (45-88% yield), with a broad substrate scope, when using deep eutectic solvents [choline chloride (ChCl)/glycerol (1:2 mol/mol) and ChCl/urea (1:2 mol/mol)] as environmentally benign and non-innocent reaction media, by modulating the temperature (25 or 80 °C) in the presence or absence of bases (Et3N).

Palladium-Catalyzed Cyclocarbonylation Approach to Thiadiazafluorenones: A Correction.

The palladium-catalyzed carbonylation of 2-(propynylthio)benzimidazoles bearing a terminal triple bond leads to 2-methyl-1-thia-4a,9-diazafluoren-4-ones instead of the previously reported 3-methyl isomers, as unequivocally established by XRD analysis of a representative product. A correction is therefore provided here in order to rectify the previous erroneous assignment of the position of the methyl group. Moreover, the process has been generalized to substrates bearing an internal triple bond, which lead to 3-alkyl-2-methyl-1-thia-4a,9-diazafluoren-4-ones, whose structure was confirmed by XRD analysis of two representative derivatives.

Water and Sodium Chloride: Essential Ingredients for Robust and Fast Pd-Catalysed Cross-Coupling Reactions between Organolithium Reagents and (Hetero)aryl Halides.

Direct palladium-catalysed cross-couplings between organolithium reagents and (hetero)aryl halides (Br, Cl) proceed fast, cleanly and selectively at room temperature in air, with water as the only reaction medium and in the presence of NaCl as a cheap additive. Under optimised reaction conditions, a water-accelerated catalysis is responsible for furnishing C(sp3 )-C(sp2 ), C(sp2 )-C(sp2 ), and C(sp)-C(sp2 ) cross-coupled products, in competition with protonolysis, within a reaction time of 20 s, in yields of up to 99 %, and in the absence of undesired dehalogenated/homocoupling side products even when challenging secondary organolithiums serve as the starting material. It is worth noting that the proposed protocol is scalable and the catalyst and water can easily and successfully be recycled up to 10 times, with an E-factor as low as 7.35.

Supramolecular Hydro- and Ionogels: A Study of Their Properties and Antibacterial Activity.

Diimidazolium-based organic salts, bearing peptides or amino acids as anions have been synthesised and tested for their gelling ability in biocompatible solvents. These low molecular weight salts were successfully used as gelators in phosphate buffered saline (PBS) solution and ionic liquids. Then, the properties of the obtained soft materials were analysed in terms of melting temperature and gel strength as accounted for by rheological investigations. The gel-phase formation was studied by using UV/Vis and resonance light scattering measurements, whereas the morphology of the soft materials was analysed by using polarised optical microscopy and scanning electron microscopy. To get information about the organisation of the gelator in the gelatinous matrix, X-ray diffraction measurements were performed both on the neat gelators and their gels. The results collected show that the properties of the gel phases, like the thermal stability, the self-repairing ability, the resistance to flow as well as the morphology, are dependent on the nature of the anion. Furthermore, bioassays revealed that the obtained diimidazolium organic salts possessed antimicrobial activity, against gram-negative and gram-positive tester strains. In particular and noteworthy, the diimidazolium organic salts exert a bactericidal capability, which was retained even if they are included in the gel phase. Thus, a novel kind of bioactive soft material was obtained that could be fruitfully employed as a non-covalent coating exerting antibacterial capability.

Unprecedented Nucleophilic Additions of Highly Polar Organometallic Compounds to Imines and Nitriles Using Water as a Non-Innocent Reaction Medium.

In contrast to classic methods carried out under inert atmospheres with dry volatile organic solvents and often low temperatures, the addition of highly polar organometallic compounds to non-activated imines and nitriles proceeds quickly, efficiently, and chemoselectively with a broad range of substrates at room temperature and under air with water as the only reaction medium. Secondary amines and tertiary carbinamines are furnished in yields of up to and over 99 %. The significant solvent D/H isotope effect observed for the on-water nucleophilic additions of organolithium compounds to imines suggests that the on-water catalysis arises from proton transfer across the organic-water interface. The strong intermolecular hydrogen bonds between water molecules may play a key role in disfavoring protonolysis, which occurs extensively in other protic media such as methanol. This work lays the foundation for reshaping many fundamental s-block metal-mediated organic transformations in water.

COX-1 Inhibitors: Beyond Structure Toward Therapy.

Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed.

Asymmetric chemoenzymatic synthesis of 1,3-diols and 2,4-disubstituted aryloxetanes by using whole cell biocatalysts.

Regio- and stereo-selective reduction of substituted 1,3-aryldiketones, investigated in the presence of different whole cell microorganisms, was found to afford ß-hydroxyketones or 1,3-diols in very good yields (up to 95%) and enantiomeric excesses (up to 96%). The enantiomerically enriched aldols, obtained with the opposite stereo-preference by baker's yeast and Lactobacillus reuteri DSM 20016 bioreduction, could then be diastereoselectively transformed into optically active syn- or anti-1,3-diols by a careful choice of the chemical reducing agent (diastereomeric ratio up to 98 : 2). The latter, in turn, were stereospecifically cyclized into the corresponding oxetanes in 43-98% yields and in up to 94% ee, thereby giving a diverse selection of stereo-defined 2,4-disubstituted aryloxetanes.

An Expeditious and Greener Synthesis of 2-Aminoimidazoles in Deep Eutectic Solvents.

A high-yield one-pot two-step synthesis of 2-aminoimidazoles (2-AI), exploiting an under-air heterocyclodehydration process between α-chloroketones and guanidine derivatives, and using deep eutectic solvents (DESs) as nonconventional, "green" and "innocent" reaction media, has been accomplished successfully. The combination of either glycerol or urea with choline chloride (ChCl) proved to be effective for decreasing the reaction time to about 4-6 h in contrast to the 10-12 h usually required for the same reaction run in toxic and volatile organic solvents and under an argon atmosphere. In addition, the use of the ChCl-urea as a DES also enables the direct isolation of triaryl-substituted 2-AI derivatives by means of a simple work-up procedure consisting in filtration and crystallization, and allows the recycle of the DES mixture. A plausible mechanism highlighting the potential role played by hydrogen bonding catalysis has also been illustrated.

Aggregation Processes of Perylene Bisimide Diimidazolium Salts.

The supramolecular aggregation of three diimidazolium-functionalized perylene bisimides, differing in the alkyl chain length was investigated. These salts form aggregates in solvents like chloroform, dichloromethane, and glycerol. Solvent-, concentration-, and temperature-dependent spectroscopic studies were carried out, evidencing the occurrence of an isodesmic, enthalpy-driven aggregation process, underpinned by π-π stacking and hydrogen bonding. Moreover, dynamic light scattering (DLS) measurements and SEM images revealed that these salts aggregate in chloroform into elongated structures.