Unraveling the Source of Self-Induced Diastereomeric Anisochronism in Chiral Dipeptides.

Mastering of analytical methods for accurate quantitative determinations of enantiomeric excess is a crucial aspect in asymmetric catalysis, chiral synthesis, and pharmaceutical applications. In this context, the phenomenon of Self-Induced Diastereomeric Anisochronism (SIDA) can be exploited in NMR spectroscopy for accurate determinations of enantiomeric composition, without using a chiral auxiliary that could interfere with the spectroscopic investigation. This phenomenon can be particularly useful for improving the quantitative analysis of mixtures with low enantiomeric excesses, where direct integration of signals can be tricky.

A Squaramide-Based Organocatalyst as a Novel Versatile Chiral Solvating Agent for Carboxylic Acids.

A squaramide-based organocatalyst for asymmetric Michael reactions has been tested as a chiral solvating agent (CSA) for 26 carboxylic acids and camphorsulfonic acid, encompassing amino acid derivatives, mandelic acid, as well as some of its analogs, propionic acids like profens (ketoprofen and ibuprofen), butanoic acids and others. In many cases remarkably high enantiodifferentiations at H, C and F nuclei were observed. The interaction likely involves a proton transfer from the acidic substrates to the tertiary amine sites of the organocatalyst, thus allowing for pre-solubilization of the organocatalyst (when a chloroform solution of the substrate is employed) or the simultaneous solubilization of both the catalyst and the substrate.

A Thiourea Derivative of 2-[(1)-1-Aminoethyl]phenol as a Chiral Sensor for the Determination of the Absolute Configuration of -3,5-Dinitrobenzoyl Derivatives of Amino Acids.

In the exploration of chiral solvating agents (CSAs) for nuclear magnetic resonance (NMR) spectroscopy designed for the chiral analysis of amino acid derivatives, notable advancements have been made with thiourea-CSAs. , derived from 2-[(1)-1-aminoethyl]phenol and benzoyl isothiocyanate, is effective in the enantiodifferentiation of -3,5-dinitrobenzoyl (-DNB) amino acids. In order to broaden the application of for configurational assignment, enantiomerically enriched -DNB amino acids were analyzed via NMR.

Isohexide-Based Tunable Chiral Platforms as Amide- and Thiourea-Chiral Solvating Agents for the NMR Enantiodiscrimination of Derivatized Amino Acids.

New arylamide- and arylthiourea-based chiral solvating agents (CSAs) were synthesized starting from commercially available isomannide and isosorbide. The two natural isohexides were transformed into the three amino derivatives, having isomannide, isosorbide, and isoidide stereochemistry, then the amino groups were derivatized with 3,5-dimethoxybenzoyl chloride or 3,5-bis(trifluoromethyl)phenyl isothiocyanate to obtain the CSAs. Bis-thiourea derivative containing the 3,5-bis(trifluoromethyl)phenyl moiety with exo-exo stereochemistry was remarkably efficient in the differentiation of NMR signals (NH and acetyl) of enantiomers of -acetyl (-Ac) amino acids in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO).

Chiral distinction between hydroxychloroquine enantiomers in binding to angiotensin-converting enzyme 2, the forward receptor of SARS-CoV-2.

Soon after the outset of the Coronavirus Disease 2019 (COVID-19) pandemic (March-April 2020), formulations of the old antimalarial racemic drug hydroxychloroquine (HCQ) sulfate were authorized by the U.S. Food and Drug Administration (FDA) for emergency treatment of hospitalized patients with COVID-19.

The Phenomenon of Self-Induced Diastereomeric Anisochrony and Its Implications in NMR Spectroscopy.

Nuclear magnetic resonance (NMR) spectroscopy is an analytical technique largely applied in the analysis of discrimination processes involving enantiomeric substrates and chiral agents, which can interact with the analyte either via covalent bonding or via formation of diastereomeric solvates. However, enantiodiscrimination has been observed, in some cases, even in the absence of any additional chiral selector. The reasons behind this phenomenon must be found in the capability of some chiral substrates to interact with themselves by forming diastereomeric solvates in solution that can generate nonequivalences in the NMR spectra of enantiomerically enriched mixtures.

Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics.

Silylated-acetylated cyclodextrin (CD) derivatives have recently been investigated, via nuclear magnetic resonance (NMR) spectroscopy, as chiral sensors for substrates that are endowed and devoid of fluorine atoms, and the importance of Si-F interaction in the discrimination phenomena has been assessed. Here, the contributions of both superficial interactions and inclusion processes were further evaluated by extending the records to other chiral fluorinated substrates of interest for pharmaceutical applications. Non-equivalences were measured for both the H and F resonances in equimolar mixtures with the CDs; the promising results also supported the use of chiral sensors in -stoichiometric amounts.

Physicochemical characterization of green sodium oleate-based formulations. Part 3. Molecular and collective dynamics in rodlike and wormlike micelles by proton nuclear magnetic resonance relaxation.

Hypothesis: Sodium oleate (NaOL) self-aggregates in water forming rodlike micelles with different length depending on NaOL concentration; when KCl is added wormlike micelles form, which entangle giving rise to a viscoelastic dispersion. It is expected that aggregates with different size and shape exhibit different internal and overall molecular motions and collective dynamics.

Experiments: Two low viscosity NaOL/water and two viscoelastic NaOL/KCl/water formulations with different NaOL concentration (0.

A Unique and Stable Polyproline I Helix Sorted out from Conformational Equilibrium by Solvent Polarity.

Polyproline I helical structures are often considered as the hidden face of their most famous geminal sibling, Polyproline II, as PPI is generally spotted only within a conformational equilibrium. We designed and synthesized a stable Polyproline I structure exploiting the striking tendency of ()-indoline-2-carboxylic acid to drive the peptide bond conformation toward the amide isomer, when dissolved in polar solvents. The cooperative effect of only four amino acidic units is sufficient to form a preferential structure in solution.

NMR Investigation of the Interaction of Three Non-Steroidal Anti-Inflammatory Drugs with Human Serum Albumin.

The understanding of the interaction between non-steroidal anti-inflammatory drugs and human serum albumin plays a fundamental role in the development of new drugs and new therapeutic strategies. Several studies have been performed, nevertheless, the interaction phenomena are still not fully understood. In this work, high-field solution Nuclear Magnetic Resonance (NMR) spectroscopy was applied to compare the strength of the interaction of diclofenac sodium salt, ketorolac tris salt and flurbiprofen sodium salt toward albumin.

Renewable Resources for Enantiodiscrimination: Chiral Solvating Agents for NMR Spectroscopy from Isomannide and Isosorbide.

A new family of chiral selectors was synthesized in a single synthetic step with yields up to 84% starting from isomannide and isosorbide. Mono- or disubstituted carbamate derivatives were obtained by reacting the isohexides with electron-donating arylisocyanate (3,5-dimethylphenyl- or 3,5-dimethoxyphenyl-) and electron-withdrawing arylisocyanate (3,5-bis(trifluoromethyl)phenyl-) groups to test opposite electronic effects on enantiodifferentiation. Deeper chiral pockets and derivatives with more acidic protons were obtained by derivatization with 1-naphthylisocyanate and -toluenesulfonylisocyanate, respectively.

Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of -Acetyl and -Trifluoroacetyl Amino Acid Derivatives.

A C2-symmetrical bis-thiourea chiral solvating agent (CSA), , for NMR spectroscopy has been obtained by reacting (1,2)-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3,5-bis(trifluoromethyl)phenyl isothiocyanate. shows remarkable propensity to enantiodiscriminate -trifluoroacetyl (-TFA) and -acetyl (-Ac) derivatives of amino acids with free carboxyl functions, with the co-presence of 1,4-diazabicyclo[2.2.

Thiolated 2-Methyl-β-Cyclodextrin as a Mucoadhesive Excipient for Poorly Soluble Drugs: Synthesis and Characterization.

Thiolated cyclodextrins are structurally simple mucoadhesive macromolecules, which are able to host drugs and increase their apparent water solubility, as well as interact with the mucus layer prolonging drug residence time on the site of absorption. The aim of this study was to synthesize through green microwave-assisted process a freely soluble thiolated 2-methyl-β-cyclodextrin (MβCD-SH). Its inclusion complex properties with dexamethasone (Dex), a poor water soluble drug, and mucoadhesive characteristics were also determined.

Quinine as a highly responsive chiral sensor for the H and F NMR enantiodiscrimination of -trifluoroacetyl amino acids with free carboxyl functions.

Hydrogen-bond accepting and enantiodiscriminating abilities of quinine (Qui) have been exploited in the enantiodiscrimination of -trifluoroacetyl (TFA) derivatives of amino acids by nuclear magnetic resonance (NMR) spectroscopy. H and F NMR resonances of derivatives of alanine, valine, leucine, norvaline, phenylalanine, phenylglycine, methionine, glutamic acid, proline, and tryptophan were well differentiated employing CDCl and/or CD as solvent, with Qui acting in some cases not only as enantiodiscriminating agent, but also as solubility promoter. For derivatives soluble in both solvents, the best results were obtained in benzene-d6, with very high nonequivalence values, which were detectable not only starting from very low equimolar concentrations of 0.

Hydrolysis and Enantiodiscrimination of ()- and ()-Oxazepam Hemisuccinate by Methylated β-Cyclodextrins: An NMR Investigation.

Partially and exhaustively methylated β-cyclodextrins [(2-methyl)-β-CD (MCD), heptakis-(2,6-di--methyl)-β-CD (DIMEB), and heptakis-(2,3,6-tri--methyl)-β-CD (TRIMEB)] have been compared in the hydrolysis and enantiodiscrimination of benzodiazepine derivative ()- or ()-oxazepam hemisuccinate (OXEMIS), using nuclear magnetic resonance (NMR) spectroscopy as an investigation tool. After 6 h, MCD induced an 11% hydrolysis of OXEMIS, remarkably lower in comparison with underivatized β-CD (48%), whereas no hydrolysis was detected in the presence of DIMEB or TRIMEB after 24 h. DIMEB showed greater ability to differentiate OXEMIS enantiomers in comparison to TRIMEB, by contrast MCD did not produce any splitting of racemic OXEMIS resonances.

A Proline Mimetic for the Design of New Stable Secondary Structures: Solvent-Dependent Amide Bond Isomerization of ()-Indoline-2-carboxylic Acid Derivatives.

A thorough experimental and computational study on the conformational properties of ()-indoline-2-carboxylic acid derivatives has been conducted. Methyl ()-1-acetylindoline-2-carboxylate, both a mimetic of proline and phenylalanine, shows a remarkable tendency toward the amide isomer when dissolved in polar solvents. This behavior is opposite to the general preference of proline for the isomer, making indoline-2-carboxylic acid a good candidate for the design of different secondary structures and new materials.

A Dimeric Thiourea CSA for the Enantiodiscrimination of Amino Acid Derivatives by NMR Spectroscopy.

The reaction of benzoyl isothiocyanate with (1,2)-1,2-bis(2-hydroxyphenyl)ethylenediamine afforded a new thiourea chiral solvating agent (CSA) with a very high ability to differentiate H and C NMR signals of simple amino acid derivatives, even at low concentrations. The enantiodiscrimination efficiency was higher with respect to that of the parent monomer, a thiourea derivative of 2-((1)-1-aminoethyl)phenol, thus putting into light the relevance of the cooperativity between the two molecular portions of the dimer in a cleft conformation stabilized by interchain hydrogen bond interactions. An achiral base additive (DABCO or DMAP) played an active role in the chiral discrimination processes, mediating the interaction between the CSA and the enantiomeric mixtures.

Lopinavir/ritonavir, a new galenic oral formulation from commercial solid form, fine-tuned by nuclear magnetic resonance spectroscopy.

Objectives: The lopinavir/ritonavir combination is one of the first antiretroviral drugs to be used in the treatment of COVID-19. In incapacitated patients, such as those in intensive care, an oral liquid formulation is needed. In Italy a marketed formulation is available, but only by importing it from other European countries.

2-Methyl-β-cyclodextrin grafted ammonium chitosan: synergistic effects of cyclodextrin host and polymer backbone in the interaction with amphiphilic prednisolone phosphate salt as revealed by NMR spectroscopy.

Reduced molecular weight chitosan was quaternized with 2-chloro-N,N-diethylethylamine to obtain a water soluble derivative (N-rCh). Methylated-β-cyclodextrin (MCD), with 0.5 molar substitution, was covalently linked to N-rCh through 1,6-hexamethylene diisocyanate spacer to give the derivatized ammonium chitosan N-rCh-MCD.

Thiourea Derivative of 2-[(1)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy.

Thiourea derivatives of 2-[(1)-1-aminoethyl]phenol, (1,2)-1-amino-2,3-dihydro-1-inden-2-ol, (1,2)-(1,2)-1-amino-2,3-dihydro-1-inden-2-ol, and ()-1-phenylethanamine have been compared as chiral solvating agents (CSAs) for the enantiodiscrimination of derivatized amino acids using nuclear magnetic resonance (NMR) spectroscopy. Thiourea derivative, prepared by reacting 2-[(1)-1-aminoethyl]phenol with benzoyl isothiocyanate, constitutes an effective CSA for the enantiodiscrimination of 3,5-dinitrobenzoyl (DNB) derivatives of amino acids with free or derivatized carboxyl functions. A base additive 1,4-diazabicyclo[2.

Improvement of Peptide Affinity and Stability by Complexing to Cyclodextrin-Grafted Ammonium Chitosan.

Cyclodextrin-grafted polymers are attractive biomaterials that could bring together the host-guest complexing capability of pristine cyclodextrin and the pharmaceutical features of the polymeric backbone. The present paper is aimed at characterizing the potential application of ammonium-chitosan grafted with 2-methyl-β-cyclodextrin (N-rCh-MCD) as the functional macromolecular complexing agent for the oral administration of the neuropeptide dalargin (DAL). Specific NMR characterization procedures, along with UV and fluorescence techniques, as well as biological in vitro assessments have been performed.

Chiral mono- and dicarbamates derived from ethyl ()-lactate: convenient chiral solvating agents for the direct and efficient enantiodiscrimination of amino acid derivatives by H NMR spectroscopy.

New chiral solvating agents (CSAs) for NMR spectroscopy have been obtained from ethyl ()-lactate, a very cheap commercially available product. By a sequence of simple chemical modifications of its functional groups, monocarbamoylated and dicarbamoylated derivatives were obtained, the potentialities of which as CSAs for NMR spectroscopy have been explored. Their ability to differentiate the resonances of enantiomeric mixtures of amino acids bearing a 3,5-dinitrobenzoyl moiety at the amino group and with the carboxyl function derivatized as methyl ester or amide has been probed.

Binding and mucoadhesion of sulfurated derivatives of quaternary ammonium-chitosans and their nanoaggregates: An NMR investigation.

The effect of insertion of SH and S-protected groups on the binding and mucoadhesion properties of quaternary ammonium-chitosans and their nanoparticulate forms has been investigated by NMR spectroscopy. Diclofenac sodium salt has been assumed as low molecular weight probe to detect the different binding behaviour of polymeric materials; mucin from bovine submaxillary glands was selected as the model protein for differentiating their mucoadhesion. NMR proton selective relaxation rates of the probe molecule were remarkably sensitive to the presence of very low amounts of sulfurated moieties.

Mechanistic insight into the formation of colloidal WS nanoflakes in hot alkylamine media.

Developing convenient and reliable synthetic methodologies for solution processable 2D layered ultrathin nanostructures with lateral size control is one of the major challenges for practical applications. In this study, a rational understanding a long-chain amphiphilic surfactant assisted non-hydrolytic synthesis that is able to generate dimension-controllable 2D-WS nanocrystal flakes in a single-step protocol is proposed. The evolution of the starting soft organic-inorganic lamellar template into ultrathin few-layer 2D-WS nanostructures with lateral size modulation over a range between 3 and 30 nm is monitored.