Amino Carboxylic Acids Research Articles

Identification of N-phenyl-N-(quinolin-4-yl) amino carboxylic acids as URAT1 inhibitors with hypouricemic effects

Urate transporter 1 (URAT1) is a therapeutic target for the treatment of hyperuricemia and gout. However, the application of currently marketed URAT1 inhibitors is hampered by insufficient efficacy and poor safety profiles. A series of N-phenyl-N-(quinolin-4-yl) amino carboxylic acids were designed by adopting strategies of molecular hybridization, scaffold hopping, and functional variation. Most compounds showed apparent inhibitory activity against URAT1, and the most active compound 7 exhibited an IC50 of 0.18 μ M, which was comparable to the clinically available drug benzbromarone (IC50 = 0.39 μ M). When tested in parallel with benzbromarone, compound 7 showed significant uric acid-lowering effect in a hyperuricemia zebrafish model induced by potassium oxonate and xanthine sodium salt. Compound 7 was also more metabolically stable than benzbromarone in mouse liver microsomes. The results suggested potential therapeutic benefits of these compounds in the treatment of hyperuricemia and gout.

Natural Chiral Ligand Strategy: Metal-Catalyzed Reactions with Ligands Prepared from Amino Acids and Peptides

Amino acids and peptides are readily available biomolecules and can function as chiral ligands for transition metal catalysis. An example is the copper complex catalyzed 1,4-addition of dialkylzinc to acyclic enones, which employs peptide ligands. This review provides a dataset of amino acids and peptides reported in the literature proving to be effective ligands for metal-centered catalysts. Several parameters were highlighted, including amino acid combination, metal atoms, carboxyl and amino protecting groups, modification of natural amino acids, and the mechanism of catalysis. Along with analyzing physical-chemical properties, the SMILES representation for each amino acid and/or peptide was generated and made available online, providing an easy-to-use means of training machine learning models. This review offers an opportunity for the development of more efficient peptide ligands for enantioselective metal-centered catalysts. The available online dataset is a reliable manually curated table, it enables the benchmark for comparison of new terminal functional groups. Moreover, the review provides insight into the structures of the more successful peptide ligands and can be used as the foundation for the development of the next generation of peptide-based chiral ligands.

Insight into the interaction between amino acids and SO2: Detailed bonding modes.

Amino acids are a highly effective and environmentally friendly adsorbent for SO2. However, there has been no comprehensive study of the binding modes between amino acids and SO2 at the molecular level. In this paper, the binding modes of three amino acids (Asp, Lys, and Val) with SO2 are studied comprehensively and in detail using quantum chemical calculations. The results indicate that each amino acid has multiple binding modes: 22 for Asp, 49 for Lys, and 10 for Val. Both the amino and carboxyl groups in amino acids, as well as those in side chains, can serve as binding sites for chalcogen bonds. The binding energies range from - 6.42 to - 1.06kcal/mol for Asp, - 12.43 to - 1.63kcal/mol for Lys, and - 7.42 to - 0.60kcal/mol for Val. Chalcogen and hydrogen bonds play a crucial role in the stronger binding modes. The chalcogen bond is the strongest when interacting with an amino group, with an adiabatic force constant of 0.475 mDyn/Å. Energy decomposition analysis indicates that the interaction is primarily electrostatic attraction, with the orbital and dispersive interactions dependent on the binding mode. Amino acids and complexes of amino acids with SO2 were used to do semi-empirical MD using Molclus combined with xtb at the GFN2 level. Optimization and frequency calculations of the structures were conducted using density-functional theory (DFT) B3LYP/6-311G* (with DFT-D3 correction). Single-point energy calculations were performed for all structures using DLPNO-CCSD(T)/aug-cc-pVTZ with tightPNO. Further analysis of the structures was conducted using ESP, AIM, IGMH, and sob-EDA to gain a deeper understanding of the interactions between amino acids and SO2.

Detoxification of Mycotoxin Patulin by the Yeast Kluyveromyces marxianus YG-4 in Apple Juice.

Patulin (PAT) is a mycotoxin produced by Penicillium species, which often contaminates fruit and fruit-derived products, posing a threat to human health and food safety. This work aims to investigate the detoxification of PAT by Kluyveromyces marxianus YG-4 (K. marxianus YG-4) and its application in apple juice. The results revealed that the detoxification effect of K. marxianus YG-4 on PAT includes adsorption and degradation. The adsorption binding sites were polysaccharides, proteins, and some lipids on the cell wall of K. marxianus YG-4, and the adsorption groups were hydroxyl groups, amino acid side chains, carboxyl groups, and ester groups, which were combined through strong forces (ion interactions, electrostatic interactions, and hydrogen bonding) and not easily eluted. The degradation active substance was an intracellular enzyme, and the degradation product was desoxypatulinic acid (DPA) without cytotoxicity. K. marxianus YG-4 can also effectively adsorb and degrade PAT in apple juice. The contents of organic acids and polyphenols significantly increased after detoxification, significantly improving the quality of apple juice. The detoxification ability of K. marxianus YG-4 toward PAT would be a novel approach for the elimination of PAT contamination.

Alterations of the duodenal mucosal microbiome in patients with metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is associated with altered gut microbiota; however, there has been a focus on fecal samples, which are not representative of the entire digestive tract. Mucosal biopsies of the descending duodenum were collected. Five regions of the 16S rRNA gene were amplified and sequenced. Other assessments conducted on the study subjects included body mass index, transient elastography, liver enzymes, and lipid profile. Fifty-one subjects (36 with MASLD and 15 controls) were evaluated. There was no significant difference between the two groups regarding alpha- or beta-diversity of the duodenal mucosal microbiota. Linear discriminant analysis effect size (LEfSe) analysis showed that the genera Serratia and Aggregatibacter were more abundant in the duodenal mucosa of patients with MASLD, whereas the duodenal mucosal microbiota of the healthy controls was enriched with the genus Petrobacter. PICRUSt2 analysis revealed that genes associated with amino acid degradation and carboxylate degradation were significantly enriched in the duodenal mucosal microbiota of patients with MASLD. Our findings reveal the duodenal mucosal microbiota in patients with MASLD, which could contribute to future studies investigating the causal relationship between duodenal microbiota and MASLD.

Front Cover: Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids (Chem. Eur. J. 72/2023)

Front Cover: Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids (Chem. Eur. J. 72/2023)

Design and synthesis of fosmidomycin analogs containing aza-linkers and their biological activity evaluation.

The enzymes involved in the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway are attractive targets of a new mode of action for developing anti-infective drugs and herbicides, and inhibitors against 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC), the second key enzyme in the pathway, have been intensively investigated; however, few works are reported regarding IspC inhibitors designed for new herbicide discovery. A series of fosmidomycin (FOS) analogs were designed with nitrogen-containing linkers replacing the trimethylene linker between the two active substructures of FOS, phosphonic acid and hydroxamic acid. Synthesis followed a facile three-step route of sequential aza-Michael addition of α-amino acids to dibenzyl vinylphosphonate, amidation of the amino acid carboxyl with O-benzyl hydroxylamine, and simultaneous removal of the benzyl protective groups. Biological activity evaluation of IspC and model plants revealed that some compounds had moderate enzyme and model plant growth inhibition effects. In particular, compound 10g, which has a N-(4-fluorophenylethyl) nitrogen-containing linker, exhibited the best plant inhibition activities, superior to the control FOS against the model plants Arabidopsis thaliana, Brassica napus L., Amaranthus retroflexus and Echinochloa crus-galli. A dimethylallyl pyrophosphate rescue assay on A. thaliana confirmed that both 10g and FOS exert their herbicidal activity by blocking the MEP pathway. This result consistent with molecular docking, which confirmed 10g and FOS binding to the IspC active site in a similar way. Compound 10g has excellent herbicidal activity and represents the first herbicide lead structure of a new mode of action that targets IspC enzyme in the MEP pathway. © 2023 Society of Chemical Industry.

Evaluation of the efficiency of intersystem crossing to a triplet state of fullerene in complexes with amino acids

The important photophysical process that determines the efficiency of photosensitizers is saturation of a triplet state by intersystem crossing during light absorption. In the present work, C60 fullerene complexes with amino acids glycine, lysine, methionine and threonine were studied as promising photosensitizers. All these complexes, for which the calculations were done, demonstrate high values of rate constants of transition to triplet states and a high probability of the ability to generate reactive oxygen species through excitation in the visible spectrum. The carboxyl groups of amino acids that are not involved in electronic excitation can be used as the component of specific DNA aptamers for conjugation to photoactive complexes for a tumor-targeting drug delivery system.

Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids.

α-Aminophosphonic acids have a remarkably broad bioactivity spectrum. They can function as highly efficient transition state mimics for a variety of hydrolytic and angiotensin-converting enzymes, which makes them interesting target structures for synthetic chemists. In particular, the phosphonic acid analogs to α-aminocarboxylic acids (Pa AAs) are potent enzyme inhibitors, but many of them are only available by chiral or enzymatic resolution; sometimes only one enantiomer is accessible, and several have never been prepared in enantiopure form at all. Today, a variety of methods to access enantiopure α-aminophosphonic acids is known but none of the reported approaches can be generally applied for the synthesis of Pa AAs. Here we show that the phosphonic acid analogs of many (proteinogenic) α-amino acids become accessible by the catalytic, stereoselective asymmetric transfer hydrogenation (ATH) of α-oxo-phosphonates. The highly enantioenriched (enantiomeric excess (ee) ≥ 98 %) α-hydroxyphosphonates obtained are important pharmaceutical building blocks in themselves and could be easily converted to α-aminophosphonic acids in most studied cases. Even stereoselectively deuterated analogs became easily accessible from the same α-oxo-phosphonates using deuterated formic acid (DCO2 H).

Lipase-Catalyzed Strategies for the Preparation of Enantiomeric THIQ and THβC Derivatives: Green Aspects.

This report reviews the most important lipase-catalyzed strategies for the preparation of pharmaceutically and chemically important tetrahydroisoquinoline and tetrahydro-β-carboline enantiomers through O-acylation of the primary hydroxy group, N-acylation of the secondary amino group, and COOEt hydrolysis of the corresponding racemic compounds with simple molecular structure, which have been reported during the last decade. A brief introduction describes the importance and synthesis of tetrahydroisoquinoline and tetrahydro-β-carboline derivatives, and it formulates the objectives of this compilation. The strategies are presented in chronological order, classified according to function of the reaction type, as kinetic and dynamic kinetic resolutions, in the main text. These reactions result in the desired products with excellent ee values. The pharmacological importance of the products together with their synthesis is given in the main text. The enzymatic hydrolysis of the hydrochloride salts as racemates of the starting amino carboxylic esters furnished the desired enantiomeric amino carboxylic acids quantitatively. The enzymatic reactions, performed in tBuOMe or H2O as usable solvents, and the transformations carried out in a continuous-flow system, indicate clear advantages, including atom economy, reproducibility, safer solvents, short reaction time, rapid heating and compression vs. shaker reactions. These features are highlighted in the main text.

Acid···Amide Supramolecular Synthon for Tuning Amino Acid-Based Hydrogels' Properties.

Supramolecular hydrogels formed by the self-assembly of N-Fmoc-L-phenylalanine derivatives are gaining relevance for several applications in the materials and biomedical fields. In the challenging attempt to predict or tune their properties, we selected Fmoc-pentafluorophenylalanine (1) as a model efficient gelator, and studied its self-assembly in the presence of benzamide (2), a non-gelator able to form strong hydrogen bonding with the amino acid carboxylic group. Equimolar mixtures of 1 and 2 in organic solvents afforded a 1:1 co-crystal thanks to the formation of an acid···amide heterodimeric supramolecular synthon. The same synthon occurred in the transparent gels formed by mixing the two components in 1:1 ratio in aqueous media, as revealed by structural, spectroscopic, and thermal characterizations performed on both the co-crystal powder and the lyophilized hydrogel. These findings revealed the possibility to modulate the properties of amino acid-based hydrogels, by involving the gelator in the formation of a co-crystal. Such crystal engineering-based approach is demonstrated to be also useful for the time-delayed release of suitable bioactive molecules, when involved as hydrogel coformers.

N-Silylimine of Trifluoropyruvate in the Asymmetric Synthesis of Trifluoroalanine Derivatives

Aim. To develop a preparative method for the synthesis of N-trimethylsilylimine of trifluoropyruvate, and study its interaction with acetone under organocatalytic conditions.Results and discussion. A simple preparative approach to the first representative of N-silylimines of trifluoropyruvate was developed based on the interaction of triphenylphosphinimide and trifluoropyruvic acid methyl ester by the aza-Wittig reaction. It was found that the addition of acetone to N-silylimine occurred in the presence of L- or D-proline and led to the formation of enantiomerically enriched α-amino-γ-oxocarboxylates. The hydrolysis of the ester function resulted in (R)-α-trifluoromethyl aminocarboxylic acid, and the cyclocondensation with isocyanates or 2,5-dimethoxytetrahydrofuran yielded nitrogen-containing heterocycles containing pyrimidine or pyrrolizine nuclei.Experimental part. The synthetic procedures for the N-silylimine of trifluoropyruvate and its reaction with acetone are provided, along with the transformations of obtained α-amino-γ-oxocarboxylates (hydrolysis, cyclocondensations with isocyanates and 2,5-dimethoxytetrahydrofuran). The structures of the compounds synthesized were proven by 1H, 13C, 19F NMR spectroscopy methods, as well as by the elemental analysis.Conclusions. A convenient method for the synthesis of N-silylimine of trifluoropyruvate has been developed. Using the example of the Mannich reaction with acetone, it has been demonstrated that N-silylimine of trifluoropyruvate is a convenient substrate for the synthesis of optically active 3,3,3-trifluoroalanine derivatives.

Preparation of mixed matrix membranes by layered double hydroxides of amino acid intercalation and Pebax for ameliorated CO2 separation

CO2 capture, storage and utilization has been acknowledged as an important strategy for climate change mitigation. 2D materials have great advantages in gas separation due to their high aspect ratio and nano-sized thickness, such as LDH with tunable interlayer ions. In this work, 12-Aminododecanoic acid was incorporated as an intercalator between MgAl LDH layers and used as filler for the preparation of mixed matrix membranes (MMMs). Amino and carboxyl groups in amino acids could be used to enhance the performance of CO2 gas separation by quadrupole moment effect and increasing the layer spacing. The XRD pattern showed an increase in the layer spacing, while the characteristic peaks of amino and carboxyl groups were observed in the FTIR pattern and the initial characteristic peaks did not disappear, indicating that the amino acids were successfully intercalated into the LDH layer. The experimental results indicated that MMMs with 5 wt% 12AA-LDH achieved CO2 permeability of 92.57 Barrer and CO2/N2 selectivity of 50.8, which increasing by 125 % and 17 %, compared to pristine Pebax membranes. It could be observed that 2D materials can be used in gas separation by cross-linking and intercalation to preparing high performance separation membranes.

Recalibrating the calcium trap in amino acid carboxyl groups via classical molecular dynamics simulations.

In order to use classical molecular dynamics to complement experiments accurately, it is important to use robust descriptions of the system. The interactions between biomolecules, like aspartic and glutamic acid, and dissolved ions are often studied using standard biomolecular force-fields, where the interactions between biomolecules and cations are often not parameterized explicitly. In this study, we have employed metadynamics simulations to investigate different interactions of Ca with aspartic and glutamic acid and constructed the free energy profiles of Ca2+-carboxylate association. Starting from a generally accepted, AMBER-based force field, the association was substantially over and under-estimated, depending on the choice of water model (TIP3P and SPC/fw, respectively). To rectify this discrepancy, we have replaced the default calcium parameters. Additionally, we modified the σij value in the hetero-atomic Lennard-Jones interaction by 0.5% to further improve the interaction between Ca and carboxylate, based on comparison with the experimentally determined association constant for Ca with the carboxylate group of L-aspartic acid. The corrected description retrieved the structural properties of the ion pair in agreement with the original biomolecule - Ca2+ interaction in AMBER, whilst also producing an association constant comparable to experimental observations. This refined force field was then used to investigate the interactions between amino acids, calcium and carbonate ions during biogenic and biomimetic calcium carbonate mineralisation.

Exceptional adsorption properties of amino-carboxylic acid chelating fibers for calcium, magnesium, and strontium ions

Exceptional adsorption properties of amino-carboxylic acid chelating fibers for calcium, magnesium, and strontium ions

Friedel-Crafts Acylation of Aminocarboxylic Acids in Strong Brønsted Acid Promoted by Lewis Base P4O10.

The amino group in aminocarboxylic acids is sufficiently basic to be protonated in strong acids, and consequently, ionization of the carboxylic acid to an acylium ion is blocked due to charge-charge repulsion. Thus, acylation of aromatic compounds is significantly retarded in Friedel-Craft type reactions. We found that Friedel-Crafts acylation with aminocarboxylic acids can proceed smoothly even in a strong Brønsted acid (triflic acid, TfOH) if the Lewis base P4O10 is added. Here we describe the Friedel-Crafts acylation reactions of anthranilic acid and α- to δ-aminocarboxylic acids with benzene derivatives in the presence of P4O10. Non-amino-containing carboxylic acids as well as N-containing heteroaromatic carboxylic acids are available, and α-amino acids can be directly utilized without any protective group. Most substrates afford acylation products in high yields, although some epimerization/racemization may occur. Density functional theory (DFT) calculations suggested that P4O10 neutralizes the protonated amine, converting the N-H covalent bond to a N-hydrogen bond and allowing the carboxylic acid OH functionality to serve as a good leaving group.

Cu(II)-Catalysed Hydrocarboxylation of Imines Utilizing CO2 to Synthesize α-Unsaturated Aminocarboxylic Acids

Here, we report the Cu(II)-photocatalysed hydrocarboxylation of imines (C=N) from a series of synthesized Schiff Base derivatives, namely (E)-1-(4-((4-methylbenzylidene)amino)phenyl)ethanone, (E)-1-(3-((5-bromo-2-hydroxybenzylidene)amino)phenyl)ethanone, (E)-4-((5-bromo-2-hydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, and (E)-1,5-dimethyl-4-((4-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-one, with carbon dioxide (CO2) to generate disubstituted amino acids. Under mild conditions (atmospheric pressure of CO2, room temperature, and 30 W Blue LED light), good to excellent yields confirming the formation of substituted amino acid unsaturated acid derivatives were obtained. Single crystal X-ray diffraction (SC-XRD) and UV-Vis diffuse reflectance spectroscopy (UV-Vis-DRS) confirmed the square pyramidal geometry of the Cu(II) photocatalyst. Docking and DFT calculations of the substituted amino acid unsaturated acid derivatives showed their potential as antimicrobial molecules.

Friedel-Crafts-Type Acylation and Amidation Reactions in Strong Brønsted Acid: Taming Superelectrophiles.

In this review, we discuss Friedel-Crafts-type aromatic amidation and acylation reactions, not exhaustively, but mainly based on our research results. The electrophilic species involved are isocyanate cation and acylium cation, respectively, and both have a common +C=O structure, which can be generated from carboxylic acid functionalities in a strong Brønsted acid. Carbamates substituted with methyl salicylate can be easily ionized to the isocyanate cation upon (di)protonation of the salicylate. Carboxylic acids can be used directly as a source of acylium cations. However, aminocarboxylic acids are inert in acidic media because two positively charged sites, ammonium and acylium cation, will be generated, resulting in energetically unfavorable charge-charge repulsion. Nevertheless, the aromatic acylation of aminocarboxylic acids can be achieved by using tailored phosphoric acid esters as Lewis bases to abrogate the charge-charge repulsion. Both examples tame the superelectrophilic character.

Zwitterionic keratin coating on silk-Laponite fibrous membranes for guided bone regeneration.

Implant-related infection is one of the main challenges in periodontal diseases. According to the zwitterionic properties of keratin, we aim to develop guided bone regeneration (GBR) membrane with antibacterial and bioactivity properties using a keratin coating. In this study, electrospun silk fibroin (SF)-Laponite (LAP) fibrous membranes were developed as GBR membranes, and keratin extracted from sheep wool was electrosprayed on them. Here, the role of electrospraying time (2, 3, and 4h) on the properties of the GBR membranes was investigated. After physicochemical characterization of the keratin-modified membranes, in vitro bioactivity and degradation rate of the membranes were studied in simulated body fluid and phosphate buffer saline, respectively. Moreover, proliferation and differentiation of mesenchymal stem cells were evaluated in contact with the keratin-modified SF-LAP membrane. Finally, the antibacterial activity of membranes against gram-positive bacteria (Staphylococcus aureus) was investigated. Results demonstrated the successful formation of homogeneous wool keratin coating on SF-LAP fibrous membranes using a simple electrospray process. While wool keratin coating significantly enhanced the elongation and hydrophilicity of the SF-LAP membrane, the mechanical strength was not changed. In addition, keratin coating significantly improved the bioactivity and degradation rate of SF-LAP membranes, owing to the carboxyl groups of amino acids in keratin coating. In addition, the synergic role of LAP nanoparticles and keratin coating drastically improved osteoblast proliferation and differentiation. Finally, the zwitterionic property of wool keratin coating originating from their equal positive (NH3 + ) and negative (COO- ) charges considerably improved the antibacterial activity of the SF-LAP membrane. Overall, keratin-coated SF-LAP fibrous membranes with significant mechanical and biological properties could have the potential for GBR membranes.

Assessment of impact of a new derivative 2-(diethylamino)-N-(o-toluyl) acetamide, manifesting antiarrhythmic effect in heart rhythm disorders of peripheral origin, on cardiovascular system

Objective. To study the effect of a new derivative of arylamides of aminocarboxylic acids, which has a high antiarrhythmic activity on the state of the cardiovascular system.
 Materials and methods. To study the antiarrhythmic activity of the compound, the experiment was carried out on a model of arrhythmia caused by intravenous administration of aconitine. The effect was evaluated by its ability to prevent the occurrence of arrhythmia or to prolong the survival time of animals. In addition, an analysis of the electrocardiogram of awake rats and rabbits was carried out. The test compound and the comparison drug, lidocaine, were intravenously administered to animals in effective antiarrhythmic doses.
 Results. Diethylaminoacetic acid ortho-toluidide nitrate under conditions of aconitine arrhythmia shows a pronounced antiarrhythmic effect; under its influence, there is a statistically significant reduction in the duration of arrhythmia attacks in animals by 2.4 times compared with the control as well as protection from death. The compound does not change the parameters of electrocardiogram of animals, no statistically significant differences from the control results were found.
 Conclusions. 1. A new compound, diethylaminoacetic acid ortho-toluidide nitrate, exhibits a pronounced antiarrhythmic effect. Probably, it can be attributed to class IB antiarrhythmic drugs, since it exhibits high activity on calcium chloride and aconitine models of arrhythmia.
 2. Given that the studied compound combines high antiarrhythmic activity with no negative effect on ECG parameters, a drug based on it can be used as an effective antiarrhythmic drug.