Amino Acid Esters Research Articles

Pd-Catalyzed C(sp2)-H olefination: synthesis of N-alkylated isoindolinone scaffolds from aryl amides of amino acid esters.

Isoindolinone is a constituent of various natural products and synthetic biologically active compounds. The classical multi-step synthetic methods used to prepare various indolinone derivatives are tedious and challenging. One-pot synthetic methods are attractive and economical. Transition-metal-catalyzed C-H activation is an emerging tool for synthesizing natural products and small organic molecules via reducing the number of synthetic steps necessary. This paper describes the synthesis of N-alkyl-3-methenyl chiral isoindolinone derivatives from aryl amides of L-amino acids and non-activated alkene via Pd-catalyzed C(sp2)-H olefination. Herein, the amino acid residue acts as a directing group for olefination at the aryl ring, and then cyclization occurs at the amide NH. Hence, this methodology could be helpful to transform standard amino acids into respective chiral isoindolinone derivatives.

Chiral recognition of amino-acid esters by a glucose-derived macrocyclic receptor.

We report a glucose-based crown ether capable of chiral recognition of a wide range of amino-acid methyl esters in aqueous environments. The enantioselectivities towards amino-acids with extended hydrophobic side chains displayed by the glucose-derived macrocycle are among the highest observed for small molecule synthetic receptors to date.

Antiviral activity of glycyrrhizic acid conjugates with amino acid esters against Zika virus

Zika virus (ZIKV) is a new pathogenic flavivirus transmitted by mosquitoes Aedes spp. ZIKV infection is accompanied by serious neurological complications and is especially dangerous for pregnant women, in which it can lead to congenital malformations of the fetus and microcephaly in neonates. Currently, there are no licensed vaccines or specific post-infectious therapies for ZIKV infection. This report is devoted to the study of glycyrrhizic acid (GL) derivatives as ZIKV inhibitors. The inhibitory assays on the cytopathic effect (CPE) and viral infectivity of ZIKV in three different human cell lines revealed that the conjugation of GL with amino acids and their esters (methyl, ethyl) is influenced by the antiviral activity of the compounds. GL conjugates with Glu(OMe)-OMe 11, Glu(OH)-OMe 12, Asp(OMe)-OMe 13, TyrOMe 14, LeuOEt 15, and PheOEt 16 with free COOH groups in the triterpene moiety were active against ZIKV. The most active compounds 13 and 14 have IC50 values of 0.23 μM and 0.09 μM against low doses (MOI = 0.05) of ZIKV strain PRVABC59, 1.20 μM and 0.74 μM against high doses (MOI = 10) of ZIKV strain Natal RGN single-round infectious particles, respectively. The lead compound was 14 with a high selectivity index (SI < 500). Compound 13 showed a higher inhibitory effect on the early stage (entry) of ZIKV replication than compound 14, and was less potent than compound 14 at the post-entry stage, consistent with the docking models. Compounds 13 and 14 also had a strong interaction with the active site pocket of NS5 MTase. Compounds 13 and 14 are recommended for expanded antiviral studies against ZIKV infection.

Synthesis, spectral characterization, antimicrobial activity and docking studies against DNA Gyrase-A of new 4-chloro-3-nitrobenzene sulfonamide derivatives

A series of new 4-chloro-3-nitrobenzene sulfonamide derivatives 3(a-j) were synthesized from 4-chloro-3-nitrobenzene sulfonyl chloride by reacting various amino acid esters and amines 2(a-j) in high yields. The structures of all the synthesized compounds were characterized by the IR, NMR (1H &amp; 13C), mass and elemental analyses. Further, all the synthesized compounds were tested for the antimicrobial activity and docking studies were carried out with DNA Gyrase-A. Most of the compounds showed good to moderate antimicrobial activities and binding affinity towards DNA Gyrase-A structure.

The Proton Dissociation of Bio-Protic Ionic Liquids: [AAE]X Amino Acid Ionic Liquids.

[AAE]X composed of amino acid ester cations is a sort of typically “bio-based” protic ionic liquids (PILs). They possess potential Brønsted acidity due to the active hydrogens on their cations. The Brønsted acidity of [AAE]X PILs in green solvents (water and ethanol) at room temperature was systematically studied. Various frameworks of amino acid ester cations and four anions were investigated in this work from the viewpoint of structure–property relationship. Four different ways were used to study the acidity. Acid dissociation constants (pKa) of [AAE]X determined by the OIM (overlapping indicator method) were from 7.10 to 7.73 in water and from 8.54 to 9.05 in ethanol. The pKa values determined by the PTM (potential titration method) were from 7.12 to 7.82 in water. Their Hammett acidity function (H0) values (0.05 mol·L−1) were about 4.6 in water. In addition, the pKa values obtained by the DFT (proton-transfer reactions) were from 7.11 to 7.83 in water and from 8.54 to 9.34 in ethanol, respectively. The data revealed that the cationic structures of [AAE]X had little effect and the anions had no effect on the acidity of [AAE]X. At the same time, the OIM, PTM, Hammett method and DFT method were reliable for determining the acidic strength of [AAE]X in this study.

Ni-catalyzed asymmetric hydrogenation of N-aryl imino esters for the efficient synthesis of chiral \u03b1-aryl glycines

Chiral α-aryl glycines play a key role in the preparation of some bioactive products, however, their catalytic asymmetric synthesis is far from being satisfactory. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of N-aryl imino esters, affording chiral α-aryl glycines in high yields and enantioselectivities (up to 98% ee). The hydrogenation can be conducted on a gram scale with a substrate/catalyst ratio of up to 2000. The obtained chiral N-p-methoxyphenyl α-aryl glycine derivatives are not only directly useful chiral secondary amino acid esters but can also be easily deprotected by treatment with cerium ammonium nitrate for further transformations to several widely used molecules including drug intermediates and chiral ligands. Formation of a chiral Ni-H species in hydrogenation is detected by 1H NMR. Computational results indicate that the stereo selection is determined during the approach of the substrate to the catalyst.

Ultrasonically Assisted N-Cyanoacylation and Synthesis of Alkyl(4-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl)amino Acid Ester Derivatives.

This work represents the use of N-3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile as a cyanoacetylating agent for the synthesis of cyanoacetamide benzoic acid and benzophenone derivatives by two different methods, namely, conventional heating and ultrasonication. The cyanoacetamide derivatives were subjected to cyclization to produce N-substituted 2-pyridone derivatives under conventional heating and by an ultrasonic method as well. The ultrasonic method afforded the products in less reaction time with high yields and purities compared to the conventional method, as observed from their spectral data. N-(4-Carboxy phenyl)-4,6-dimethyl-3-cyano-2-pyridone was coupled with different amino acid esters by the OxymaPure/DIC methodology under traditional and ultrasonic conditions. Again, ultrasonication assisted the coupling step and afforded the products with higher yields and purities compared to the traditional method. Fourier transform infrared spectroscopy, NMR (1H and 13C), elemental analysis, and LC–MS were used to determine the structures of all compounds. Finally, a feature of this protocol is exploring the utilization of ultrasonication as an eco-friendly alternative conventional heating method for N-cyanoacylation and synthesis of N-substituted pyridinone derivatives and as a coupling method for the formation of an amide bond, which might be of interest for many researchers.

In Silico ADMET and Docking Studies of Thiazolidinedione-acetic-acid Hybrids as Antidiabetics with Cardioprotection

Background: Type-2-diabetes mellitus is associated with many side effects affecting vital body organs, especially heart. Thiazolidinediones are potent antidiabetics. Studies have proven that amino-acids and peptides promote glucose transport, have antioxidant properties, and fewer side effects, thus we designed hybrids by combining amino-acid esters and peptide esters with 2, 4 thiazolidinedione acetic acid moiety which can act as antidiabetic agent with cardioprotection properties. Methodology: In vitro ADME, toxicity, and docking studies were performed using Qikprop3.1.OSIRIS, PROTOX (Prediction of Rodent Oral Toxicity), and FlexX 2.1.3, respectively. Results: All the designed molecules belong to three sub-series, i.e. 2, 4-dioxothiazolidine-5-acetic acid single amino acid hybrid methyl esters, 2, 4-dioxothiazolidine-5-acetic acid dipeptide hybrid methyl esters and 2, 4-dioxothiazolidine-5-acetic acid tripeptide hybrid methyl esters. All molecules were non-toxic. SSMA2, SSMA14, SSMA49, and SSDM50 showed good docking scores in 2PRG and 2UV4, respectively. Conclusion: The selected in silico studies helped to design hybrids with less toxicity, target specificity with dual activity as potential anti-diabetic and cardioprotective agents.

A novel synthetic approach to pyran-2,4-dione scaffold production: Microwave-assisted dimerization, cyclization, and expeditious regioselective conversion into β-enamino-pyran-2,4-diones

Here, we report a novel, green, simple, low-cost, and rapid methodology for the high-yield production of pyran-2,4-dione scaffolds under microwave irradiation. Regio- and stereoselective conversions of β-diketone systems into β-enaminones were achieved using 18 primary amines and four amino acid esters. Microwave-assisted further cyclization of 3-(β-substitutedvinyl)-6-phenyl-pyran-2,4-dione into 3-benzoyl-4,7-diphenyl-2H,5H-pyrano[4,3-b]pyran-2,5-dione via reaction with ethyl benzoyl acetate.

Synthesis and Anti proliferative Activity of New N‐Pentylquinoxaline carboxamides and Their O‐Regioisomer

AbstractWe have designed a series of quinoxalinepeptidomimetic derivatives based on our previous reported scaffold in attempt to find a promising lead compound. Quinoxaline derivatives; N‐alkyl‐3‐(3‐oxo‐4‐pentyl‐3,4‐dihydro‐quinoxalin‐2‐yl)‐propanamides and methyl 2‐[3‐(3‐oxo‐4‐pentyl‐3,4‐dihydro‐quinoxalin‐2‐yl)propanamido]alkanoates and their O‐regioisomers were prepared by alkylation of the ambient nucleophile methyl 3‐(3‐oxo‐3,4‐dihydroquinoxalin‐2‐yl)propanoate with pentyl bromide to give the corresponding N‐ and O‐pentylquinoxaline ester derivatives. The N‐ and O‐pentyl‐quinoxaline ester derivatives gave the desired products by the reaction with amines and amino acid esters via azide coupling method. We have examined the anti proliferative activity of the 35 different synthesized compounds on human HCT‐116 and HEK‐293 cell lines. Out of 35 screened derivatives, 14 active compounds exhibited inhibitory action on the HCT‐116 cells with IC50 values ranging from 0.43 mM to 2.62 mM. We have also examined the impact of these active compounds on cancer cells nucleus and caspase 3 activity, we have the found that active compounds also increased in the caspase 3 activity which led to programmed cell death of cancer cells. We have also examined the impact of 35 compounds on the normal and non‐cancerous cells (HEK‐293) and we have found these active compounds did not cause any cytotoxic effect on the normal cells.

A novel use of Boc-Oxyma as reagent for tert‑butoxycarbonylation of amines and amino acid esters

Abstract A facile and suitable approach has been improved to protect different amines including sterically hindered amino acid esters using Boc-Oxyma, as their carbamates in the presence of triethylamine as a base catalyst in neat or solvent medium at room temperature. A significant advantage of this protocol is easy handling, short reaction times, simple workup process, TEA as solvent plus catalyst under mild conditions, avoid column chromatography for purification technique and excellent product yields.

Palladium-Promoted Carbon–Nitrogen Bond Cleavage in 1,3,5-Triazinane Derivatives

trans-Dichloropalladium(II) complexes with amino acid esters PdCl2L2 have been synthesized via selective hydrolytic cleavage of the nitrogen–carbon bond in 1,3,5-tris(ethoxycarbonylmethyl)- and 1,3,5-tris[(S)-1′(methoxycarbonyl)ethyl]-1,3,5-triazinane under the action of palladium(II) in methanol or in water–acetone mixture. The nucleophilic attack of water or methanol results in selective cleavage of the 1,3,5-triazinane ring in the complexes of palladium(II) with the starting triazinanes, affording the dichloropalladium(II) complexes with amino acids esters.

Effect of ketoprofen-based ionic liquids on secondary structure and thermal stability of human serum albumin

This is the first study on the interactions of ionic liquids (ILs) composed of cations amino acid esters and anion ketoprofen (KETO) with human serum albumin (HSA). The effect of the ILs on the thermal unfolding of the HSA was negligible in comparison with that of the KETO. For the IL series, the denaturating transitions tend to shift to lower temperatures by 1–3 °C. The secondary structure analyses have shown that KETO, [L-LeuOEt][KETO] and [L-ValOBu][KETO] cause folding, and HSA molecule becomes more coiled. In the presence of [L-ValOPr][KETO] and [L-ValOiPr][KETO], HSA structure although partially unfolded seemed very close to that of the native protein. In contrast, [L-ValOEt][KETO] induces the same conformational changes of HSA as ketoprofen. For the latter, we performed binding assays and we found that the affinity of the HSA to bind the IL is comparable to that for the ketoprofen. The estimated binding constants were 3.1 × 104 and 1.4 × 104 L mol−1 for ketoprofen and [L-ValOEt][KETO], respectively. This study on KETO-ILs could be a basis to the development of a new drug formulation.

Nucleophilic Aromatic Substitution of Unactivated Aryl Fluorides with Primary Aliphatic Amines by Organic Photoredox Catalysis.

In this work, a mild and transition-metal-free approach for the nucleophilic aromatic substitution (SN Ar) of unactivated fluoroarenes with primary aliphatic amines to form aromatic amines is reported. This reaction is facilitated by the formation of cationic fluoroarene radical intermediates in the presence of an acridinium-based organic photocatalyst under blue-light irradiation. Various electron-rich and electron-neutral fluoroarenes are competent electrophiles for this transformation. A wide range of primary aliphatic amines, including amino acid esters, dipeptides, and linear and branched amines are suitable nucleophiles. The synthetic utility of this protocol is demonstrated by the late-stage functionalization of several complex drug molecules.

Synthesis, biological evaluation and molecular docking studies of Combretastatin A-4 phosphoramidates as novel anticancer prodrugs

A new series of CA4P analogs (5a-g, 6a-g) has been designed and effectively synthesized via a one-pot reaction from Combretastatin A-4/Erianin, commercially available amino acid esters and phenyl dichlorophosphate. To establish new candidates with anticancer activity, the in vitro antiproliferative effect of these compounds was measured by the CCK8 method on different cancer cell lines such as human liver caricinoma (HepG2), cervical cancer (HeLa) and colorectal carcinoma (HCT-116). The structure-activity relationships between CA4P outgrowth-promoting activity and its analogs suggested that the biaryl structure linked with double bond in Part A and the steric effect at the position α-carbon atom in the amino acid ester moiety (Part B) are essential for affecting the in vitro proliferation inhibitory activity of CA4P analogs. Additionally, the results of biological activity and molecular docking simulation showed that the vast majority of these novel Phosphoramidate derivatives exhibited potent anti-cancer activities.

Synthesis of Fluorinated Quaternary α-Amino Acid Esters

Key words amino acid esters - fluorinated amino acids - aza-Friedel–Crafts alkylation - silver catalysis

Modulation of the binding affinity of naproxen to bovine serum albumin by conversion of the drug into amino acid ester salts

Naproxen (NAP) is one of the most widely prescribed non-steroidal anti-inflammatory drugs. Novel formulations of NAP aiming at better water-solubility, dosage, and the onset of action or new routes of application in order to minimize or prevent side effects of NAP are in the current interest of the pharmaceutical industry. Here, we report the synthesis, chemical, spectral and physicochemical characterization of a series of salts containing cations amino acid alkyl esters (AAE) and NAP anion, which potentially can be used as novel drug formulation. The [l-AAE][NAP] were obtained in three steps: preparation of the AAE hydrochlorides, neutralization of the hydrochlorides to the corresponding AAE, and formation of the target organic salts. All NAP derivatives, tested at a concentration as high as 100 μM, exhibited no toxicity against murine macrophage cell line (RAW 264.7). The binding parameters and stoichiometry of [AAE][NAP]s to bovine serum albumin (BSA) are in the range of that estimated for the parent NAP. Only l-valine isopropyl ester naproxenate characterizes with about one order of magnitude lower binding affinity for BSA, which suggests a faster diffusion rate in the circulatory system than the parent NAP and other derivatives, and therefore faster reach to the target system. Using molecular modeling seven binding pockets of BSA were probed for their suitability to binds the cation and the anion and results are discussed in correlation with the obtained thermodynamic parameters for the binding of NAP derivatives to BSA.

Ionic liquids derived from α-amino acid ester salts as potent green corrosion inhibitors for mild steel in 1M HCl

In 1 M HCl solution, three selected amino acid ester salt based ionic liquids ([AAE][Sac] ILs), namely L-Phenyl Alanine methyl ester saccharinate ([PheME][Sac]), L-Leucine methyl ester saccharinate ([LeuME][Sac]), and L-Alanine methyl ester saccharinate ([AlaME][Sac]) under static conditions were examined as potent green corrosion inhibitors for mild steel by means of electrochemical measurements, weight loss, FT-IR spectroscopy, contact angle measurement, UV–vis spectroscopy, SEM/EDAX study, quantum chemical calculations and Monte Carlo (MC) simulation studies. 1H NMR, and FTIR spectroscopy has confirmed the structure of obtained ILs. The investigations were done in the temperature range of 303–353 K. [AAE][Sac] ILs are assessed as an efficient steel corrosion inhibitors in 1 M HCl up to 333 K but have less inhibiting properties above 333 K i.e., 343 and 353 K. Among the [AAE][Sac] ILs analysed, [PheME][Sac] showed the greatest inhibition efficiency and obey the order as: [PheME][Sac] > [LeuME][Sac] > [AlaME][Sac]. Polarization measurements showed all the [AAE][Sac] ILs tested to be mixed-type inhibitors. The adsorption of the examined [AAE][Sac] ILs obeyed the Langmuir adsorption isotherm perfectly. The theoretical descriptors provided by quantum chemical calculations and advanced MC simulation also reinforced the experimental conclusions adequately.

Reductive Alkylation of Amines with Carboxylic Ortho Esters

AbstractWe have demonstrated for the first time that carboxylic ortho esters could be used as an alkylating agent in the reductive alkylation of amines. A variety of amines, including amino acid esters, were alkylated affording mono‐alkylated products with high selectivity in practical to high yields using standard heterogeneous catalysts. By applying acyclic ortho esters alkylation was completed at room temperature.magnified image

Production of L-alanyl-L-glutamine by immobilized Escherichia coli expressing amino acid ester acyltransferase.

Production of Ala-Gln by the E. coli expressing α-amino acid ester acyltransferase was a promising technical route due to its high enzyme activity, but the continuous production ability still needs to improve. Therefore, the immobilized E. coli expressing α-amino acid ester acyltransferase was applied for the continuous production of Ala-Gln. Four materials were selected as embedding medium for the whole cell entrapment of recombinant bacteria. Calcium alginate beads were found to be the most proper entrapment carrier for production of Ala-Gln. The temperature, pH, and repeatability of the immobilized cell were compared with free cells. Results showed that immobilization cell could maintain a wider range of temperature/pH and better stability than free cell (20-35°C/pH8.0-9.0, and 25°C/pH8.5, respectively). On this basis, continuous production strategy was put forward by filling the immobilized cell in the tubular reactor with multiple control conditions. The Ala-Gln by immobilization cell achieved the productivity of 2.79mg/(min*mL-CV) without intermittent time. Consequently, these findings suggest that the immobilization technique has potential applications in the production of Ala-Gln by biotechnological method. KEY POINTS: • Immobilization helps to achieve high efficiency production of Ala-Gln. • Immobilized cells have better stability than free cells. • Sodium alginate is the most suitable immobilized material.