Amino Acid Alkyl Esters Research Articles

Comprehensive evaluation of ibuprofenate amino acid isopropyl esters: insights into antioxidant activity, cytocompatibility, and cyclooxygenase inhibitory potential

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain relief and inflammation management, but there are challenges related to poor solubility and bioavailability. We explored modifications of ibuprofen (IBU) by forming ionic pairs using amino acid alkyl esters to enhance solubility without compromising the ability to inhibit cyclooxygenase (COX)-1 and COX-2). We comprehensively evaluated the pharmacological properties of the IBU derivatives, focusing on antioxidant activity (based on the ability to scavenge DPPH and ABTS), biocompatibility (using human dermal fibroblasts), and COX inhibitory potential. The antioxidant activity assays significantly enhanced DPPH scavenging activity for several IBU derivatives, particularly [l-SerOiPr][IBU], suggesting potential therapeutic benefits. There was enhanced cell viability with select derivatives, indicating possible stimulatory effects on cellular proliferation. Finally, predominant COX-1 inhibition across derivatives was consistent with IBU’s profile. This study provides insights into the pharmacological properties of IBU amino acid derivatives, highlighting their potential as therapeutic agents. Further exploration into structure–activity relationships and in vivo efficacy warranted to advance these derivatives toward clinical applications, offering prospects for novel NSAIDs with enhanced efficacy and reduced side effects.

Increase of ibuprofen penetration through the skin by forming ion pairs with amino acid alkyl esters and exposure to the electromagnetic field

A method of increasing the permeability of ibuprofen through the skin using a rotating magnetic field (RMF) is presented. This study evaluated whether 50 Hz RMF modifies ibuprofen’s permeability through the skin. Ibuprofen and its structural modifications in the form of ibuprofenates of isopropyl esters of L-amino acids such as L-valine, L-phenylalanine, L-proline, and L-aspartic acid were used in the research. To this end, Franz cells with skin as membrane were exposed to 50 Hz RMF with 5% ibuprofen and its derivatives in an ethanol solution for 48 h. Following the exposures, the amount of penetrated compound was analysed. Regardless of the compound tested, a significant increase in drug transport through the skin was observed. The differences in the first 30 min of permeation are particularly noticeable. Furthermore, it was shown that using RMF increases the permeability of ibuprofen from 4 to 244 times compared to the test without the RMF. The greatest differences were observed for unmodified ibuprofen. However, it is noteworthy that the largest amounts of the active substance were obtained with selected modifications and exposure to RMF. The RMF may be an innovative and interesting technology that increases the penetration of anti-inflammatory and anti-ache drugs through the skin.

Binding behavior of ibuprofen-based ionic liquids with bovine serum albumin: Thermodynamic and molecular modeling studies

• Nine ibuprofen-based ionic liquids containing cations amino acid alkyl esters [AAOR] were synthesized and characterized. • The [AAOR][Ibu] are not toxic against mouse fibroblasts and keratinocytes. • Ibu-ILs bind spontaneously to bovine serum albumin with moderate affinities (Ka 1–3.7 × 10 5 L/mol) at 25 °C. • Depending on their structures, [AAOR] showed differences at the preferred binding site of bovine serum albumin. Ionic liquids based on active-pharmaceutical ingredients are an attractive alternative to classical drugs because they are able to overcome problems with drug solubility and polymorphism, hence bioavailability and as well as to propose different routes of administration and/or improve the pharmacokinetics of the drug. In this manuscript, we report the synthesis of nine amino acid alkyl esters of ibuprofen [AAOR][Ibu]. The estimated half-maximum inhibitory constants toward murine embryotic fibroblasts and human dermal keratinocytes are in the millimolar range, which makes them practically not toxic. The conversion of ibuprofen into ionic liquids does not affect the binding affinity of ibuprofen to bovine serum albumin (BSA). Molecular modeling studies have shown that bulky cations such as L-PheOEt and L-PheOPr are able to bind effectively in three different BSA binding sites. On the other hand, smaller cations preferably bind to Sudhow’s site I, the same that binds ibuprofen.

Salicylic Acid as Ionic Liquid Formulation May Have Enhanced Potency to Treat Some Chronic Skin Diseases.

In recent years, numerous studies have shown that conversion of conventional drugs in ionic liquid (IL) formulation could be a successful strategy to improve their physicochemical properties or suggest a new route of administration. We report the synthesis and detailed characterization of eight salicylic acid-based ILs (SA-ILs) containing cation non-polar or aromatic amino acid esters. Using in vitro assays, we preliminary evaluated the therapeutic potency of the novel SA-ILs. We observed that conversion of the SA into ionic liquids led to a decrease in its cytotoxicity toward NIH/3T3 murine embryo fibroblasts and human HaCaT keratinocytes. It should be mentioned is that all amino acid alkyl ester salicylates [AAOR][SA] inhibit the production of the proinflammatory cytokine IL-6 in LPS-stimulated keratinocytes. Moreover, keratinocytes, pretreated with [PheOMe][SA] and [PheOPr][SA] seem to be protected from LPS-induced inflammation. Finally, the novel compounds exhibit a similar binding affinity to bovine serum albumin (BSA) as the parent SA, suggesting a similar pharmacokinetic profile. These preliminary results indicate that SA-ILs, especially those with [PheOMe], [PheOPr], and [ValOiPr] cation, have the potential to be further investigated as novel topical agents for chronic skin diseases such as psoriasis and acne vulgaris.

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.

Synthesis of peptides with narrow molecular weight distributions via exopeptidase-catalyzed aminolysis of hydrophobic amino-acid alkyl esters

This is the first report on exopeptidase-catalyzed oligopeptide synthesis. Oligo(l-leucine) was synthesized using the exopeptidase carboxypeptidase Y while preventing enzymatic hydrolysis. A high yield of the polypeptide with a narrow polydispersity was successfully obtained by limiting polypeptide cleavage during aminolysis.

ChemInform Abstract: Divergent Reactivity of Amino Acid Alkyl Ester Hydrochlorides with 2‐Oxoaldehydes: Role of Selenium Dioxide to Promote Regioselective Synthesis of Imidazoles.

Novel amino acid substituted imidazoles engendered from amino acid alkyl ester hydrochlorides and 2-oxoaldehydes as a result of selenium dioxide promoted unconventional reaction in a basic environment is presented for the first time. Despite the nature of the 2-oxoaldehydes/amino acids used, the imidazoles generated had a functional core structure, and all of the reactions meticulously retained regioselectivity. The imperative feature of these reactions was the uniqueness of selenium dioxide in fixing two nitrogen atoms from amino acids through an in situ generated ArCOCHN1N2 system.

Divergent Reactivity of Amino Acid Alkyl Ester Hydrochlorides with 2-Oxoaldehydes: Role of Selenium Dioxide To Promote Regioselective Synthesis of Imidazoles.

Novel amino acid substituted imidazoles engendered from amino acid alkyl ester hydrochlorides and 2-oxoaldehydes as a result of selenium dioxide promoted unconventional reaction in a basic environment is presented for the first time. Despite the nature of the 2-oxoaldehydes/amino acids used, the imidazoles generated had a functional core structure, and all of the reactions meticulously retained regioselectivity. The imperative feature of these reactions was the uniqueness of selenium dioxide in fixing two nitrogen atoms from amino acids through an in situ generated ArCOCHN1N2 system.

Synthesis, Structures, and Conformations of Linked Bis-Glyoxylamides Derived from Bis-Acylisatins

A series of bis-glyoxylamides possessing hydrophobic alkyl chains was successfully synthesised by ring opening of bis-acylisatins with amines or amino acid alkyl esters. The crystal structures revealed the interplay of intra- and intermolecular interactions (NH···O and C=O···C=O interactions) and the conformations of these long molecules.

A Study of Aminoacid Esterification with Nonanol

An effective procedure for the synthesis of long-chain alkyl esters of aminoacids is described. The procedure was studied for the practical synthesis of methionine nonylate, using tosyl chloride to generate in situ intermediate tosylates of aminoacids.

Toward the Synthesis of Benzothiazolyl Fluoroaminosulfones

Due to the importance of allylamines in organic synthesis, the synthesis of reagents as potent precursors of aminofluoroolefins is reported from functionalized benzothiazolylsulfones. The key intermediate, a fluorovinyl sulfone, was prepared and functionalized by addition of aliphatic, aromatic amines and amino acid alkyl esters through an aza-Michael addition reaction.

Synthesis and Bioactivity of Some New 2‐(Alkoxy carbonyl alkyl)‐6‐bromo‐3,4‐dihydro‐3‐(α‐methyl benzyl)‐2‐oxo‐benzo[e] [2H‐1,3,2‐oxazaphosphinine] Derivatives

AbstractSynthesis of some new 2‐(alkoxy carbonyl alkyl)‐6‐bromo‐3,4‐dihydro‐3‐(α‐methyl benzyl)‐2‐oxo‐3‐benzo‐ [e][2H‐1,3,2‐oxazaphosphinine] derivatives was accomplished through a two step process, which involves the condensation of 2‐[(α‐methylbenzyl amino)methyl]‐4‐bromophenol (1) with phosphorus oxychloride in equimolar quantities in the presence of triethylamine in dry toluene in 50–55 °C producing the corresponding intermediate (2), and subsequent reaction with the amino acid alkyl ester in dry tetrahydrofuran in the presence of triethylamine at different temperatures. They exhibited significant antibacterial and fungal activity.

A highly enantioselective aminopeptidase from sunflower seed—Kinetic studies, substrate mapping and application to biocatalytic transformations

The sunflower seed ( Helianthus annuus L.) major aminopeptidase primary specificity has been assessed with a number of specially designed amino acid amides and alkyl esters. Studies with amino acid 4-nitroanilides with straight alkyl side chains suggest the enzyme possesses an S 1 hydrophobic binding site of limited size and effects of substrate sorption are present in both its binding and turnover. The enzyme S 1′-subsite is able to accommodate a number of different leaving groups—primary amide, one- and two-ring condensed aromatic structures, amino acid residues and alkyl ester moieties. The hydrolysis of amide substrates is affected by both their P 1 and the P 1′ part. The replacement of the amide leaving group with an ester one tents to minimize the P 1-part effect. The enzyme's high enantioselectivity towards the configuration of the substrate P 1-part has been successfully utilized for resolution of racemic amino acid amides.

De novo synthesis of trideuteromethyl esters of amino acids for use in GC–MS and GC-tandem MS exemplified for ADMA in human plasma and urine: Standardization, validation, comparison and proof of evidence for their aptitude as internal standards

Asymmetric dimethylarginine (ADMA, N G, N G-dimethyl- l-arginine) is an endogenous inhibitor of nitric oxide (NO) synthesis, a potential risk factor for cardiovascular diseases and a powerful biochemical parameter in clinical studies. In our previous work we have reported on a GC-tandem MS method for the accurate and precise quantification of ADMA in biological fluids using de novo synthesized [ 2H 3]-methyl ester ADMA (d 3Me-ADMA) as internal standard (IS). This method provides basal ADMA concentrations in biological fluids that agree with those obtained by other groups using other validated methods for ADMA. Unanimously, de novo synthesized stable-isotope labeled analogues are considered not ideal IS, because they must be prepared in a matrix different from the biological sample. Recently, [2,3,3,4,4,5,5- 2H 7]-ADMA (d 7-ADMA) has become commercially available and we took this opportunity to test the reliability of the de novo synthesized d 3Me-ADMA as an IS for ADMA in GC-tandem MS. In this article, we report on the re-validation of the previously reported GC-tandem MS method for ADMA in human plasma and urine using d 7-ADMA as IS, and on comparative quantitative analyses of ADMA by GC-tandem MS using d 7-ADMA and d 3Me-ADMA. After thorough standardization of d 7-ADMA and methods validation, we obtained by GC-tandem MS very similar ADMA concentrations in plasma and urine using d 7-ADMA and d 3Me-ADMA. The present study gives a proof of evidence for the aptitude of 2H 3-ADMA as IS in GC-tandem MS and suggests that de novo synthesis of stable-isotope labeled alkyl esters of amino acids and amino acid derivates may be a generally applicable method in mass spectrometry-based methods for amino acids. This approach is especially useful for amino acids for which no stable-isotope labeled analogues are commercially available.

Mild Regeneration of the Carboxylic Group of Amino Acid Alkyl Esters by Aqueous Methanolic Sodium Hydrogen Carbonate via 5‐Oxazolidinones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Mild regeneration of the carboxylic group of amino acid alkyl esters by aqueous methanolic sodium hydrogen carbonate via 5-oxazolidinones

A simple racemization-free procedure allows the regeneration of the carboxylic acid group of amino acid alkyl esters by way of an intermediate 5-oxazolidinone which is hydrolyzed by treatment with sodium hydrogen carbonate in aqueous methanol.

Supported liquid membrane separation of amine and amino acid derivatives with chiral esters of phosphoric acids as carriers

Studies on the possible use of phosphate and phosphonate esters bearing chiral menthol or nopol moieties as carriers for the transport of amines, amino acids, and amino acid esters through supported liquid membranes (SLM) are presented. Additionally, the enantioselectivity of the SLM transport of alkyl esters of aromatic amino acids and a non-protein amino acid was also evaluated. It could be concluded that the extent of transport strongly depends on the hydrophobicity of the amino compound. Moreover, the carrier structure also influences the transport of those compounds through SLM: chiral phosphate and phosphonate esters appear to be poor or moderate carriers for enantioselective SLM transport of amino acids and their esters. The transport efficiency and selectivity is strongly dependent on the structure of both the transported compounds and the carrier. However, no meaningful relationship exists between these structural features and transportation or enantioselectivity.

Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine.

Glycyrrhizic Acid (GL) is the major bioactive triterpene glycoside of licorice root (Glycyrrhiza Radix) extracts possessing a wide range of pharmacological properties (anti-inflammatory, anti-ulcer, anti-allergic, anti-dote, anti-oxidant, anti-tumor, anti-viral etc.). Official sources of GL are Glycyrrhiza glabra L. and Gl. uralensis Fish. (Leguminosae). The content of GL in licorice root is 2-24% of the dry weight. GL is one of the leading natural compounds for clinical trials of chronic active viral hepatitis and HIV infections (preparation Stronger Neo-Minophagen C, SNMC), and its monoammonium salt (glycyram, tussilinar) is used as an anti-inflammatory and anti-allergic remedy. The synthetic transformations of GL on carboxyl and hydroxyl groups were carried out to produce new bioactive derivatives for medicine. GL esters were produced containing fragments of bioactive acids (4-nitrobenzoic, cinnamic, salycilic, acetylsalycilic, nicotinic, isonicotinic). Bioactive amides of GL were synthesized using chloroanhydride technique and N,N'-diciclohexylcarbodiimide (DCC) method. The synthesis of acylthioureids and semicarbazones was carried out via the reaction of triacylisothiocianate of penta-O-acetyl-GL with primary amines and hydrazines. The chain of transformations of trichloranhydride of penta-O-acetyl-GL was made with the introduction of diazoketone groups in the molecule. A new group of GL derivatives to be triterpene glycopeptides was prepared by the activated esters method (N-hydrohysuccinimide-DCC or N-hydroxybenzotriazol-DCC) using alkyl (methyl, ethyl, propyl, butyl, tert-butyl) or benzyl (4-nitrobenzyl) esters of amino acids. The glycyrrhizyl analogs of the known immunostimulator, N-acetyl-muramoyldipeptide (MDP), were synthesized using Reagent Woodward K. A series of ureids and carbamates of GL was synthesized containing 5-amino-5-desoxy-D-xylopyranose units. The synthesis of 4-nitro-4-desoxy-glycosides, modified analogs of GL, was carried out by the oxidative splitting of the carbohydrate part of GL with NaIO(4). Triterpene 2-desoxy-D-glycosides, analogs of GL, were prepared by the glycal method in the presence of iodine-containing promoters or sulfonic acid cation-exchange resin KU-2-8 (H+) and LiBr. New anti-inflammatory and anti-ulcer agents were found among GL derivatives such as esters, amides, ureids, carbamates, thioureids and glycopeptides. GL glycopeptides are of interest as immunomodulators. Some of the chemically modified GL derivatives (salts, amides, glycopeptides) were potent HIV-1 and HIV-2 inhibitors in vitro. Preparation niglizin (penta-O-nicotinate of GL) was studied clinically as an anti-inflammatory agent and is of interest for studies as hepatoprotector and HIV inhibitor.

N-Cholyl Amino Acid Alkyl Esters − A Novel Class of Organogelators

Several N-cholyl amino acid alkyl esters were found to act as novel, potent organogelators for aromatic solvents and cyclohexene. These novel organogelators afford stable, transparent, and thermoreversible gels. Modification of the molecular structure and IR measurements show that gelation takes place by means of a hydrogen-bonded network and involves at least the amide bond and several hydroxy groups of the cholic acid component. The chiral center of the amino acid component seems to play an important role in gelation. Although a wide variety of derivatives display gelation behavior, a small change in molecular structure can have a dramatic effect on the gelling capability. Electron microscopy reveals a fibrous structure in the gels. Differential scanning calorimetry shows several transitions in the melting behavior of the gels.

ESTERIFICATION OF AMINO ACIDS AND MONO ACIDS USING TRIPHOSGENE

Alkyl esters of several amino acids and acids were prepared using triphosgene [t richloromethyl carbonate, TPA (2)].