N-benzoylamino Acids Research Articles

Synthesis of N-benzoyl Amino Esters and N-benzoyl Amino Acids and their Antifungal Activity

Abstract. A series of N-benzoyl amino esters and N-benzoyl amino acids were synthesized from commercially-available amino acids (Val, Ile, Leu, Ala, Phe, Trp) and were evaluated for their antifungal activity against two filamentous fungi, A. fumigatus and F. temperatum. According to the in vitro assays, five compounds (5-7, 10, 13) exhibited relevant antifungal activity against F. temperatum and two compounds (5 and 7) showed remarkable activity against both fungi strains. Some structure-activity relationships were established regarding the side chain at Ca and the type of substituents on the aromatic ring in the benzoyl moiety. Docking calculations were performed in order to predict binding affinities between compounds prepared herein and fungal chitinase, a potential target against fungi; interactions involving the aromatic rings, the influence on the number of methyl substituents, and configurations on the a-carbon have been analyzed.
 
 Resumen. Una serie de derivados N-benzoilamino ésteres y N-benzoilaminoácidos, sintetizados a partir de aminoácidos disponibles comercialmente (Val, Ile, Leu, Ala, Phe, Trp), se evaluaron como agentes antifúngicos frente a dos hongos filamentosos, A. fumigatus y F. temperatum. De acuerdo con los ensayos in vitro, cinco compuestos (5-7, 10, 13) exhibieron una actividad relevante contra F. temperatum y dos derivados (5 y 7) mostraron una actividad notable contra ambas cepas. Algunas relaciones de estructura actividad permitieron observar el efecto de la cadena lateral del aminoácido, y de los sustituyentes del grupo benzoílo, en la actividad biológica. Se realizaron cálculos de acoplamiento molecular con el propósito de predecir afinidades de enlace entre los compuestos sintetizados y la enzima quitinasa, considerada un blanco molecular potencial. Se analizaron las interacciones que involucran anillos aromáticos, la influencia de los sustituyentes metilo, así como la configuración del Ca.

Dynamic Kinetic Resolution of Azlactones via Phase-Transfer Catalytic Alcoholysis

Phase-transfer catalytic asymmetric alcoholysis of azlactones via dynamic kinetic resolution proceeded for a wide range of alcohols and azlactones, affording the corresponding α-chiral amino acid esters in up to 98% yield and up to 99:1 er. In addition, this catalytic system was also applied to the asymmetric alcoholysis of N-benzoyl amino acid hexafluoroisopropyl ester providing the desired product in good yield with high stereoselectivity (71% yield, 98:2 er). The catalyst loading could be reduced to 0.1 mol % without significant loss of stereoselectivity (turnover number = 411). Furthermore, a gram-scale reaction and transformations of the enantioenriched products involving hydrogenolysis, LAH-reduction, and Suzuki–Miyaura coupling reactions were successfully achieved. Detailed computational studies using a pseudotransition state (pseudo-TS) conformational search with ConFinder and density functional theory (DFT) calculations indicated a TS model that accounted for the origin of the stereoselectivity. In this TS model, water or alcohol molecules activate the azlactone substrate by H-bonding with the nitrogen atom, and concomitant accumulated weak interactions, including H-bonding interactions, C–H−π, and π–π interactions, stabilize the TS, leading to the major enantiomer.

Cu(Ⅱ)-promoted oxidative C-N bond cleavage of N-benzoylamino acids to primary aryl amides

Cu(Ⅱ)-promoted oxidative C-N bond cleavage of N-benzoylamino acids to primary aryl amides

Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors.

The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated virtual screening hit NSC137546, a series of N-benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT-dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure-activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L-glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration-dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies.

Determination of Carboxypeptidase Activity in Clinical Pathogens by Gas Chromatography–Mass Spectrometry

ABSTRACTA novel method for the determination of benzoic acid has been employed to identify carboxypeptidase activities in clinically relevant pathogens. Benzoic acid was determined after chemical derivatization by gas chromatography–mass spectrometry (GC–MS). N-Benzoyl amino acid substrates were evaluated for the detection of carboxypeptidase activities in a number of clinical pathogens. Upon enzymatic hydrolysis of these substrates, benzoic acid was produced which was detected by extraction from the liquid culture supernatant, derivatization as the trimethylsilyl ester, with subsequent analysis by GC–MS. Enzymatic hydrolysis of N-benzoyl glycine was observed for S. agalactiae, M. morganii, and A. baumannii. In addition, P. fluorescens was found to hydrolyze N-benzoyl-L-glutamic acid. Although the method provides an alternative approach for determining carboxypeptidase activity, ultimately it would not be a suitable method in a clinical setting. However, the method is well-suited for identifying carboxypeptidase activities that have not been previously described or to corroborate a carboxypeptidase assay with the ninhydrin reagent.

Antifungal metabolites from the rhizospheric Penicillium sp. YIM PH 30003 associated with Panax notoginseng

Two new N-benzoylamino acids, peniginseng A-B (1–2), and two new fatty acids, peniciginseng A-B (5–6), were isolated during the fermentation of Penicillium sp. YIM PH30003, an endophytic fungus associated with Panax notoginseng (Burk.) F.H. Chen. Their structures were assigned based on a combination of 1D and 2D NMR and mass spectral data. The N-benzoylamino acids (1–4) might share similar biosynthetic pathways with the rare siderophore pistillarin. Compounds 1–10 showed antifungal activities (MICs 16–128μg/mL) against Fusarium solani, the pathogenic fungus of P. notoginseng.

Cross aldol condensation of acetaldehyde and formaldehyde in the presence of bifunctional systems

Liquid-phase cross-aldol condensation of acetaldehyde and formaldehyde in the presence of salts of various saturated and unsaturated linear amines, aromatic amines, diamines, and nitrogen bases, as well as in the presence of substituted piperazines, linear and cyclic amino acids and their derivatives, and nitrogen-containing ionic liquids, was studied. The cross-condensation products were formed in considerable amounts when amine hydrochlorides, N-benzoyl amino acids, and amino acid esters were used as catalyst. The formation of cross-condensation products is favored by increased basicity of the amino nitrogen atom in the salt and of the solvent.

Probing the Acyl-Binding Pocket of Aminoacylase-1

The aminoacylase-1/metallopeptidase 20 (Acy1/M20) family features several l-aminoacylases useful in biocatalysis. Mammalian Acy1, in particular, has been applied in racemic resolution and reverse hydrolysis. Despite recent advances in our understanding of the active site architecture and functioning, determinants of Acy1 substrate specificity have remained uncharted. Comparison to bacterial homologues points to a sterically more restricted acyl-binding pocket for Acy1. Here we sought to map characteristics of the acyl-binding pocket of human and porcine Acy1. Toward this end, we determined Michaelis constants for an analogue series of aliphatic N-acyl- l-methionine substrates and translated the values into three-dimensional quantitative structure-activity relationship models employing the minimal topological difference-partial least square method. The QSAR models for the two enzymes suggest overall similar binding pockets in the acetyl-binding portion and indicate a general preference for straight-chain acyl moieties. Embedding of the QSAR map for human Acy1 in the structure of its metal-binding domain associates the side chain of Ile177 with limited acyl chain elongation which was not observed for the porcine enzyme. The topological model further supports roles of Thr347 and Leu372, which are both conserved in the porcine enzyme, in restricting acyl chain branching at the alpha- and beta-positions, respectively. Mutational analyses confirmed our predictions for Thr347 and Leu372. Moreover, the T347S variant of human Acy1 exhibited markedly increased catalytic efficiency against N-benzoylamino acids, demonstrating the potential for engineering of substrate specificity in Acy1. We discuss the more general application of the employed procedure for protein design.

Highly Efficient Dynamic Kinetic Resolution of Azlactones by Urea‐Based Bifunctional Organocatalysts

Novel tasks for a venerable molecule: Bifunctional organocatalysts of the type shown, with a quasi Lewis acidic urea or thiourea unit and a Brønsted basic amine functionality, effect the dynamic kinetic resolution of azlactones with high enantioselectivity. N-Benzoyl amino acid esters were obtained with up to 91 % ee in high yields from racemic azlactones.

N-Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: Structure–activity relationship of the benzoyl moiety

o-Bromobenzoyl l-tryptophan 1 inhibits the association of LFA-1 with ICAM-1 with an IC50 of 1.7μM. Evaluation of the structure–activity relationship of the benzoyl moiety shows that 2,6-di-substitutions greatly enhance potency of this class of inhibitors. Electronegative substitutions that favor a 90° angle between the benzoyl ring and the amide bond yield the most potent compounds. There is a strong correlation between the potency of the compounds and the difference between the ab initio energy at 90° and the global minima energy for given compounds. Combining the favored benzoyl substitutions with l-histidine and l-asparagine resulted in a 15-fold increase in potency over compound 1.

Simple and efficient cleavage reaction of the boc group in heterocyclic compounds

AbstractDedicated to the memory of Pr. Ladjama Daif A series of chiral cyclosulfamides have been synthesized by alkaline cyclisation starting from N‐benzoylamino acids (Ala, Val, Leu, Phe) derivatives and chlorosulfonyl isocyanate. A simplified and regioselective deprotection of the cyclic compounds (cyclosulfamides) containing the tert‐butyloxycarbonyl group (Boc) has been achieved in good yield by fusion under reduced pressure.

N-Benzoyl amino acids as LFA-1/ICAM inhibitors 1: amino acid structure–activity relationship

The association of ICAM-1 with LFA-1 plays a critical role in several autoimmune diseases. N-2-Bromobenzoyl l-tryptophan, compound 1, was identified as an inhibitor to the formation of the LFA-1/ICAM complex. The SAR of the amino acid indicates that the carboxylic acid is required for inhibition and that l-histidine is the most favored amino acid.

Dynamic kinetic resolution: synthesis of optically active α-amino acid derivatives

Candida antarctica lipase B (Novozyme) is an effective catalyst for the dynamic kinetic resolution of racemic 2-benzyl-4-substituted-5(4 H)-oxazolones, in the presence of an alcohol, yielding optically active N-benzoyl amino acid esters. The reaction has been optimised with respect to the solvent and the effect of a catalytic amount of organic base is investigated.

Coordination behavior of N-benzoylamino acids: Synthesis and structure of mixed-ligand complexes of palladium (II) with N-benzoylamino acid dianion and diamine

Coordination behavior of N-benzoylamino acids: Synthesis and structure of mixed-ligand complexes of palladium (II) with N-benzoylamino acid dianion and diamine

Effects of organic modifiers on the chiral recognition by different types of silica-immobilized bovine serum albumin

We prepared three columns containing bovine serum albumin immobilized on silica by different means and the effects of organic modifiers in the eluent on chiral separation were studied using N-substituted amino acids. Adsorption on silica, covalent immobilization to diol-silica with carbonyldiimidazole (CSP-II) and covalent immobilization to amino-silica with glutaraldehyde were studied. CSP-II had the highest stereoselectivity and was the most affected by organic modifiers in the eluent. The hydrophobicity of amino acid moiety affected the chiral recognition of N-benzoylamino acids and the aromaticity of the N-substituted group was important.

Protective effects of N-benzoyl amino acids on cisplatin nephrotoxicity in rats.

The protective effects of N-benzoyl amino acids (NAAs) and piperacillin (PIP), anionic transport inhibitors, against the nephrotoxicity of cisplatin were examined in rats. Male Wistar rats were injected i.p. with 6 mg/kg of cisplatin combined with i.p. NAAs or PIP. Rats were sacrificed on day 5 after cisplatin injection to weigh the kidney and liver, and to determine blood urea nitrogen (BUN) and serum creatinine (serum Cr) levels. Treatments with NAAs were an effective means of protection against cisplatin-induced nephrotoxicity. The combination of cisplatin with NAAs containing a short and straight chain significantly suppressed (p < 0.05) the changes in body, kidney and liver weights, BUN and serum Cr. Further, betamipron (BP) at a 2000 mg/kg dose showed no apparent effect on the body, kidney and liver weights, BUN and serum Cr levels in rats. The combination of cisplatin with PIP caused a loss in body weight. The protective effects of PIP against cisplatin toxicity are inferior to those of BP when compared at 250 mg/kg doses.

Reaction of N-benzoyl amino acids with oxalyl chloride: a facile route to 4-substituted 2-phenyloxazole-5-carboxylates

N-benzoyl amino acids 1a–g react with excess oxalyl chloride at room temperature followed by addition of alcohols to afford 4-substituted 2-phenyloxazole-5-carboxylates 3a–g.

Chromenone derivatives as receptors for N-benzoylamino acids

The chromenone derivative 5, easy to synthesize from 2-hydroxyacetophenone 1, has been used to prepare the hosts 7–10 and 12. These combine three hydrogen bonds, π-stacking and chargetransfer interactions for the complexation of N-benzoylamino acids in CDCl3.

Chemo-enzymatic asymmetric synthesis of amino acids. Enantioselective hydrolyses of 2-phenyl-oxazolin-5-ones.

Porcine pancreatic lipase and the lipase of Aspergillus niger catalyze the enantioselective hydrolysis of a series of 4-substituted-2-phenyl-oxazolin-5-ones to yield optically active ( S )-and ( R )-N-benzoyl amino acids respectively.

Studies on chromone derivatives. A direct and efficient one-pot synthesis of 4-chromone-linked 3-(N-acylamino)azetidin-2-ones from imines and N-acylalanine

Chlorosulfonylmethylene(dimethyl)ammonium chloride 1 is found to be an efficient cyclodehydrating agent for the one-pot synthesis of various novel chromone-linked azetidin-2-ones 6via cyclo-addition reactions of 3-(aryliminomethyl)chromones 5 with in situ generated oxazolones 3, directly from the corresponding N-benzoylamino acids and there is no evidence for the formation of pyridones 7. The azetidinones 6a–g were obtained in 85–90% yields and their structures are fully corroborated by spectral and elemental analyses.