N-substituted Amino Research Articles

ChemInform Abstract: The First Iodine Improved 1,3‐Dipolar Cycloaddition: Facile and Novel Synthesis of 2‐Substituted Benzo[f]isoindole‐4,9‐diones.

Abstract The first novel protocol of the synthesis of 2-substituted benzo[f]isoindole-4,9-dione framework via the one-pot, 1,3-dipolar cycloaddition of quinones, paraformaldehyde and N-substituted amino ester hydrochlorides in the present of iodine at refluxing acetonitrile was reported. All these reactions proceed with good to excellent yields. The promising results obtained 1,3-dipolar cycloaddition will have the potential application in natural product exhibiting important biological activities.

N-substituted amino acids as multifunctional additives used in cooling water. I. N-Hydroxymethyl amino acids

The aim of our research was to synthesize and apply chemicals that can control both the electrochemical and microbiological corrosion. In order to achieve this result Nhydroxymethylated amino acids were synthesized and used as corrosion inhibitors and as biocides. With weight loss tests and linear polarisation experiments were proven their efficiency as corrosion inhibitors. The biocide activity was measured in microbiological experiments. It was important to learn whether these molecules can control the growth both of the planktonic as well as of the biofilm-embedded microbes, too. With different calculations correlation was found between the molecular structure and their efficiency.

The Synthesis of Benzo[f]isoindole-1,3-dicarboxylates via an I2-Induced 1,3-Dipolar Cycloaddition Reaction

An I2-induced 1,3-dipolar cycloaddition reaction has been developed for the synthesis of benzo[f]isoindole-1,3-dicarboxylates from quinones and N-substituted amino esters. The reaction proceeds in good to excellent yields in one step from 3 equiv of amino ester to react with the quinone structure. The utility of this transformation has been highlighted by its use for the construction of benzo[f]isoindole-1,3-dicarboxylates, which have been identified in natural products exhibiting important biological activities.

The first iodine improved 1,3-dipolar cycloaddition: facile and novel synthesis of 2-substituted benzo[f]isoindole-4,9-diones

The first novel protocol of the synthesis of 2-substituted benzo[f]isoindole-4,9-dione framework via the one-pot, 1,3-dipolar cycloaddition of quinones, paraformaldehyde and N-substituted amino ester hydrochlorides in the present of iodine at refluxing acetonitrile was reported. All these reactions proceed with good to excellent yields. The promising results obtained 1,3-dipolar cycloaddition will have the potential application in natural product exhibiting important biological activities.

Synthesis of N-substituted acyclic β-amino acids and their investigation as GABA uptake inhibitors

In this publication, we describe the synthesis of new inhibitors for the GABA transporter subtypes GAT1 and especially GAT3. We started with 3-aminopropanoic acid possessing a distinct preference for GAT3 in comparison to GAT1 and furthermore its homolog 3-aminobutanoic acid. A series of respective N-substituted amino acids was synthesized by selective N-monoalkylation of these parent structures with 6 different arylalkyl alcohols via a Mitsunobu-type reaction. The resulting compounds were investigated for their inhibitory potency GABA transporter subtypes. Among all tested compounds the 4,4-diphenylbut-3-enyl substituted 3-aminobutanoic acid (rac)-6b showed highest potency with a pIC50 value of 5.34 at GAT1. Unfortunately, the expected GAT3 potency for 2-[tris(4-methoxyphenyl)methoxy]ethyl substituted derivatives was not as high as observed for the respective nipecotic acid derivatives.

Iodine mediated reaction of quinones and N-substituted amino esters to 2-substituted benzo[f]isoindole-4,9-diones

A novel and efficient synthesis of benzo[f]isoindole-4,9-diones through the I2-promoted cyclization reaction of N-substituted amino acid esters and quinones has been realized successfully via an unprecedented 1,3-dipolar cycloaddition using KF as the base. Different substituted amino esters were found able to react with quinones through a cycloaddition reaction to afford 2-substituted benzo[f]isoindole-4,9-diones. The unexpected, short, attractive and direct synthesis of these interesting compounds is important and relevant, and provides an extremely preferable method for the synthesis of 2-substituted benzo[f]isoindole-4,9-diones.

Design and synthesis of new N-substituted amino methyl-[1,2,3] triazolyl moieties of fluoroquinolones as antibacterial agents

A series of twenty new N-substituted amino methyl-[1,2,3] triazolyl derivatives at C-7 position of fluoroquinolones were designed and synthesized through multistep synthesis. The synthesized compounds were characterized by 1H NMR, 13C NMR, ESI–MS, and IR. The antibacterial activities of these new fluoroquinolones were evaluated using a standard broth micro dilution technique. Out of the twenty derivatives, aryl substituted amino derivatives (6m to 6q) exhibited very good potency in inhibiting the growth of Methicillin-sensitive Staphylococcus aureus (MSSA), Methicillin-resistant Staphylococcus aureus (MRSA), and Vancomycin-Resistant Enterococcus faecalis (VRE faecalis) (MIC: 0.25–4.00 μg/mL) as compared to the marketed drugs Linezolid and Ciprofloxacin.

Equimolar CO2 Capture by N‐Substituted Amino Acid Salts and Subsequent Conversion

Steric bulk controls CO(2) absorption: N-substituted amino acid salts in poly(ethylene glycol) reversibly absorb CO(2) in nearly 1:1 stoichiometry. Carbamic acid is thought to be the absorbed form of CO(2); this was supported by NMR and in situ IR spectroscopy, and DFT calculations. The captured CO(2) could be converted directly into oxazolidinones and thus CO(2) desorption could be sidestepped.

Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines

A number of new 2-(pyridin-3-ylamino)-4H-(substituted) benz[e]-1,3-oxazin-4-ones were synthesized 10a–g. These were then reacted with the hydro-halogen salt of 2, 3 and 4-(halo-methyl) pyridine in the presence of Cs2CO3 to give eighteen new 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11a–i, 13a–c, and 15a–f). X-ray crystallography was used to confirm that the 2-N-substituted structures 11 and 13 were formed rather than the 3-N-substitution analogues 12 and 14. Eleven of the new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active inhibitory compound was 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 10 ± 2 μM. DNA-dependent protein kinase (DNA-PK) inhibition data for 12 previously prepared 2-morpholino substituted-1,3-benzoxazines (compounds 19–31) were measured and showed high to moderate activity where the most active compound was compound 27 with an IC50 of 0.28 μM. Furthermore DNA-PK inhibition data for six newly prepared 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11b, 13a–b, 15a–b and 15e) and 8-methyl-7-(pyridin-3-ylmethoxy)-3-(pyridin-3-ylmethyl)-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 17d were measured and moderate to low inhibitory activity was observed, with the most active of the compounds in this series being 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 2.5 μM. PI3K inhibition studies revealed that compound 27 is highly potent (IC50 for PI3Kα = 0.13 μM, PI3Kβ = 0.14 μM, PI3Kγ = 0.72 μM, PI3Kδ = 2.02 μM). Compound 22 with 7-[2-(4-methylpiperazin-1-yl)ethoxy] group shows greater inhibition of DNA-PK over PI3K.Docking of some 2-morpholino-substituted-1,3-benzoxazine compounds 19–31 within the binding pocket and structure–activity relationships (SAR) analyses were performed with results agreeing well with observed activities.

Design of N-substituted Amino Caproic Hydroxamic Acid Histone Deacetylase Inhibitors Reveal an Essential Role for Cap Atomic Composition

A series of N-substituted amino caproic hydroxamic acid histone deacetylase inhibitors derivatives was designed in good-toexcellent yields and evaluated for their antiproliferative activity in a panel of human cancer cell lines, showing half maximum effective concentration varying from 700 nM to > 100 μM. Interestingly, the replacement of a furyl group by a thienyl one impacted very significantly the cap role on this antiproliferative activity and on histone acetylation induced by these drugs in cell-based but also in cell-free enzyme assays, suggesting an important role of the electronic density attached to the oxygen or sulfur atoms.

Electron attachment to the N-substituted amino acids N-methylglycine and N-methylalanine: Effective cleavage of the N–Cα bond at sub-excitation energies

Dissociative electron attachment to gas phase N-methylglycine and N-methylalanine is studied by means of a crossed beams apparatus. Effective cleavage of the N–Cα bond is observed within a low energy resonance peaking at 1.8eV in both compounds and observable via the appearance of the fragment CH2COOH− from N-methylglycine and CH(CH3)COOH− from N-methylalanine. In glycine and alanine cleavage of the N–Cα bond was only observed as a weak reaction in combination with hydrogen transfer. As for previously studied amino acids, the most dominant anionic fragment is due to the loss of hydrogen atom from the respective target molecule resulting in the formation of the closed shell dehydrogenated parent anion (M–H)−.

Synthesis and antiviral activity of 1,2,4-triazine derivatives

Interaction of 3-aryl-1,2,4-triazin-5(4H)-ones with indole and its methyl derivative in the presence of N-substituted amino acids activated with dicyclohexylcarbodiimide or ethyl chloroformate led to the formation of 1-acyl-6-indolyl-3-phenyl-1,6-dihydro-1,2,4-triazin-5(4H)-ones. The cytotoxic and antiviral actions of the 12 resulting compounds were studied using vaccinia virus.

A domino synthetic strategy leading to two-carbon-tethered fused acridine/indole pairs and fused acridine derivatives

A series of new poly-functionalized two-carbon-tethered fused acridine/indole pairs were synthesized via Brønsted acid-promoted domino reactions between indoline-2,3-dione and C(2)-tethered indol-3-yl enaminones. The reactions were further expanded to prepare C-tethered fused acridine/pyridine pairs, N-substituted amino acids, N-cyclopropyl and N-aryl substituted fused acridine derivatives, as well as bis-furan-3-yl-substituted indoles. During these reaction processes, the domino construction of a fused acridine skeleton with concomitant formation of two new rings was readily achieved in a one-pot operation. The procedures are facile, avoiding time-consuming and costly syntheses, tedious work-up and purification of precursors.

Synthesis of 5-alkyl-2-amino-1,3,4-thiadiazoles and α,ω-bis(2-amino-1,3,4-thiadiazol-5-yl)alkanes in ionic liquids

Reaction of thiosemicarbazide with carboxylic acids, including N-substituted amino acids, in ionic liquids with H2SO4 as a catalyst affords 5-R-2-amino-1,3,4-thiadiazoles. On using alkanedicarboxylic acids, α,ω-bis(2-amino-1,3,4,-thiadiazol-5-yl)alkanes were obtained.

Synthesis of Novel 8,9-Dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones

Practical and efficient methods have been developed for the synthesis of 4,6,8,9-tetrasubstituted 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones from 4,6-dicholoropyrimidine aldehyde, N-substituted amino acid esters, and amines in five steps. This synthetic strategy is based on suitably substituted pyrimidines as bis-electrophilic species reacting with various amines to construct the pyrimido[4,5-e][1,4]diazepine core with a strategically anchored functional group for further derivatization. The utility of this methodology was demonstrated through the preparation of a 33-membered library of representative 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones in good to excellent yields.

抗癌研究第3報 新規2-N-置換アミノ-10-アルキル-2-デオキソ-5-デアザフラビン類の合成，抗腫瘍活性，及びPTKへの分子ドッキング研究

抗癌研究第3報 新規2-N-置換アミノ-10-アルキル-2-デオキソ-5-デアザフラビン類の合成，抗腫瘍活性，及びPTKへの分子ドッキング研究

Synthesis of amino acid derivatives of hydrazones and oximes of spirodihydropyranochromen-2-ones

Sulfur-and nitrogen-containing derivatives of spirodihydropyranochromen-2-ones at the exocyclic oxygen atom have been synthesized. Modification of the oximes and hydrazones of the spiro-substituted pyranocoumarins with N-substituted amino acids were carried out using activated ester and symmetrical anhydride methods.

N-Cinnamoyl-l-phenyl-alanine methyl ester.

As part of an ongoing investigation into the development of N-substituted amino acids as building blocks for dynamic combinatorial chemistry, we report the structure of the title compound, C19H19NO3. This compound crystallizes as discrete mol­ecules. The cinnamoyl group is non-planar, with the phenyl ring and the amide twisted out of the ethyl­ene plane. The benzyl and ester groups lie above and below the amide plane. The mol­ecules stack along the crystallographic c axis, connecting through C(4) chains of N—H⋯O hydrogen bonds, with the extended structure stabilized by C—H⋯O inter­actions and π–π inter­actions [centroid-to-centroid distances 3.547 (8) and 3.536 (8) Å].

Antitumor studies. Part 3: Design, synthesis, antitumor activity, and molecular docking study of novel 2-methylthio-, 2-amino-, and 2-( N-substituted amino)-10-alkyl-2-deoxo-5-deazaflavins

Various novel 10-alkyl-2-deoxo-2-methylthio-5-deazaflavins have been synthesized by reaction of 6-( N-alkylanilino)-2-methylthiopyrimidin-4(3 H)-ones with Vilsmeier reagent. The similar 2-( N-substituted amino) derivatives were prepared by nucleophilic replacement reaction of the 2-methylthio moiety by appropriate amines. The 2-oxo derivatives (i.e., 5-deazaflavins) were obtained by acidic hydrolysis of the 2-methylthio derivatives. The antitumor activities against CCRF-HSB-2 and KB cells and the antiviral activities against HSV-1 and HSV-2 have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK has been done for lead optimization of these compounds as potential PTK inhibitors. Whereas, the designed 2-deoxo-5-deazaflavins connected with amino acids at the 2-position exhibited the good binding affinities into PTK with more hydrogen bonds.

Preparation and characterization of d 6 tungsten compounds with amino acid derivatized diimine ligands and preparation of dipeptide derivatives using peptide coupling agents

Attempts to prepare dipeptide compounds from organometallic N-substituted amino acids are reported. Condensation of pyridine-2-carboxaldehyde, α-amino acids (H- l-Ala-OH or H- l-Asp-OH) and W(CO) 4(pip) 2 leads to formation of W(CO) 4(pyca-Et) ( 1) (pyca refers to the α-diimine fragment, C 5H 4NCH N) following decarboxylation of one or two equivalents of CO 2. This decarboxylation does not occur for β-alanine or GABA (γ-aminobutyric acid). Coupling of [Hpip][W(CO) 4(pyca-β-Ala-O)] ( 2) or [Hpip][W(CO) 4(pyca-GABA-O)] ( 3) to amino acid esters, H- l-Ala-OEt, or H- l-Val-OMe, using the standard 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) procedure produced four new dipeptide compounds, 4– 7. The reactions proceed in good yield and compounds were characterized spectroscopically. The dipeptide complex, W(CO) 4(pyca-Ala-Ala-OMe) ( 8), was prepared by reaction of W(CO) 4(pip) 2 with H- l-Ala- l-Ala-OMe and pyridine-2-carboxaldehyde. In addition the molecular structure of W(CO) 4(pyca-β-Ala-Val-OMe) ( 5) is reported.