Amide Nitrogen Atom Research Articles

DABCO[sbnd]Catalyzed Tandem Si–Csp-Desilylation–Addition Reactions of 3-Trimethylsilyl-2-propynamides with Acetylenic Alcohols and Diols: Synthesis of β-(Propargyloxy)acrylamides

A number of previously unknown amide-containing propargyl vinyl ethers has been synthesized in a total yield of 54–92 % by DABCO-catalyzed, tandem desilylation–addition reactions of 3-trimethylsilyl-2-propynamides with acetylenic alcohols and diols. The effect of substituents at the triple bond in acetylenic alcohol (diol) and at the nitrogen atom in amides on the reaction outcome is studied.

Synthesis, characterization and reactivity of a Mn(III)–hydroxido complex as a biomimetic model for lipoxygenase

Manganese hydroxido (Mn–OH) complexes supported by a tripodal N,N′,N″-[nitrilotris(ethane-2,1-diyl)]tris(P,P-diphenylphosphinic amido) ([poat]3−) ligand have been synthesized and characterized by spectroscopic techniques including UV–vis and electron paramagnetic resonance (EPR) spectroscopies. X-ray diffraction (XRD) methods were used to confirm the solid-state molecular structures of {Na2[MnIIpoat(OH)]}2 and {Na[MnIIIpoat(OH)]}2 as clusters that are linked by the electrostatic interactions between the sodium counterions and the oxygen atom of the ligated hydroxido unit and the phosphinic (P=O) amide groups of [poat]3−. Both clusters feature two independent monoanionic fragments in which each contains a trigonal bipyramidal Mn center that is comprised of three equatorial deprotonated amide nitrogen atoms, an apical tertiary amine, and an axial hydroxido ligand. XRD analyses of {Na[MnIIIpoat(OH)]}2 also showed an intramolecular hydrogen bonding interaction between the MnIII–OH unit and P=O group of [poat]3−. Crystalline {Na[MnIIIpoat(OH)]}2 remains as clusters with Na+---O interactions in solution and is unreactive toward external substrates. However, conductivity studies indicated that [MnIIIpoat(OH)]− generated in situ is monomeric and reactivity studies found that it is capable of cleaving C-H bonds, illustrating the importance of solution-phase speciation and its direct effect on chemical reactivity.Synopsis: Manganese–hydroxido complexes were synthesized to study the influence of H-bonds in the secondary coordination sphere and their effects on the oxidative cleavage of substrates containing C-H bonds.

Boosting Effect of Sterically Protected Glucosyl Substituents in Formic Acid Dehydrogenation by Iridium(III) 2-Pyridineamidate Catalysts.

[Cp*Ir(R-pica)Cl] (Cp*=pentamethylcyclopentadienyl anion, pica=2-picolineamidate) complexes bearing carbohydrate substituents on the amide nitrogen atom (R=methyl-β-D-gluco-pyranosid-2-yl, 1; methyl-3,4,6-tri-O-acetyl-β-D-glucopyranosid-2-yl, 2) were tested as catalysts for formic acid dehydrogenation in water. TOFMAX values over 12000 h-1 and 50000 h-1 were achieved at 333 K for 1 and 2, respectively, with TON values over 35000 for both catalysts. Comparison with the simpler cyclohexyl-substituted analogue (3) indicated that glucosyl-based complexes are much better performing under the same experimental conditions (TOFMAX=5144 h-1, TON=5000 at pH 2.5 for 3) owing to a lower tendency to isomerize to the less active k2-N,O isomer upon protonation. The 5-fold increase in TOFMAX observed for 2 with respect to 1 is reasonably due to an optimal steric protection by the acetyl substituent, which may prevent unproductive inner-sphere reactivity. These results showcase a powerful strategy for the inhibition of the common deactivation pathways of [Cp*Ir(R-pica)X] catalysts for FA dehydrogenation, paving the way for the development of better performing hydrogen storage systems.

Novel secondary pyridinyl amides: Synthesis, in vitro antiproliferative screenings, and molecular docking studies

A novel series of secondary pyridinyl amides, reinforced with the methylsulfonyl pharmacophore unit, was designed and synthesized. Further, we determined the antiproliferative activities of these compounds through experimental assays and analyzed their interactions with Breakpoint Cluster Region/Abelson (bcr/abl), Epidermal Growth Factor Receptor (EGFR), and Human Epidermal Growth Factor Receptor 2 (HER2) tyrosine kinases using molecular autodocking techniques. We grouped these amides into three categories, classified by the type of spacer that binds the pyridine ring to the amide nitrogen atom. Additionally, within each group, we strategically positioned the amide moiety at the ortho, meta, or para position on the pyridyl ring. Among the studied amides, compound 3 exhibited the best overall antiproliferative activity against human immortalized myelogenous leukemia (K562) (IC50 = 26 µM), human leukemia monocytic cell line (THP-1) (IC50 = 81 µM), and human hepatocellular carcinoma (HepG2) (IC50 = 210 µM). Molecular docking studies revealed that compound 3 binds effectively to bcr/abl, EGFR, and HER2 tyrosine kinases, demonstrating strong interactions with crucial active site amino acids, indicative of its targeted antiproliferative mechanism. All investigated compounds showed either very minor or no cytotoxicity against human dermal fibroblast adult cells.

SN2 Reaction at the Amide Nitrogen Center Enables Hydrazide Synthesis

AbstractNucleophilic substitutions are fundamentally important transformations in synthetic organic chemistry. Despite the substantial advances in bimolecular nucleophilic substitutions (SN2) at saturated carbon centers, analogous SN2 reaction at the amide nitrogen atom remains extremely limited. Here we report an SN2 substitution method at the amide nitrogen atom with amine nucleophiles for nitrogen–nitrogen (N−N) bond formation that leads to a novel strategy toward biologically and medicinally important hydrazide derivatives. We found the use of sulfonate‐leaving groups at the amide nitrogen atom played a pivotal role in the reaction. This new N−N coupling reaction allows the use of O‐tosyl hydroxamates as electrophiles and readily available amines, including acyclic aliphatic amines and saturated N‐heterocycles as nucleophiles. The reaction features mild conditions, broad substrate scope (>80 examples), excellent functional group tolerability, and scalability. The method is applicable to late‐stage modification of various approved drug molecules, thus enabling complex hydrazide scaffold synthesis.

SN2 Reaction at the Amide Nitrogen Center Enables Hydrazide Synthesis.

Nucleophilic substitutions are fundamentally important transformations in synthetic organic chemistry. Despite the substantial advances in bimolecular nucleophilic substitutions (SN2) at saturated carbon centers, analogous SN2 reaction at the amide nitrogen atom remains extremely limited. Here we report an SN2 substitution method at the amide nitrogen atom with amine nucleophiles for nitrogen-nitrogen (N-N) bond formation that leads to a novel strategy toward biologically and medicinally important hydrazide derivatives. We found the use of sulfonate-leaving groups at the amide nitrogen atom played a pivotal role in the reaction. This new N-N coupling reaction allows the use of O-tosyl hydroxamates as electrophiles and readily available amines, including acyclic aliphatic amines and saturated N-heterocycles as nucleophiles. The reaction features mild conditions, broad substrate scope (>80 examples), excellent functional group tolerability, and scalability. The method is applicable to late-stage modification of various approved drug molecules, thus enabling complex hydrazide scaffold synthesis.

Spectroscopic Study on the Complexation of trivalent Actinide and Lanthanide ions with TEDGA in Solution

AbstractNMR spectroscopy studies on the complexation of La(III), Sm(III), Lu(III), Y(III) and Am(III) with N,N,N′,N′‐tetraethyldiglycolamide (TEDGA) have been performed. Initial studies concerning the stoichiometry of the complexes prove the formation of [M(TEDGA)3]3+ in D2O and [M(TEDGA)1‐3]3+ in CD3CN. Decreasing the solvent polarity translates to an increase of the complex stability as shown by complementary TRLFS studies with Cm(III). Due to delocalization of the lone electron pair of the amide nitrogen atom, the M(III)−O interaction has been studied indirectly by collecting 13C and 15N NMR data. The observed chemical shifts prove that the interaction of the trivalent ions, An(III) and Ln(III), and TEDGA is almost identical.

Suberoylanilide Hydroxamic Acid Analogs with Heteroaryl Amide Group and Different Chain Length: Synthesis and Effect on Histone Deacetylase.

This review covers the last 25 years of the literature on analogs of suberoylanilide hydroxamic acid (SAHA, known also as vorinostat) acting as an HDAC inhibitor. In particular, the topic has been focused on the synthesis and biological activity of compounds where the phenyl group (the surface recognition moiety, CAP) of SAHA has been replaced by an azaheterocycle through a direct bond with amide nitrogen atom, and the methylene chain in the linker region is of variable length. Most of the compounds displayed good to excellent inhibitory activity against HDACs and in many cases showed antiproliferative activity against human cancer cell lines.

Synthesis, molecular docking, and molecular dynamic simulation studies of new 1,3,4-thiadiazole derivatives as potential apoptosis inducers in A549 lung cancer cell line

1,3,4-Thiadiazoles are structures that are bioisosteres of 1,3,4-oxadiazole and pyrimidine ring, which are found in the structure of many drugs and anticancer active newly studied derivatives. In the past, high effect profiles have been observed in many molecules created, based on the anticancer effects of the 2-amino-1,3,4-thiadiazole (NSC 4728) molecule and acetazolamide molecules. Focusing on these molecules and evaluating them in terms of mechanistic effects, twelve new N-[5-((3,5-dichlorophenoxy) methyl]-1,3,4-thiadiazole derivatives (3a–3i) were synthesized and their biological activities were investigated in lung cancer cells. The anticancer effects of the compounds were evaluated on the A549 and L929 cell lines. Compound 3f, namely 2-[(5-chlorobenzotiyazol-2-yl)thio]-N-[5-[(3,5-dichlorophenoxy)methyl]-1,3,4-thiadiazol-2-yl]acetamide, showed better activity than cisplatin, exhibiting high inhibitory potency (IC50: <0.98 μg/mL) and selectivity against A549 cell line even at the lowest concentration tested. Compounds 3c, 3f, and 3h with the lowest IC50 values of the compounds exhibited an excellent percentage of apoptosis between 72.48 and 91.95% compared to cisplatin. The caspase-3 activation and mitochondrial membrane potential change of the aforementioned three compounds were also studied. Moreover, matrix metalloproteinase-9 (MMP-9) inhibition potential of all final compounds was also investigated and IC50 values for compounds 3b and 3g were identified as 154.23 and 107.28 µM. Molecular docking and molecular dynamic simulation studies for MMP-9 enzyme inhibition were realized on these compounds and the nitrogen atoms of amide and thiadiazole moieties’ ascertained that they play a key role in chelating with Zn metal, at the same time, (thio)ether moieties allow conformational change resulting in the ligand can make more stable contacts. Communicated by Ramaswamy H. Sarma

Site-specific relaxation of peptide bond planarity induced by electrically attracted proton/deuteron observed by neutron crystallography.

In structural biology, peptide bonds, fundamental linkages between hundreds of amino acids, of which a protein molecule is composed, have been commonly treated as a plane structure just as Linus Pauling et al. proposed. In this paper, a site-specific peptide bond relaxation mechanism by deuterons whose localization has been suggested by neutron crystallography is proposed. Such deuteron was observed as an arm of neutron scattering length density protruding from the carbonyl oxygen atoms in the main chain in the omit map drawn by neutron crystallography of human lysozyme. Our comprehensive study using x-ray and neutron diffraction and 15 N chemical shifts of individual amide nitrogen atoms within the same peptide bond strongly suggests the relaxation of the electronic resonance structure because of site-specific modulation by protons/deuterons localized on the electron orbital of the carbonyl oxygen. All experimental data used in this examination were obtained at room temperature, which is preferable for enzymatic activity. Such a close interaction between the electron resonance structure of a peptide bond and the exchangeable protons/deuterons well agreed with that observed in an intermediate state in an amide hydrolytic reaction simulated by the ab-initio calculation including water molecules.

Crystal structure of meglumine diatrizoate, (C7H18NO5)(C11H8I3N2O4)

The crystal structure of meglumine diatrizoate has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. Meglumine diatrizoate crystallizes in space group P21 (#4) with a = 10.74697(4), b = 6.49364(2), c = 18.52774(7) Å, β = 90.2263(3), V = 1292.985(5) Å3, and Z = 2. Two different crystal structures, which yielded essentially identical refinement residuals and positions of the non-H atoms, were obtained. The differences were in the H atom positions and the hydrogen bonding. One structure was 123.0 kJ/mol/cell lower in energy than the other and was adopted for the final description. The crystal structure consists of alternating double layers of cations and anions along the c-axis. The hydrogen bonds link the cations and anions into a three-dimensional framework. Each of the hydrogen atoms on the ammonium nitrogen of the cation acts as a donor in a strong N–H⋯O hydrogen bond. One of these is to a hydroxyl group of another cation, and the other is to the carboxylate group of the anion. Each of the amide nitrogen atoms of the anion forms a strong N–H⋯O intermolecular hydrogen bond, one to a carbonyl and the other to a carboxylate group. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

Effect of bis(methylimidazolium) ionic liquid on the extraction of actinides and lanthanides with bis(carbamoylmethylphosphine oxide) extractant from nitric acid solutions

Abstract A novel bis(methylimidazolium) ionic liquid 3,3′-(pentane-1,5-diyl) bis(1-methylimidazolium) bis(trifluoromethanesulfonul)imide [C5(mim)2][Tf2N]2 has been synthesized. Its effect on the extraction of U(VI), Th(IV), Am(III), and lanthanides(III) from nitric acid solutions with a polydentate neutral bis(carbamoylmethylphosphine oxide) ligand L containing two bidentate fragments Ph2P(O)CH2C(O)NH–, interconnected by 4,7,10-trioxatridecane spacer through amide nitrogen atoms has been investigated. The efficiency of the extraction of metal ions with solutions of L in 1,2-dichloroethane (DCE) significantly increases in the presence of [C5(mim)2][Tf2N]2. A synergistic effect in the extraction of metal ions in this system has been explained with the high hydrophobicity of the Tf2N− anions, which are involved in the formation of extracted complexes as counterions. The value of the synergistic effect decreases with increasing acidity of the aqueous phase. The influence of the composition of the aqueous and organic phases on the efficiency of the extraction of metal ions into the organic phase is considered, and the stoichiometry of the extracted complexes is determined. The effect of the HTf2N coextraction with L on the extraction of metal ions in the L – [C5(mim)2][Tf2N]2 system is discussed. The synergistic effect in the extraction of Ln(III) from 3 M HNO3 solutions with the mixture of L and [C5(mim)2][Tf2N]2 in DCE is higher than that in the L – [C4mim][Tf2N] – DCE system.

Inverse Polyamidoamine (i‐PAMAM) Dendrimer Antimicrobials

AbstractHere we redesigned the branches of polyamidoamine (PAMAM) dendrimers by moving the amide carbonyl group on the other side of the amide nitrogen atom, transforming the β‐alaninyl‐amidoethylamine branch, which easily undergoes retro‐Michael reactions and renders PAMAMs intrinsically unstable, into a more stable glycyl‐amidopropylamine branch. The resulting inverse PAMAM (i‐PAMAM) dendrimers have the same carbon framework as PAMAMs and only differ by the position of the carbonyl group. In contrast to PAMAMs which are prepared in solution and are difficult to purify, we synthesize i‐PAMAMs using high‐temperature solid‐phase peptide synthesis by iterative coupling and deprotection of the commercially available N,N‐bis(N′‐Fmoc‐3‐aminopropyl)glycine and purify them preparative reverse phase HPLC. Our i‐PAMAM dendrimers show no detectable degradation over time. We demonstrate this new class of dendrimers with the synthesis of antimicrobial dendrimers with potent yet non‐membrane disruptive activities against both Gram‐negative and Gram‐positive bacteria.

Discovery of Bonding-active Chemical Species Containing Nitrogen Atoms

In this review, the authors review and explain their research on "Discovery of Bonding Active Species Containing Nitrogen Atoms" from the past to the present. The authors are interested in new chemical phenomena, especially in the activation of chemical bonds containing nitrogen atoms, and have conducted research to discover chemical bonds with new properties. The activated chemical bonds containing nitrogen atoms are the following (Fig. 1). (1) Rotationally activated C-N bonds by pyramidalization of amide nitrogen atoms (2) N-N bond cleavage ability with reduced bond strength by pyramidalization of nitrosamine nitrogen atoms (3) Transient hetero atom-N bond formation by neighboring group participation of a halogen electron to the nitrogen cation. (4) A unique carbon cation reaction involving nitrogen atoms, especially nitro groups (C-NO2 bond) and ammonium ions (C-NH3+ bond). These purely basic chemistry discoveries unexpectedly led to the creation of functional materials, especially biologically active molecules. We will explain how new chemical bonds led to the creation of new functions.

N-(4-Methoxy-2-nitrophenyl)-2-(3-methyl-2-oxo-1,2-dihydroquinoxalin-1-yl)acetamide.

The quinoxaline unit in the title mol-ecule, C18H16N4O5, is slightly puckered [dihedral angle between the rings = 2.07 (12)°] while the whole mol-ecule adopts an L-shaped conformation. Intra-molecular hydrogen bonding determines the orientation of the substituted phenyl ring and the amide nitro-gen atom is almost planar. The packing in the crystal is governed by C-H⋯O hydrogen bonds and slipped π-stacking inter-actions.

Design, Synthesis, and Study of the Anxiolytic Activity of New Pyrrolo[1,2-&lt;i&gt;a&lt;/i&gt;]pyrazine-Containing TSPO Ligands

A new group of 1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamides, in which substituents at the amide nitrogen atom are alkyl, benzyl or alkoxyphenylalkyl groups, amino acid residues or their derivatives, has been obtained in this work. The synthesized compounds have high theoretical affinities for the 18 kDa translocator protein (TSPO) and a favorable profile of ADMET characteristics, which makes them promising for drug development. Anxiolytic activity was detected for eight compounds at doses of 0.1–5.0 mg/kg when administered intraperitoneally under conditions of emotional stress in the open field test in Balb/c mice and in the elevated plus maze test in ICR mice. N-Benzhydryl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide was selected as a lead compound for further development as a potential anxiolytic agent, which showed the presence of anti-anxiety activity in a wide range of doses in both tests used.

Simultaneous Formation of Isomeric and Polycyclic Proton Sponges Derived from 1,8‐Diaminonaphthalenes and Xylylene Dibromides

AbstractThe interaction of 1,8‐diaminonaphthalene with o‐xylylene dibromide leads to two topologically relevant isomeric products, 1,8‐di(isoindolin‐2‐yl)naphthalene (reported previously), and its structural isomer with the bridgehead nitrogens in a bicyclic system (reported for the first time). This is the first case of isolating two heterocyclic analogs of 1,8‐bis(dimethylamino)naphthalene (proton sponge or DMAN) in one reaction. Both isomers are formed in parallel reactions and are not interconverted upon acid treatment. The first representative of heterocyclic “amide proton sponges”, which is still able to participate in intramolecular protonation due to the amide nitrogen atom, was synthesized by direct oxidation of the corresponding isoindoline derivative. Using p‐xylylene dibromide as a bridging bielectrophile, a macroheterocyclization was effectively realized to construct the first paracyclophane extended by two DMAN subunits. Mostly driven by the proximity effect, the molecular structure, unusual protonation trends and reactivity of peri‐diaminonaphthalenes N‐linked with o‐ and p‐xylylene fragments are also discussed.

Crystal structure of vismodegib, C19H14Cl2N2O3S

The crystal structure of vismodegib has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Vismodegib crystallizes in space group P21/a (#14) with a = 16.92070(20), b = 10.20235(4), c = 12.16161(10) Å, β = 108.6802(3)°, V = 1988.873(9) Å3, and Z = 4. The crystal structure consists of corrugated layers of molecules parallel to the bc-plane. There is only one classical hydrogen bond in the structure, between the amide nitrogen atom and the N atom of the pyridine ring. Pairs of these hydrogen bonds link the molecules into dimers, with a graph set R2,2(14) &gt; a &gt; a. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

Synthesis, spectroscopic characterization, biological application and molecular docking studies of some transition metal complexes of isophthalamide ligand

Various spectrum techniques were used to analyze the newly synthesized isophthalamide ligand, N1,N3-bis(1-hydrazinyl-1-oxopropan-2-yl)isophthalamide (L). The reaction of isophthalamide ligand with Fe(III), Co(II), Ni(II) and Zn(II) ions produced complexes of 1:1 (M:L) stoichiometry. The spectral data, FTIR and NMR disclosed that the isophthalamide ligand chelated the central metal ions in neutral tetradentate manner via the two carbonyl oxygens and two amide nitrogen atoms. The octahedral configuration of the complexes has been elucidated by electronic and magnetic moment measurements. The molar conductivity described the electrolytic nature of the synthesized complexes. The structural features of the title compounds were investigated based on mass spectral analysis which showed good agreement between the calculated and experimental data and in concise with the elemental analyses data. The thermal decomposition characteristics of the ligand and its complexes are measured using thermogravimetric analysis. The DFT quantum chemical simulation validated the suggested structures and was used to calculate HOMO-LUMO energies. To optimize the structural formula for the examined ligand, the Gaussian09 program was used. The existence of Fe(III) and Ni(II) complexes in the nanostructure was confirmed using a scanning electron microscope (SEM). The isophthalamide ligand and its transition metal complexes were studied for their antibacterial characteristics against two Gram-positive bacteria (Bacillissubtilis and Staphylococcus aureus) and two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) microorganisms. Title complexes were shown to be more physiologically active than the parent ligand. The title compounds have a positive interaction with the crystal structures of 3t88-E. coli, 3ty7-Staphylococcus aureus, 5h67-Bacillus subtilis, and 5i39-Pseudomonas aeruginosa, according to molecular docking study.

The ion-neutral complex-mediated fragmentation reaction in electrospray ionization tandem mass spectrometric analysis of N-phenyl-3-(phenylthio)propanamides.

Amides are the fundamental units of both peptides and proteins, and also important functional groups of medical chemicals. Investigation of the fragmentation mechanism of amides in the gas phase is scientifically important for structural analysis. However, understanding of this problem is still elusive. Protonated N-phenyl-3-(phenylthio)propanamide and its derivatives were investigated using positive ion tandem mass spectrometry (ESI-MS/MS) with an LCQ mass spectrometer. Accurate mass analysis was conducted with a micrOTOF-QII mass spectrometer. Density functional theory (DFT) calculations using the Gaussian 03 program and deuterium-labelling (D-labelling) experiments were performed to verify the proposed fragmentation mechanism. Interpretation of the fragment ions in the collision-induced dissociation mass spectra showed that the ionizing proton in the protonated ion transferred from the most thermodynamically favorable carbonyl oxygen to the dissociative protonation site at amide nitrogen or sulfur atom upon collisional activation. The dissociation of the amide or the C-S bond was induced by such proton transfer. An ion-neutral complex (INC) was generated via the dissociation of the amide bond. In the INC, it was observed that the carbocation of the ionic part attacked the ortho phenyl carbon atom adjacent to the sulfur atom, and proton transfer from the carbon atom to the nitrogen atom led to the formation of protonated aniline. The fragmentation mechanism of protonated N-phenyl-3-(phenylthio)propanamide and its derivatives was proposed and elucidated. All the compounds studied showed similar fragmentation pathways, and the competitive formation of two ions, RC9 H9 OS+ and C6 H8 N+ , was observed. The generation of protonated aniline is mediated by INC in ESI-MS/MS.