Related Amides Research Articles

A Unified Synthesis of Electron-Deficient 1,4- and 1,1,4-Substituted 1,3-Dienes through a Base-Promoted Allylation Followed by Retro-Michael Vinylogous Dehydrosulfinylation.

We disclose a general 2-step synthesis of electron-poor 1,4- and 1,1,4-substituted buta-1,3-dienes bearing electron-withdrawing substituents at both termini of the conjugated system. The method relies on a base-promoted C-allylation of primary or secondary alkylsulfones with γ-bromocrotonate or related amide, nitrile, or sulfone and subsequent vinylogous retro-Michael dehydrosulfinylation. The geometry of the resulting dienes is substrate-dependent, and predominantly E,E-dienes are formed from E-electrophiles. This phosphorus- and transition-metal-free method tolerates a variety of functionalities and could serve as a supplement to Wittig, HWE, and Julia olefinations.

The added value of relative amide proton transfer (rAPT) to advanced multiparametric MR imaging for brain glioma characterization

BackgroundDifferentiation between the grades of brain gliomas is a crucial step in the management of patients. The gold standard technique for grading is biopsy but MR imaging may play a more substantial role as a non-invasive method by using promising molecular sequences. Our purpose was to assess the added value of the relative amide proton transfer signal [rAPT] to advanced multiparametric MRI protocol.MethodsWe enrolled a pathologically confirmed 102 patients with low-grade glioma [n = 38] and high-grade glioma [n = 64] who underwent advanced multiparametric MRI protocol on the same scanner. The protocol included anatomic, diffusion, MRS, and perfusion sequences. The newly added sequence was Amide proton transfer. The rAPT values of all lesions were investigated by two neuroradiologists to assess the inter-rater agreement of using interclass correlation coefficient [ICC]. HGGs demonstrated significantly higher mean values of relative cerebral blood volume (rCBV), choline to creatine ratio (Cho/cr), and rAPT with lower Apparent diffusion coefficient (ADC) values compared to LGGs. ROC analyses revealed medium to high diagnostic performance with an AUC of 0.941 for rAPT, 0.907 for mean ADC, and 0.906 for rCBV. Discriminant function analysis of two models, the first one included mean ADC, rCBV, and Cho/Cr, while in the second Model, we added rAPT to them. Model two demonstrated higher accuracy and a significant difference in the AUC after adding the rAPT. The inter-rater agreement was reasonable (ICC 0.61).ConclusionsrAPT adds significant value to multiparametric MRI for distinguishing LGG from HGG.

Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system.

Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system.

Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum.

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.

NiH-catalyzed asymmetric hydroarylation of N-acyl enamines to chiral benzylamines

Enantiomerically pure chiral amines and related amide derivatives are privilege motifs in many pharmacologically active molecules. In comparison to the well-established hydroamination, the transition metal-catalysed asymmetric hydrofunctionalization of enamines provides a complementary approach for their construction. Here we report a NiH-catalysed enantio- and regioselective reductive hydroarylation of N-acyl enamines, allowing for the practical access to a broad range of structurally diverse, enantioenriched benzylamines under mild, operationally simple reaction conditions.

Societal issues and policy implications related to the use of cannabinoids, cannabis, and cannabis-based medicines for pain management.

Societal issues and policy implications related to the use of cannabinoids, cannabis, and cannabis-based medicines for pain management.

Cover Picture

The cover picture shows the copper‐catalyzed Ullmann‐Ma reaction of aryl halides with nucleophiles by the assistance of two‐generation ligands, amino acids and oxalic diamides or related amides. Ullmann‐Ma reaction is one of the most important transformations for the construction of aryl carbon‐carbon and carbon‐heteroatom bonds in organic chemistry. For the details about the history, development, scope and applications of Ullmann‐Ma reaction, please see the article by Cai et al. on page 879–893.image

Ullmann‐Ma Reaction: Development, Scope and Applications in Organic Synthesis†

SummaryCopper‐catalyzed cross‐couplings of aryl halides and nucleophiles, traditionally called Ullmann‐type coupling reactions, were initially reported by Ullmann et al. from 1901—1929. A seminal report in 1998 by Ma et al. from Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences revealed an accelerating effect caused by amino acids, which brought Ullmann‐type coupling reactions into a ligand‐accelerating era. From 1999 to the first 10 years of 2000s, the first‐generation ligands were developed by many researchers and promoted Ullmann‐type coupling reactions of aryl iodides and bromides under relatively mild conditions. Amino acid ligands, developed by Ma and coworkers, are one class of the most important first‐generation ligands. In the second 10 years of 2000s, Ma et al. led the discovery of second‐generation ligands for copper‐catalyzed cross‐coupling reactions. Two great breakthroughs have been realized by using second‐generation oxalic diamide and related amide ligands, with aryl chlorides as general coupling partner and with low catalyst loadings. Now copper‐catalyzed cross coupling reactions of aryl halides and nucleophiles with amino acids or oxalic diamides and related amides as ligands are recognized as Ullmann‐Ma reactions and have found extensive applications in organic synthesis.

Identification and development of non-cytotoxic cell death modulators: Impact of sartans and derivatives on PPARγ activation and on growth of imatinib-resistant chronic myelogenous leukemia cells

4’-((2-Propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid derived from telmisartan was identified as lead for the design of cell death modulators. In this study, we evaluated the efficacy of telmisartan itself and other sartans in combination with imatinib against K562-resistant cells. The findings were directly used to further optimize the lead structure. Telmisartan and candesartan cilexetil represented the most effective sartans, thus the influence of carboxyl/methyl carboxylate groups at positions 7 (compounds 6, 7) or 4 (compounds 12–14) at the benzimidazole core was studied. Additionally, according to the results of a former structure-activity study, telmisartan was transformed to the related amide (1). Telmisartan amide 1, as well as the esters 6 and 12 markedly sensitized the resistant CML cells to imatinib treatment. Correlation with their potency to activate PPARγ is not given. Candesartan cilexetil, telmisartan and 1 showed the profile of partial agonists at PPARγ with EC50 values of 4.2, 4.3 and 9.1 μM, respectively, while 6 and 12 caused only marginal intrinsic activation at 10 μM (Amax = 22% and 13%). However, the repression of the STAT5 phosphorylation relates with the possibility to sensitize K562-resistant CML cells to imatinib treatment. It is worth mentioning that all compounds were per se non-cytotoxic at relevant concentrations.

New 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives. Evaluation of different moieties on the 6-aryl ring to obtain potent and selective human A2A adenosine receptor antagonists

In this work, further structural investigations on the 8-amino-2-phenyl-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-one series were carried out to achieve potent and selective human A2A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1–9 and 10–18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like properties.Compounds 11–16, bearing the amide linker, possessed high affinity and selectivity for the hA2A AR (Ki = 3.6–11.8 nM). Also derivatives 1–9, featuring an ether linker, preferentially targeted the hA2A AR but with lower affinity, compared to those of the relative amide compounds. Docking studies, carried out at the hA2A AR binding site, highlighted some crucial ligand-receptor interactions, particularly those provided by the appended substituent whose nature deeply affected hA2A AR affinity.

A piperic acid CoA ligase produces a putative precursor of piperine, the pungent principle from black pepper fruits

Black pepper (Piper nigrum L.) is known for its high content of piperine, a cinnamoyl amide derivative regarded as largely responsible for the pungent taste of this widely used spice. Despite its long history and worldwide use, the biosynthesis of piperine and related amides has been enigmatic up to now. In this report we describe a specific piperic acid CoA ligase from immature green fruits of P.nigrum. The corresponding enzyme was cloned and functionally expressed in E.coli. The recombinant enzyme displays a high specificity for piperic acid and does not accept the structurally related feruperic acid characterized by a similar C-2 extension of the general C6-C3 phenylpropanoid structure. The enzyme is also inactive with the standard set of hydroxycinnamic acids tested including caffeic acid, 4-coumaric acid, ferulic acid, and sinapic acid. Substrate specificity is corroborated by in silico modelling that suggests a perfect fit for the substrate piperic acid to the active site of the piperic acid CoA ligase. The CoA ligase gene shows its highest expression levels in immature green fruits, is also expressed in leaves and flowers, but not in roots. Virus-induced gene silencing provided some preliminary indications that the production of piperoyl-CoA is required for the biosynthesis of piperine in black pepper fruits.

Sodium 4‐amino‐5‐hydroxy‐7‐sulfonaphthalene‐2‐sulfonate an efficient ligand for click reaction in water: Synthesis of 1,2,3‐triazole pharmacophore linked‐quinazolinone scaffold

AbstractWater soluble sodium 4‐amino‐5‐hydroxy‐7‐sulfonaphthalene‐2‐sulfonate ligand was used successfully for the preparation of 1,2,3‐triazoles pharmacophore linked‐quinazolinone scaffold. The reaction of ethyl 4‐oxo‐3,4‐dihydroquinazoline‐2‐carboxylate and related amide compounds with propargyl bromide afforded ethyl 4‐oxo‐3‐(prop‐2‐yn‐1‐yl)‐3,4‐dihydroquinazoline‐2‐carboxylate and its amide derivatives. The reaction of propargylated compounds with azides catalyzed by copper (II) salt, in the presence of Sodium 4‐amino‐5‐hydroxy‐7‐sulfonaphthalene‐2‐sulfonate as a ligand in water produced novel 1,2,3‐triazole pharmacophore linked‐quinazolinone‐4‐one scaffold with high‐to‐excellent yields. The ligand assisted in the click reaction and reduced loading of copper salt to 2 mol%. Simplicity, short reaction times, use of water as green solvent, and low catalyst loading are the main advantages of this procedure.

Piperidines from acid-catalysed cyclisations: Pitfalls, solutions and a new ring contraction to pyrrolidines

The success of acid-catalysed cyclisations of alka-4-enylamine derivatives to piperidines depends very much on the nature of the amine protecting group: while carbamates and related amides can usually be readily and cleanly transformed, the corresponding sulfonamides react further by ring contraction leading to pyrrolidines, especially when such substrates are sterically crowded.

Rotational barriers in five related amides

Interest in the low carbonyl IR frequency of 2-hydroxy-N,N-bis(2-hydroxyethyl)acetamide (2) initially prompted our interest in the amide rotational barrier of this molecule and four related amides that present a variety of hydrogen-bonding possibilities. In the course of this study, a previously incorrect structural assignment was established as N,N-bis[2-(acetyloxy)ethyl]-acetamide (6). In acetonitrile-d3, the carbonyl IR frequencies of the five amides were all essentially normal amide frequencies. Despite very different hydrogen-bonding possibilities in the five amides, no clear trends emerged in the comparison of the rotational barriers (ΔG‡), and the rotational barriers were essentially normal for amides. The rotational barrier of 2 did not vary over one order of magnitude difference in concentration.

Highly Enantioselective Hydrogenation of Amides via Dynamic Kinetic Resolution Under Low Pressure and Room Temperature.

High-throughput screening and lab-scale optimization were combined to develop the catalytic system trans-RuCl2((S,S)-skewphos)((R,R)-dpen), 2-PrONa, and 2-PrOH. This system hydrogenates functionalized α-phenoxy and related amides at room temperature under 4 atm H2 pressure to give chiral alcohols with up to 99% yield and in greater than 99% enantiomeric excess via dynamic kinetic resolution.

A computational study on the mechanism of ynamide-mediated amide bond formation from carboxylic acids and amines.

This paper reports a computational study elucidating the reaction mechanism for ynamide-mediated amide bond formation from carboxylic acids and amines. The mechanisms have been studied in detail for ynamide hydrocarboxylation and the subsequent aminolysis of the resulting adduct by an amine. Ynamide hydrocarboxylation is kinetically favorable and thermodynamically irreversible, resulting in the formation of a key low-lying intermediate CP1 featuring geminal vinylic acyloxy and sulfonamide groups. The aminolysis of CP1 by the amine is proposed to be catalyzed by the carboxylic acid itself that imparts favourable bifunctional effects. In the proposed key transition state TSaminolysis-acid-iso2, the amine undergoes direct nucleophilic substitution at the acyl of CP1 to replace the enolate group in a concerted way, which is promoted by secondary hydrogen bonding of carboxylic acid with both the amine and CP1. These secondary interactions are suggested to increase the nucleophilicity of the amine and to activate the Cacyl-O bond to be cleaved, thereby stabilizing the aminolysis transition state. The concerted aminolysis mechanism is competitive with the classic stepwise nucleophilic acyl substitution mechanism that features sequential amine addition to acyl/intramolecular proton transfer/C-O bond cleavage and a key tetrahedral intermediate. Based on the mechanistic model, the carboxylic acid substrate effect and studies of more acidic CF3SO3H as the catalyst are in good agreement with the experimental observations, lending further support for the mechanistic model. The bifunctional catalytic effect of the carboxylic acid substrate may widely play a role in related amide bond-forming reactions and peptide formation chemistry.

Plasma-enabled sensing of urea and related amides on polyaniline

The atmospheric pressure plasma jet (APPJ) was used to enhance the sensitivity of industrially important polyaniline (PANI) for detection of organic vapors from amides. The gas sensing mechanism of PANI is operating on the basis of reversible protonation or deprotonation, whereas the driving force to improve the sensitivity after plasma modifications is unknown. Herein we manage to solve this problem and investigate the sensing mechanism of atmospheric plasma treated PANI for vapor detection of amides using urea as a model. The results from various analytical techniques indicate that the plausible mechanism responsible for the improved sensitivity after plasma treatment is operating through a cyclic transition state formed between the functional groups introduced by plasma treatment and urea. This transition state improved the sensitivity of PANI towards 15 ppm of urea by a factor of 2.4 times compared to the non-treated PANI. This plasma treated PANI is promising for the improvement of the sensitivity and selectivity towards other toxic and carcinogenic amide analytes for gas sensing applications such as improving material processing and controlling food quality.

Quantitative assessment of the effects of water proton concentration and water T1 changes on amide proton transfer (APT) and nuclear overhauser enhancement (NOE) MRI: The origin of the APT imaging signal in brain tumor.

To quantify pure chemical exchange-dependent saturation transfer (CEST) related amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) signals in a rat glioma model and to investigate the mixed effects of water content and water T1 on APT and NOE imaging signals. Eleven U87 tumor-bearing rats were scanned at 4.7 T. A relatively accurate mathematical approach, based on extrapolated semisolid magnetization-transfer reference signals, was used to remove the concurrent effects of direct water saturation and semisolid magnetization-transfer. Pure APT and NOE signals, in addition to the commonly used magnetization-transfer-ratio asymmetry at 3.5 ppm, MTRasym (3.5ppm), were assessed. The measured APT signal intensity of the tumor (11.06%, much larger than the value reported in the literature) was the major contributor (approximately 80.6%) to the MTRasym (3.5ppm) contrast between the tumor and the contralateral brain region. Both the water content ([water proton]) and water T1 (T1w ) were increased in the tumor, but there were no significant correlations among APT, NOE, or MTRasym (3.5ppm) signals and T1w /[water proton]. The effect of increasing T1w on the CEST signal in the tumor was mostly eliminated by the effect of increasing water content, and the observed APT-weighted hyperintensity in the tumor should be dominated by the increased amide proton concentration. Magn Reson Med 77:855-863, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Ruthenium(II) complexes incorporating salicylaldiminato-functionalized N-heterocyclic carbene ligands as efficient and versatile catalysts for hydration of organonitriles

We describe a new synthetic procedure for synthesis of ruthenium(II) complexes containing salicylaldiminato functionalized mixed N-heterocyclic carbene (NHC) ligand and phosphine co-ligand. The complexes (3a–3d) have been obtained in good to excellent yields by transmetalation from the corresponding Ag–NHC complexes (2a–2d) as carbene transfer reagents. All the [Ru–NHC] complexes have been characterized by elemental analyses, spectroscopic methods as well as ESI mass spectrometry. The ligands 1a–1d show their versatility by switching to be O,N,C-chelating in these ruthenium(II) complexes. The resulting complexes have been evaluated as potential catalysts for the selective hydration of nitriles to primary amides, and related amide bond forming reactions, in environmentally friendly medium. The reaction tolerated ether, hydroxyl, nitro, bromo, formyl, pyridyl, benzyl and alkyl functional groups. The catalyst was stable for weeks and could be recovered and reused more than six times without significant loss of activity.

Modelling of copper(II) binding to pentapeptides related to atrial natriuretic factor using the 3χv connectivity index / Modeliranje vezivanja bakra(II) za pentapeptide povezane s atrijalnim natriuretičkim faktorom pomoću indeksa povezanosti 3χv

Abstract Using molecular graph theory we studied the binding of NSFRY-NH2 and 12 related pentapeptide amides to Cu(II) as a model system for atrial natriuretic factor (ANF) peptide interactions with copper. Linear regression models based on the valence connectivity index of the 3rd order (3χv) reproduced experimental stability constants (log β) for 1N, 2N, 3N, and 4N coordinated complexes with the standard error of 0.30-0.39 log β units. We developed separate models for seven tyrosinic (N=28) and five non-tyrosinic peptides (N=20), and a common model for both kinds of peptides (N=48) with an indicator (dummy) variable. The results indicate additional aromatic stabilisation in 4N complexes due to metal cation-π interactions with tyrosine but not with the phenylalanine residue. We have also amended the log K and log K* values to correct miscalculations published by Janicka-Klos et al. in 2013