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Acta Crystallographica. Section C,... Feb 2016Carbamazepine (CBZ) is well known as a model active pharmaceutical ingredient used in the study of polymorphism and the generation and comparison of cocrystal forms. The...
Carbamazepine (CBZ) is well known as a model active pharmaceutical ingredient used in the study of polymorphism and the generation and comparison of cocrystal forms. The pharmaceutical amide dihydrocarbamazepine (DCBZ) is a less well known material and is largely of interest here as a structural congener of CBZ. Reaction of DCBZ with strong acids results in protonation of the amide functionality at the O atom and gives the salt forms dihydrocarbamazepine hydrochloride {systematic name: [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium chloride, C15H15N2O(+)·Cl(-)}, dihydrocarbamazepine hydrochloride monohydrate {systematic name: [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium chloride monohydrate, C15H15N2O(+)·Cl(-)·H2O} and dihydrocarbamazepine hydrobromide monohydrate {systematic name: [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium bromide monohydrate, C15H15N2O(+)·Br(-)·H2O}. The anhydrous hydrochloride has a structure with two crystallographically independent ion pairs (Z' = 2), wherein both cations adopt syn conformations, whilst the two hydrated species are mutually isostructural and have cations with anti conformations. Compared to neutral dihydrocarbamazepine structures, protonation of the amide group is shown to cause changes to both the molecular (C=O bond lengthening and C-N bond shortening) and the supramolecular structures. The amide-to-amide and dimeric hydrogen-bonding motifs seen for neutral polymorphs and cocrystalline species are replaced here by one-dimensional polymeric constructs with no direct amide-to-amide bonds. The structures are also compared with, and shown to be closely related to, those of the salt forms of the structurally similar pharmaceutical carbamazepine.
Topics: Amides; Azepines; Carbamazepine; Crystallization; Crystallography, X-Ray; Hydrogen Bonding; Molecular Structure
PubMed: 26846502
DOI: 10.1107/S2053229616001133 -
Molecules (Basel, Switzerland) Apr 2020Amide bonds are among the most interesting and abundant molecules of life and products of the chemical pharmaceutical industry. In this work, we describe a method of the...
Amide bonds are among the most interesting and abundant molecules of life and products of the chemical pharmaceutical industry. In this work, we describe a method of the direct synthesis of amides from carboxylic acids and amines under solvent-free conditions using minute quantities of ceric ammonium nitrate (CAN) as a catalyst. The reactions are carried out in an open microwave reactor and allow the corresponding amides to be obtained in a fast and effective manner when compared to other procedures of the direct synthesis of amides from acids and amines reported so far in the literature. The amide product isolation procedure is simple, environmentally friendly, and is performed with no need for chromatographic purification of secondary amides due to high yields. In this report, primary amines were used in most examples. However, the developed procedure seems to be applicable for secondary amines as well. The methodology produces a limited amount of wastes, and a catalyst can be easily separated. This highly efficient, robust, rapid, solvent-free, and additional reagent-free method provides a major advancement in the development of an ideal green protocol for amide bond formation.
Topics: Amides; Amines; Carboxylic Acids; Catalysis; Cerium; Drug Industry; Environment; Green Chemistry Technology; Insecticides; Microwaves; Pharmaceutical Preparations
PubMed: 32290373
DOI: 10.3390/molecules25081761 -
European Biophysics Journal : EBJ Apr 2016Aurein 2.6-COOH and aurein 3.1-COOH were studied along with their naturally occurring C-terminally amidated analogues. Circular dichroism (CD) and molecular dynamic (MD)...
Aurein 2.6-COOH and aurein 3.1-COOH were studied along with their naturally occurring C-terminally amidated analogues. Circular dichroism (CD) and molecular dynamic (MD) simulations were used to study the effects of amidation on the interaction of antimicrobial peptides (AMPs) with lipid bilayers. CD measurements and MD analysis suggested that both peptide analogues were predominantly random coil and adopted low levels of α-helical structure in solution (<30%) and in the presence of a lipid bilayer the peptides formed a stable α-helical structure. In general, amidated analogues have a greater propensity than the non-amidated peptides to form a α-helical structure. MD simulations predicted that aurein 2.6-COOH and aurein 3.1-CHOOH destabilised lipid bilayers from 1,2-dimyristoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3-phosphoserine via angled bilayer penetration. They also showed that aurein 2.6-CONH₂ and aurein 3.1-CONH₂ formed a helix horizontal to the plane of an asymmetric interface.
Topics: Amides; Antimicrobial Cationic Peptides; Dimyristoylphosphatidylcholine; Lipid Bilayers; Molecular Dynamics Simulation
PubMed: 26745958
DOI: 10.1007/s00249-015-1094-x -
Journal of the American Chemical Society Sep 2022Amide synthesis is one of the most widely practiced chemical reactions, owing to its use in drug development and peptide synthesis. Despite the importance of these...
Amide synthesis is one of the most widely practiced chemical reactions, owing to its use in drug development and peptide synthesis. Despite the importance of these applications, the attendant effort to eliminate waste associated with these protocols has met with limited success, and pernicious α-epimerization is most often minimized but not eliminated when targeting challenging amides (e.g., -aryl amides). This effort has focused on what is essentially a single paradigm in amide formation wherein an electrophilic acyl donor reacts with a nucleophilic amine. Umpolung amide synthesis (UmAS) emerged from α-halo nitroalkane reactions with amines and has since been developed into a method for the synthesis of enantiopure amides using entirely catalytic, enantioselective synthesis. However, its inability to forge -aryl amides has been a longstanding problem, one limiting its application more broadly in drug development where α-chiral -aryl amides are increasingly common. We report here the reaction of α-fluoronitroalkanes and -aryl hydroxyl amines for the direct synthesis of -aryl amides using a simple Brønsted base as the promoter. No other activating agents are required, and experiments guided by mechanistic hypotheses outline a mechanism based on the UmAS paradigm and confirm that the -aryl amide, not the -aryl hydroxamic acid, is the direct product. Ultimately, select chiral α-amino--aryl amides were prepared with complete conservation of enantioenrichment, in contrast to a parallel demonstration of their ability to epimerize using the conventional amide synthesis alternative.
Topics: Amides; Amines; Catalysis; Hydroxamic Acids; Peptides
PubMed: 36067492
DOI: 10.1021/jacs.2c05986 -
BMC Emergency Medicine May 2023Ketamine and etomidate are commonly used as sedatives in rapid sequence intubation (RSI). However, there is no consensus on which agent should be favored when treating...
BACKGROUND
Ketamine and etomidate are commonly used as sedatives in rapid sequence intubation (RSI). However, there is no consensus on which agent should be favored when treating patients with trauma. This study aimed to compare the effects of ketamine and etomidate on first-pass success and outcomes of patients with trauma after RSI-facilitated emergency intubation.
METHODS
We retrospectively reviewed 944 patients who underwent endotracheal intubation in a trauma bay at a Korean level 1 trauma center between January 2019 and December 2021. Outcomes were compared between the ketamine and etomidate groups after propensity score matching to balance the overall distribution between the two groups.
RESULTS
In total, 620 patients were included in the analysis, of which 118 (19.9%) were administered ketamine and the remaining 502 (80.1%) were treated with etomidate. Patients in the ketamine group showed a significantly faster initial heart rate (105.0 ± 25.7 vs. 97.7 ± 23.6, p = 0.003), were more hypotensive (114.2 ± 32.8 mmHg vs. 139.3 ± 34.4 mmHg, p < 0.001), and had higher Glasgow Coma Scale (9.1 ± 4.0 vs. 8.2 ± 4.0, p = 0.031) and Injury Severity Score (32.5 ± 16.3 vs. 27.0 ± 13.3, p < 0.001) than those in the etomidate group. There were no significant differences in the first-pass success rate (90.7% vs. 90.1%, p > 0.999), final mortality (16.1% vs. 20.6, p = 0.348), length of stay in the intensive care unit (days) (8 [4, 15] (Interquartile range)), vs. 10 [4, 21], p = 0.998), ventilator days (4 [2, 10] vs. 5 [2, 13], p = 0.735), and hospital stay (days) (24.5 [10.25, 38.5] vs. 22 [8, 40], p = 0.322) in the 1:3 propensity score matching analysis.
CONCLUSION
In this retrospective study of trauma resuscitation, those receiving intubation with ketamine had greater hemodynamic instability than those receiving etomidate. However, there was no significant difference in clinical outcomes between patients sedated with ketamine and those treated with etomidate.
Topics: Humans; Etomidate; Ketamine; Retrospective Studies; Anesthetics, Intravenous; Rapid Sequence Induction and Intubation; Trauma Centers; Intubation, Intratracheal; Republic of Korea
PubMed: 37248552
DOI: 10.1186/s12873-023-00833-7 -
Molecules (Basel, Switzerland) Jan 2024This 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... (Review)
Review
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.
Topics: Humans; Vorinostat; Histone Deacetylases; Amides; Histone Deacetylase Inhibitors; Cell Line
PubMed: 38202821
DOI: 10.3390/molecules29010238 -
The Journal of Chemical Physics Jan 2023The form of the amide I infrared absorption band provides a sensitive probe of the secondary structure and dynamics of proteins in the solution phase. However, the...
The form of the amide I infrared absorption band provides a sensitive probe of the secondary structure and dynamics of proteins in the solution phase. However, the frequency coincidence of the amide I band with the bending vibrational mode of HO has necessitated the widespread use of deuterated solvents. Recently, it has been demonstrated that ultrafast 2D-IR spectroscopy allows the detection of the protein amide I band in HO-based fluids, meaning that IR methods can now be applied to study proteins in physiologically relevant solvents. In this perspective, we describe the basis of the 2D-IR method for observing the protein amide I band in HO and show how this development has the potential to impact areas ranging from our fundamental appreciation of protein structural dynamics to new applications for 2D-IR spectroscopy in the analytical and biomedical sciences. In addition, we discuss how the spectral response of water, rather than being a hindrance, now provides a basis for new approaches to data pre-processing, standardization of 2D-IR data collection, and signal quantification. Ultimately, we visualize a direction of travel toward the creation of 2D-IR spectral libraries that can be linked to advanced computational methods for use in high-throughput protein screening and disease diagnosis.
Topics: Spectrophotometry, Infrared; Proteins; Solvents; Amides; Water
PubMed: 36681646
DOI: 10.1063/5.0129480 -
Angewandte Chemie (International Ed. in... Nov 2016Recent studies have demonstrated that amides can be used in nickel-catalyzed reactions that lead to cleavage of the amide C-N bond, with formation of a C-C or...
Recent studies have demonstrated that amides can be used in nickel-catalyzed reactions that lead to cleavage of the amide C-N bond, with formation of a C-C or C-heteroatom bond. However, the general scope of these methodologies has been restricted to amides where the carbonyl is directly attached to an arene or heteroarene. We now report the nickel-catalyzed esterification of amides derived from aliphatic carboxylic acids. The transformation requires only a slight excess of the alcohol nucleophile and is tolerant of heterocycles, substrates with epimerizable stereocenters, and sterically congested coupling partners. Moreover, a series of amide competition experiments establish selectivity principles that will aid future synthetic design. These studies overcome a critical limitation of current Ni-catalyzed amide couplings and are expected to further stimulate the use of amides as synthetic building blocks in C-N bond cleavage processes.
Topics: Amides; Catalysis; Esters; Molecular Conformation; Nickel; Organometallic Compounds
PubMed: 27813308
DOI: 10.1002/anie.201607856 -
Anesthesiology Aug 2017We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis.
BACKGROUND
We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis.
METHODS
Mice (n = 5/group) were injected intraperitoneally with lipopolysaccharide (10 mg/kg) and 6 h later randomized to receive ketamine (100 mg/kg), etomidate (30 mg/kg), or saline. At two time points (12 and 48 h), messenger RNA levels of hypothalamic corticotropin-releasing hormone, pituitary proopiomelanocortin, and four adrenal enzymes (P450 side-chain cleavage, 3β-hydroxysteroid deshydrogenase, 21-hydroxylase, and 11β-hydroxylase) were measured by in situ hybridization (results are presented as optical density), and plasma levels of corticosterone and adrenocorticotropin hormones were measured by enzyme-linked immunosorbent assay (mean ± SD).
RESULTS
At 12 h, lipopolysaccharide induced an overexpression of corticotropin-releasing hormone (32 ± 5 vs. 18 ± 6, P < 0.01), proopiomelanocortin (21 ± 3 vs. 8 ± 0.9, P < 0.0001), P450 side-chain cleavage (32 ± 4 vs. 23 ± 10, P < 0.05), 21-hydroxylase (17 ± 5 vs. 12 ± 2, P < 0.05), and 11β-hydroxylase (11 ± 4 vs. 6 ± 0.5, P = 0.001), and an elevation of corticosterone (642 ± 165 vs. 98.3 ± 63 ng/ml, P < 0.0001). Etomidate and ketamine reduced P450 side-chain cleavage (19 ± 7 and 19 ± 3 vs. 32 ± 4, P < 0.01), 21-hydroxylase (8 ± 0.8 and 8 ± 1 vs. 17 ± 5, P < 0.001), 11β-hydroxylase (4 ± 0.5 and 7 ± 1 vs. 11 ± 4, P < 0.001 and P < 0.05), and corticosterone (413 ± 189 and 260 ± 161 vs. 642 ± 165 ng/ml, P < 0.05 and P < 0.01). Ketamine also inhibited adrenocorticotropin hormone production (2.5 ± 3.6 vs. 36 ± 15 pg/ml, P < 0.05). At 48 h, all four adrenal enzymes were down-regulated by lipopolysaccharide administration with corticosterone levels similar to the control group. Ketamine and etomidate did not modify corticosterone plasma levels.
CONCLUSIONS
Our endotoxemic model induces an initial activation of the hypothalamic-pituitary-adrenal axis, followed by a secondary inhibition of adrenal steroidogenesis processes. Ketamine and etomidate inhibit the enzyme expression and activity of the adrenal gland at the early stage.
Topics: Analgesics; Animals; Corticosterone; Corticotropin-Releasing Hormone; Disease Models, Animal; Down-Regulation; Endotoxemia; Etomidate; Hypnotics and Sedatives; Hypothalamo-Hypophyseal System; Ketamine; Male; Mice; Mice, Inbred C57BL; Pituitary-Adrenal System; Pro-Opiomelanocortin; Steroid 21-Hydroxylase
PubMed: 28542000
DOI: 10.1097/ALN.0000000000001704 -
Chembiochem : a European Journal of... Sep 2022N-Acetyl-d-glucosamine (GlcNAc) is one of the most common amino sugars in nature, but the conformation of its N-acetyl group has drawn little attention. We report herein...
N-Acetyl-d-glucosamine (GlcNAc) is one of the most common amino sugars in nature, but the conformation of its N-acetyl group has drawn little attention. We report herein the first identification of NH protons of the amide cis forms of α- and β-GlcNAc by NMR spectroscopy. Relative quantification and thermodynamic analysis of both cis and trans forms was carried out in aqueous solution. The NH protons were further utilized by adapting protein NMR experiments to measure eight J-couplings within the N-acetyl group, of which six are sensitive to the H2-NH conformation and two are sensitive to the amide conformation. For amide cis and trans forms, the orientation between H2 and NH was determined as anti conformation, while a small percentage of syn conformation was predicted for the amide trans form of β-GlcNAc. This approach holds great promise for the detailed conformational analysis of GlcNAc in larger biomolecules, such as glycoproteins and polysaccharides.
Topics: Acetylglucosamine; Amides; Glucosamine; Magnetic Resonance Spectroscopy; Protein Conformation; Protons
PubMed: 35713405
DOI: 10.1002/cbic.202200338