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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.

A concise and efficient ring-opening difluorination strategy was developed for the synthesis of highly functionalized hydroxy-containing α,α-difluoro-β-ketoamides from the one-pot multicomponent reaction of 4-aminocoumarins, NFSI, and water in dimethyl carbonate (DMC) as a green solvent. The reactions were smoothly achieved under visible light irradiation in air at room temperature without the addition of any other external photocatalysts. With this protocol, various α,α-difluoro-β-ketoamides were successfully synthesized under mild conditions (25 examples, 73-91% yields). This transition-metal-free synthetic procedure shows good functional group compatibility and attractive practical potential for large-scale synthesis.

An unprecedented DMAP-catalysed amidation of aryl and alkyl carboxylic acids with organo-cyanamides has been developed for the first time, enabling the efficient synthesis of a range of structurally diverse amides in useful to good yields.

Photoluminescent polymer nanoparticles based on organic compounds are a new category of advanced materials with potential applications in various fields such as chemosensors, optical devices, drug-delivery systems, anticounterfeiting inks and bioimaging. Herein, amide functionalized copolymer nanoparticles with a particle size in the range of 42-139 nm were synthesized by emulsion copolymerization of methylmathacrylate (MMA) and methacrylamide (MAAm) with different concentrations in the range of 0-20 wt%. Afterward, the photoluminescent copolymer nanoparticles (PLCNPs) were prepared by physical modification of amide functionalized copolymer nanoparticles with 5 wt% of oxazolidine derivative (OXOH). Investigation of optical properties include of photoluminescence and UV-vis spectra displayed significant dependency of emission and absorbance bands to the local polarity or the concentration of the amide groups on the surface of the nanoparticles. Study of Commission Internationale de l'Eclairage (CIE) colorimetric diagrams for PLCNPs samples confirmed the results of photoluminescence and UV-vis spectra, which a logical shift in color of the photoluminescence emission was observed by an increase in the concentration of the amide groups. The PLCNPs samples have remarkable stability (in physical and optical properties) when applied on polar substrates such as polymer sheet and cellulose paper. Therefore, the PLCNPs samples were used for development of eco-friendly water based anticounterfeiting inks, photoluminescence organic light emitting diodes (OLEDs), and also the photodetection of scratches in a fast and facile manner. The printed security tags and hand-written phrases on cellulosic papers have orange fluorescent emission with maximum intensity because nanoscale size of particles, which reduced the light scattering and increased the accessible concentration of OXOH for light absorption. A coating of poly(vinyl alcohol) (PVA)/PLCNPs solution onto a blue LED (365 nm) was led to a change in the color of emission from blue to purple, because of the excitation of OXOH molecules at 365 nm with the subsequent emission of purple light. The photodetection of created scratch on polycarbonate sheet was carried out by spray of PLCNPs solution on sheet and then illumination with UV irradiation (365 nm). Developed water based PLCNPs samples have interesting optical properties, high stability on different surfaces and nanoscale particle size which are applicable in multiple applications such as eco-friendly photoluminescent inks for anticounterfeiting technologies, photoluminescence OLEDs, and also optical detector for monitoring of scratches on different substrates.

Background. Despite the clinical effectiveness of the programmed intermittent bolus (PIB) method for epidural analgesia, evidence for this method in continuous interscalene brachial plexus block (CIBPB) is unclear. This study aimed to investigate the pain relief effect after arthroscopic shoulder surgery according to the administration method by comparing the PIB and continuous infusion methods among the administration methods of local anesthetics. Methods. Sixty-four patients aged >19 years scheduled for elective arthroscopic shoulder surgery were enrolled and divided into two groups. Ultrasound-guided CIBPB was performed to control postoperative pain. The infusion pump was programmed so that 0.2% ropivacaine was continuously injected at 1.1 mL/h in group A, whereas in group B, 0.1 mL/h was continuously injected and 4 mL was periodically injected at 4 h intervals. In both groups, a further infusion of 4 mL of 0.2% ropivacaine was administered if the patient requested additional analgesia, and the lockout time was set at 30 min. Postoperative pain quality was assessed using a visual analog scale (VAS), and the incidence of patients requiring additional analgesics, motor blockade using a modified Bromage scale (MBS), and consumed doses of local anesthetic were assessed. Results. The VAS and incidence of rescue analgesics were performed when the patient could communicate voluntarily after admission to the post-anesthetic care unit, and at 24 and 48 h after surgery showed no significant difference between the two groups. The MBS at 24 h after surgery was significantly higher in group B ( p = 0.038). In the comparison of consumed doses of local anesthetic, group B had a significantly higher bolus injection dose ( p = 0.047) and frequency of bolus use in the 24 h after surgery ( p = 0.034). Conclusion. The PIB method in CIBPB after arthroscopic shoulder surgery provided a similar analgesic effect, with a higher bolus injection dose of local anesthetic and increased motor blockade than the continuous infusion method.

This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. This demonstrates a significant expansion of the accessible chemical space of azole-2-amides, compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C-H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates. A diverse azole substrate scope designed via machine-learning-guided analysis demonstrates the broad utility of the sequence. Density functional theory calculations provide detailed insights into the role of silyl triflates in the reaction mechanism. Transferrable applications of the protocol are successfully established: (i) A low pressure (CO

We report a combined experimental and mechanistic study on the Buchwald-Hartwig amination and C-S/S-H metathesis of aryl sulfides by selective activation of C-S bonds mediated by well-defined, air-and moisture-stable Pd(II)-NHC precatalysts, [Pd(NHC)(mu-Cl)Cl]2. This class of Pd(II)-NHC precatalysts displays excellent activity in the cross coupling of aryl sulfides. Most crucially, we unravel the unified mechanism for activation of C-S bonds in the C-N cross-coupling and C-S metathesis manifolds, where the inert C-S bond serves as a precursor to valuable amine or thioether products.

An approach for the copper-catalyzed synthesis of enantioenriched amides bearing an α-stereogenic center is disclosed. This method involves the addition of an allyl copper species to an isocyanate and allows access to α-substituted chiral amides in high yields and high-to-excellent enantioselectivities. The utility of α-vinyl β-boryl amides in synthesis is highlighted by the diversification of products to afford highly useful scaffolds. DFT calculations reveal that the catalyst preferentially coordinates to the oxygen of the isocyanate. Enantiocontrol arises from the steric repulsion between the boryl group and the stereodirecting phenyl of the chiral ligand.

Phototheranostics, a local non-invasive approach that integrates light-based diagnostics and therapeutics, enables precise treatment using nanotheranostic agents with minimal damage to normal tissues. However, ensuring high-efficiency ablation of cancer cells using phototheranostics for one time irradiation is highly challenging. Herein, we designed and synthesized a single-walled carbon nanohorns-based nanotheranostic agent, HA-IR808-SWNHs, by loading IR808, a photosensitizer, conjugated hyaluronic acid (HA) with an amide bond on the surface of single-walled carbon nanohorns (SWNHs) through noncovalent π-π interaction by the sonication method. The HA in HA-IR808-SWNHs improves the water dispersibility of SWNHs and endows SWNHs with targeting capabilities. Importantly, overexpressed endogenous hyaluronidase in cancer cells actively disassembles HA-IR808-SWNHs, forming small HA-IR808 fragments. The fragments exhibit a strong fluorescence signal and can be used to guide programmed photodynamic therapy for sequentially eliminating the residual living cancer cells. The current study confirms that HA-IR808-SWNHs is an endogenous enzyme-responsive nanotheranostic agent that can be employed to precisely track and ablate residual cancer cells in a spatiotemporal manner. The results strengthen the understanding of SWNH functionalization and expand its potential biomedical application, especially in cancer theranostics.

In order to monitor the risk of pesticide pollutants in drinking water, an analytical method based on online-solid phase extraction coupled with ultra performance liquid chromatography-triple quadrupole mass spectrometry (online-SPE-UPLC-MS/MS) was established for the simultaneous rapid screening and determination of 107 pesticides and metabolites (organophosphorus, organic nitrogen, organic heterocycle, carbamate, amide, benzoyl urea, neonicotinoid, etc.) in raw water and drinking water. Different injection volumes (5, 10, and 15 mL) were compared. The detection response increased with an increase in the injection volume, but the matrix effect also became more pronounced. Under the premise of ensuring the sensitivity of the method and meeting the detection requirements, the injection volume was selected as 5 mL. Accordingly, the samples were filtered through a 0.22-μm hydrophilic polytetrafluoroethylene filter, and then, 5 mL samples were injected into the online-SPE system by the automatic sampler. After adsorption on an X Bridge C

Abstract: Favipiravir is a potential antiviral drug undergoing clinical trials to manage various viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Favipiravir possesses antiviral properties against RNA viruses, including SARS-CoV-2. Unfortunately, these viruses do not have authorized antiviral drugs for the management of diseases resulting from their infection, hence the dire need to accentuate the discovery of antiviral drugs that are efficacious and have a broad spectrum. Favipiravir acts primarily by blocking inward and outward movements of the virus from cells. Favipiravir is a prodrug undergoing intracellular phosphorylation and ribosylation to form an active form, favipiravir-RTP, which binds viral RNA-dependent RNA polymerase (RdRp). Considering the novel mechanism of favipiravir action, especially in managing viral infections, it is vital to pay more attention to the promised favipiravir hold in the management of SARS-CoV-2, its efficacy, and dosage regimen, and interactions with other drugs. In conclusion, favipiravir possesses antiviral properties against RNA viruses, including COVID- 19. Favipiravir is effective against SARS-CoV-2 infection through inhibition of RdRp. Pre-clinical and large-scalp prospective studies are recommended for efficacy and long-term safety of favipiravir in COVID-19.

The purpose of this study was to investigate whether amide proton transfer (APT) imaging and intravoxel incoherent motion (IVIM) imaging can predict tumor response to concurrent chemoradiotherapy (CCRT) in patients with squamous cell carcinoma of the cervix (SCCC).Fifty-nine women (mean age, 54 years ± 10 [standard deviation] years; age range: 32-81 years) with pathologically confirmed SCCC underwent magnetic resonance imaging examination of the pelvis including APT and IVIM before concurrent chemoradiotherapy. They were divided into complete remission (CR) and non-CR groups according to therapeutic effect. APT values and IVIM-derived parameters were measured. Intra- and interobserver agreement for IVIM and APT parameters was assessed using intraclass correlation coefficient (ICC) The independent samples t-test was performed to compare the evaluated parameters between the two groups. Predictive performance for treatment response was evaluated by receiver operator characteristic (ROC) curve analysis.There were 38 and 21 patients in the non-CR and CR groups, respectively. Excellent interobserver and intraobserver agreement were obtained for all IVIM and APT parameters, with ICCs ranging from 0.844 to 0.962. Perfusion fraction (f) and APT values were lower in the CR group compared with the non-CR group (both P0.05). The combination of f and APT values showed good diagnostic performances in predicting response to concurrent chemoradiotherapy, with an area under the ROC curve of 0.852 (95% CI: 0.744-0.961), 79% sensitivity (95% CI: 63-90%), 90% specificity (95% CI: 70-99%) and 83% accuracy (95% CI: 71-92%).APT and IVIM imaging may serve as noninvasive tools for predicting response to concurrent chemoradiotherapy in patients with SCCC.

Several classes of ribosomally synthesized and post-translationally modified peptides (RiPPs) are composed of multiple macrocycles. The enzymes that assemble these macrocycles must surmount the challenge of installing a single specific set of linkages out of dozens of distinct possibilities. One class of RiPPs that includes multiple macrocycles are the graspetides, named after the ATP-grasp enzymes that install ester or amide linkages between pairs of nucleophilic and electrophilic side chains. Here, using heterologous expression and NMR spectroscopy, we characterize the connectivity and structure of amycolimiditide, a 29 aa graspetide with a stem-loop structure. The stem includes four esters and extends over 20 Å. The loop of amycolimiditide is distinguished by the presence of an aspartimide moiety, installed by a dedicated

Despite several synthetic approaches that have been developed for α-deuterated amino acids, the synthesis of β-deuterated amino acids has remained a challenge. Herein, we disclose a palladium catalyzed H/D exchange protocol for a β-deuterated N-protected amino amide, which can be converted to a β-deuterated amino acid simply by removal of protecting groups. This protocol is highly efficient, simply manipulated, and appliable for deuterium-labeling of many amino amides. In addition, deuterium labeling of phenylalanine derivatives was also successful when pivalic acid served as an additive to promote the H/D exchange process.

Amide bond reduction is a versatile transformation offering access to various alcohols and amines which could be used as valuable precursors in the chemical and pharmaceutical industries, e.g. for manufacturing plastics, textiles, dyes, agrochemicals, etc. Over the last two decades, catalytic amide hydrogenation employing homogenous catalysis has gained more attention due to the atom efficiency and low environmental impact of this transformation. Owing to the inherent strength of amide bonds, amide hydrogenation procedures often involve high temperatures and pressures, which is why efforts are being channeled to finding protocols with lower energy input. Here, we report a mild amide hydrogenation method involving commercially available precursors Ru(acac)3 and 1,2-bis(di-tert-butylphosphinomethyl)benzene (L4), which under basic conditions, at 80 ˚C and under 30 bar of H2 can selectively hydrogenate a series of 2˚-benzamides to anilines and alcohols with yields ranging from 36–98% and 29–92%, respectively. Additionally, 1˚- and 3˚-amides proved to be appropriate substrates, however, low to moderate yields were obtained. The catalyst is believed to operate via an inner-sphere mechanism with a hemiaminal being the likely intermediate during the hydrogenation process.

Molecular catalysts for ammonia oxidation to dinitrogen represent enabling components to utilize ammonia as a fuel and/or source of hydrogen. Ammonia oxidation requires not only the breaking of multiple strong N-H bonds, but also controlled N-N bond formation. We report a novel β-diketiminato copper complex [iPr2NNF6]Cu-NH3 ([Cu(I)]-NH3 (2)) as a robust electrocatalyst for NH3 oxidation in acetonitrile under homogeneous conditions. Complex 2 operates at a moderate overpotential (700 mV) with a TOFmax = 940 h-1 as determined from CV data in 1.3 M NH3 MeCN solvent. Prolonged (>5 h) controlled potential electrolysis (CPE) reveals the stability and robustness of the catalyst under electrocatalytic conditions. Detailed mechanistic investigations indicate that electrochemical oxidation of [Cu(I)]-NH3 forms {[Cu(II)]-NH3}+ (4) which undergoes deprotonation by excess NH3 to form reactive copper(II)-amide [Cu(II)]-NH2 (6) unstable towards N-N bond formation to give the dinuclear hydrazine complex [Cu(I)]2(mu-N2H4). Electrochemical studies reveal that the bisammine complex [Cu(I)](NH3)2 (7) forms at high ammonia concentration as part of the {[Cu(II)](NH3)2}+/[Cu(I)](NH3)2 redox couple that is electrocatalytically inactive. DFT analysis reveals a much higher thermodynamic barrier for deprotonation of {[Cu(II)](NH3)2}+ (8) by NH3 to give the four-coordinate copper(II) amide [Cu(II)](NH2)(NH3) (9) (dG = 31.7 kcal/mol) as compared to deprotonation of the three coordinate {[Cu(II)]-NH3}+ by NH3 to provide the reactive three coordinate parent amide [Cu(II)]-NH2 (dG = 18.1 kcal/mol) susceptible to N-N coupling to form [Cu(I)]2(mu-N2H4) (dG = -11.8 kcal/mol).

Yb(III) complexes of macrocyclic ligands based on1,4,7,10-tetraazacyclododecane were synthesized. The ligands carried a carbostyril chromophore for Yb(III) sensitization, and carboxylate or carbamide donors for metal binding, forming complexes of 0, +1, +2, or +3 overall charge. The coordination geometry was little affected by the replacement of carboxylates with amides, as shown by paramagnetic 1H NMR spectroscopy. The Yb(III)/Yb(II) reduction potentials were dependent on the nature of the metal binding site, and the more positively charged complexes were easier to reduce. Carbostyril excitation resulted in Yb(III) luminescence in every complex. The residual carbostyril fluorescence quantum yields were smaller in complexes containing more reducible Yb(III) centers decreasing from 5.9% for uncharged complexes to 3.1−4.4% in +3 charged species, suggesting photoinduced electron transfer (PeT) from the antenna to the Yb(III). The relative Yb(III) luminescence quantum yields were identical within the experimental error, except for the +3 charged complex with fully methylated coordinating amides, which was the most intense Yb(III) emitter of the series in water. Quenching of the Yb(III) excited state by NH vibrations proved to limit Yb(III) emission. No clear improvement of the Yb(III) sensitization efficiency was shown upon faster PeT. This result can be explained by the concomitant sensitization of Yb(III) by phonon-assisted energy transfer (PAEnT) from the antenna triplet excited state, which was completely quenched in all of the Yb complexes. Depopulation of the triplet by PeT quenching of the donor singlet excited state would be compensated by the sensitizing nature of the PeT pathway, thus resulting in a constant overall sensitization efficiency across the series.

Synthesis of drug metabolites, which often have complex structures, is an integral step in the evaluation of drug candidate metabolism, pharmacokinetic (PK) properties, and safety profiles. Frequently, such synthetic endeavors entail arduous, multiple-step de novo synthetic routes. Herein, we present the one-step Shono-type electrochemical synthesis of milligrams of chiral α-hydroxyl amide metabolites of two orexin receptor antagonists, MK-8133 and MK-6096, as revealed by a small-scale (pico- to nano-mole level) reaction screening using a lab-built online electrochemistry (EC)/mass spectrometry (MS) (EC/MS) platform. The electrochemical oxidation of MK-8133 and MK-6096 was conducted in aqueous media and found to produce the corresponding α-piperidinols with exclusive regio- and stereoselectivity, as confirmed by high-resolution nuclear magnetic resonance (NMR) characterization of products. Based on density functional theory (DFT) calculations, the exceptional regio- and stereoselectivity for this electrochemical oxidation are governed by more favorable energetics of the transition state, leading to the preferred secondary carbon radical α to the amide group and subsequent steric hindrance associated with the U-shaped conformation of the cation derived from the secondary α-carbon radical, respectively.

Creatine (Cr) supplementation is a well-established strategy to enhance gains in strength, lean body mass, and power from a period of resistance training. However, the effectiveness of creatyl-L-leucine (CLL), a purported Cr amide, is unknown. Therefore, the purpose of this study was to assess the effects of CLL on muscle Cr content. Twenty-nine healthy men (n = 17) and women (n = 12) consumed 5 g/day of either Cr monohydrate (n = 8; 28.5 ± 7.3 years, 172.1 ± 11.0 cm, 76.6 ± 10.7 kg), CLL (n = 11; 29.2 ± 9.3 years, 170.3 ± 10.5 cm, 71.9 ± 14.5 kg), or placebo (n = 10; 30.3 ± 6.9 years, 167.8 ± 9.9 cm, 69.9 ± 11.1 kg) for 14 days in a randomized, double-blind design. Participants completed three bouts of supervised resistance exercise per week. Muscle biopsies were collected before and after the intervention for quantification of muscle Cr. Cr monohydrate supplementation which significantly increased muscle Cr content with 14 days of supplementation. No changes in muscle Cr were observed for the placebo or CLL groups. Cr monohydrate supplementation is an effective strategy to augment muscle Cr content while CLL is not.

Nitrile hydratase (NHase; EC 4.2.1.84) is widely used to synthesize the corresponding amides from nitriles, which is the most successful green biocatalyst. However, the limited acceptability of substrates and instability under harsh reaction conditions have hindered its widespread industrial application. Here, a gene encoding an extremophilic NHase from Streptomyces thermoautotrophicus (S.t NHase) was successfully overexpressed in Escherichia coli. The enzyme exhibited excellent thermostability, retaining50 % of residual activity after heat treatment at 65 °C for 252 min. To further improve the catalytic performance of S.t NHase, semi-rational engineering of its substrate access tunnel was performed. A mutant βL48D showed a specific activity of 566.18 ± 18.86 U/mg towards 3-cyanopyridine, which was 7.7 times higher than its parent enzyme (73.80 ± 5.76 U/mg). Molecular dynamics simulation showed that the introduction of aspartic acid into βLeu48 resulted in a larger and more frequent opening of the substrate access tunnel entrance. On this basis, a "toolbox" containing various mutants on the substrate access tunnel was further established, whose catalytic activity towards various nitrile substrates was extensively improved, showing great potential for efficient synthesis of multiple high-value amides.

The preparation, structure, physical properties, and reactivities of sodium isopropyl(trimethylsilyl)amide (NaPTA) are described. Solubilities at room temperature range from n-heptane (0.55 M), n-hexane (0.60 M), toluene (0.65 M), MTBE (1.7 M), Et(3)N (3.2 M), and THF (>6.0 M). The half-life to destruction in neat THF is >1 year at 25 °C and 7 days at 70 °C, which compares favorably to 2.5 months and 1.5 days, respectively, for LDA in neat THF. The manuscript focuses on NaPTA/THF solutions. (29)Si spectroscopy shows exclusively a mixture of cis and trans stereoisomeric dimers in 0.10–12 M THF in hexane. Density functional theory (DFT) computations suggest the pK(b) is intermediate between dimeric sodium diisopropylamide (NaDA) and dimeric sodium hexamethyldisilazide (NaHMDS). Metalations of arenes, epoxides, ketones, hydrazones, alkenes, and alkyl halides show higher reactivities than LDA (kNaPTA/LDA = 1–30). While the rates of arene metalation are high, the lower pK(b) of NaPTA limits the substrates. Metalation of pseudoephedrate-based carboxamides to form disodiated Myers enolates solves several challenging technical problems.

The methods of the α-proton chemical shift index (CSI) and the amide proton (NH) chemical shift temperature coefficient (Δδ/ΔT) were found experimentally by a number of studies on proton NMR chemical shifts of peptides and proteins in an aqueous solution, and have been widely accepted. They provide an insight into secondary structures and intra-molecular hydrogen bonds in peptides and proteins without complex calculation. Our question is whether the methods are applicable to helical peptides in methanol. Melittin, a peptide of 26 amino acid residues found in bee venom, has been known to consist of two helices (the residues 2-11 and 13-26) connected by a kink section (the residues 11-13). Employing the methods for melittin in methanol, we have shown that most of the CSI's for the residues 3-10 and 14-26 are - 1, and the Δδ/ΔT's for the residues 5-26 except 6 and 14 are more positive than - 6 ppb/℃. If the methods are applicable to melittin in methanol, these results indicate that helix structures are formed in the regions of the residues 3-10 and 14-26 and NH's in the residues 5-26 except 6 and 14 are involved in intra-molecular hydrogen bonds. The helical structure evaluated from the methods, hence, agrees nearly with the known helix structure. We also apply the methods to D-Pro14 melittin (synthetic melittin) and alamethicin (a peptide of 20 amino acid residues) in methanol, and show that they virtually work well.

This manuscript reports the effect of hydrogen-bonding functionality on the supramolecular assembly of naphthalene-diimide (NDI)-derived amphiphilic building blocks in water. All the molecules contain a central NDI chromophore, functionalized with a hydrophilic oligo-oxyethylene (OE) wedge in one arm and a phenyl group on the opposite arm. They differ by a single H-bonding functionality, which links the NDI chromophore and the phenyl moiety. The H-bonding functionalities are amide, thioamide, urea, and urethane in NDI-A, NDI-TA, NDI-U, and NDI-UT, respectively. All of these molecules exhibit π-stacking in water, as evident from their distinct UV/vis absorption spectra when compared to that of the monomeric dye in THF. However, among these four, only NDI-A and NDI-TA show hydrogelation, while the other two precipitate out of the medium. The NDI-A hydrogel also exhibits transient stability and leads to a crystalline precipitate within ∼5 h. Only NDI-TA produces stable transparent hydrogel with the entangled fibrillar morphology that is typical for gelators. Both NDI-A and NDI-TA showed a thermoresponsive property with a lower critical solution temperature of about 41-42 °C. Powder XRD studies show a parallel orientation for NDI-A and an antiparallel orientation for NDI-TA. Computational studies support this experimental observation and indicate that the NDI-A assembly is highly stabilized by strong H-bonding among the amide groups and π-stacking interaction in the parallel orientation. On the other hand, due to weak H-bonding among the thioamide groups, the binding energy of the parallelly oriented NDI-TA was significantly lower and the optimized structure was disordered. Instead, its antiparallel orientation was more stable, with criss-cross aligned H-bonding interactions and π-π interactions between adjacent aromatic rings. The NDI-TA hydrogel with less ordered OE chains on the surface showed prominent adsorption of serum protein BSA. In sharp contrast, NDI-A did not exhibit any notable interaction with BSA, as evident from the ITC studies.

Amino acids are important nitrogen-containing compounds and organic carbon components that exist widely in the atmosphere. The formation of atmospheric aerosols is affected by their interactions with amides. The dimers formed by glutamic acid (Glu) or protonated glutamic acid (Glu

An iron-catalyzed four-component sulfonylthiocyanation between α,β-unsaturated amides/esters, TMSNCS, aryldiazonium tetrafluoroborates, and sulfur dioxide (from SOgen) is demonstrated. This protocol is characterized by mild reaction conditions, good functional group compatibility, broad substrate scope, and good to excellent yields, providing a feasible method for the preparation of

Fe(II) and Ni(II) paraCEST contrast agents containing the di-pyridine macrocyclic ligand 2,2',2″-(3,7,10-triaza-1,5(2,6)-dipyridinacycloundecaphane-3,7,10-triyl)triacetamide (DETA) are reported here. Both [Fe(DETA)]

We herein report the use of phenyl trimethylammonium iodide (PhMesub3/subNI) as a safe, nontoxic, and easy-to-handle reagent for an absolutely monoselective N-methylation of amides and related compounds as well as for the N-methylation of indoles. In addition, we expanded the method to N-ethylation using PhEtsub3/subNI. The ease of operational setup, high yields of ≤99%, high functional group tolerance, and especially the excellent monoselectivity for amides make this method attractive for late-stage methylation of bioactive compounds.

Background Bladder cancer is classified into high and low grades with different clinical treatments and prognoses. Thus, accurate preoperative evaluation of the histologic grade through imaging techniques is essential. Purpose To investigate the potential of amide proton transfer-weighted (APTw) MRI in evaluating the grade of bladder cancer and to evaluate whether APTw MRI can add value to diffusion-weighted imaging (DWI) at MRI. Materials and Methods In this single-center prospective study, participants with pathologic analysis-confirmed bladder cancer with no previous treatment, lesions larger than 10 mm, and adequate MRI quality were enrolled from July 2020 to September 2021 in a university teaching hospital. All participants underwent preoperative multiparametric MRI, including APTw MRI and DWI. The mean APTw and apparent diffusion coefficient (ADC) values of the primary tumor were measured independently by two radiologists. Receiver operating characteristic curves were generated to evaluate the diagnostic performance of these quantitative parameters. Results In total, 83 participants (mean age, 64 years ± 13 [SD]; 72 men) were evaluated: 51 with high-grade and 32 with low-grade bladder cancer. High-grade bladder cancer showed higher APTw values (6% [IQR, 4%-12%] vs 2% [IQR, 1%-3%]

Inflammation is at the core of many chronic conditions and exacerbates infectious conditions, including the severity of coronavirus disease 2019 (COVID-19) infections.This study aimed to examine the effects of a novel food supplement, palmitoylethanolamide (PEA), specifically Levagen+, as compared with a placebo on proinflammatory biomarkers in adults recently diagnosed with COVID-19 who were unvaccinated and nonhospitalized.This study was a double-blind randomized placebo-controlled trial conducted October 2020-March 2021 (clinicaltrials.gov: NCT04912921). Participants aged 19-53 y were unvaccinated and recently infected with COVID-19 as indicated by a positive test result per RT-PCR or antigen test, and they reported to the test site following diagnosis as allowed by the CDC's return-to-work policy. Participants were stratified by age, sex, and BMI and randomly assigned by coin toss to receive 600 mg Levagen+ twice daily (LEV) or placebo tablets twice daily (CON) for 4 wk. At baseline and week 4, participants completed health histories, 24-h dietary recalls, anthropometrics, and nonfasting blood sampling. The primary outcomes were the 4-wk change between groups for IL-6, C-reactive protein, ferritin, intercellular adhesion molecule 1, soluble P-selectin (sP-selectin), and neutrophil/lymphocyte ratio. Multiple linear regression models were utilized to assess treatment effects on outcomes, adjusting for covariates.A total of 60 participants completed the study (LEV: n = 30; CON: n = 30). After 4 wk of supplementation, sP-selectin (β = -11.5; 95% CI: -19.8, -3.15; P = 0.0078), IL-1β (β = -22.9; 95% CI: -42.4, -3.40; P = 0.0222), and IL-2 (β = -1.73; 95% CI: -3.45, -0.065; P = 0.0492) concentrations were significantly reduced in the LEV group compared with the CON group.Inflammatory mechanisms are crucial to optimal resolution of infectious conditions, yet unchecked secretion of inflammatory mediators can promote the dysregulated immune response implicated in COVID-19 complications. Overall, PEA supplementation produced anti-inflammatory effects in individuals recently diagnosed with COVID-19 who were nonhospitalized.

Rosmarinic acid (RA) and tanshinone IIA (TA) which are effective components in Salvia miltiorrhiza show anti-inflammatory potential against atherosclerosis. Based on polysulfated propylene-polyethylene glycol (PPS-PEG), RA was grafted onto this polymer via amide bonds to form a micelle carrier for TA encapsulation: PPS-PEG-RA@TA. A potent inhibitory effect on lipopolysaccharide (LPS) -induced proliferation of endothelial cells with significant intracellular uptake was observed with this system. This could have been the result of release of TA in a reactive oxygen species (ROS) environment and stronger antioxidant effect of RA. The synergistic effect was optimized when the combination was used in a molar ratio of 1:1. Mechanistic studies showed that, compared with PPS-PEG-RA and TA+RA, PPS-PEG-RA@TA micelles could more effectively regulate the nuclear factor-kappa B (NF-κB) pathway to reduce expression of vascular cell adhesion molecule-1 (VCAM-1), inhibit the inflammatory cascade and reduce endothelial-cell injury. One month after intravenous injection of PPS-PEG-RA@TA micelles, the plaque area in murine aortic vessels was reduced significantly, and serious toxic side-effects were not observed in vivo, along with excellent biocompatibility. In summary, PPS-PEG-RA@TA micelles could achieve synergistic treatment of atherosclerosis.

To investigate the optimal amide proton transfer (APT) imaging parameters for bladder cancer (BCa), the influence of different protein concentrations and pH values on APT imaging, and to establish the reliability of APT imaging in healthy volunteers and patients with BCa.The optimal APT imaging parameters for BCa were experimentally optimised using cross-linked bovine serum albumin (BSA) phantoms. BSA phantoms were scanned with different values for the saturation power, saturation duration and number of excitations. Meanwhile, BSA phantoms containing different protein concentrations and solutions of different pH levels were scanned. The interobserver agreement of the asymmetric magnetisation transfer ratio (MTRThe optimal scanning scheme consisted of 1 excitation, a saturation power of 2 μT, and a saturation time of 2 s. The APT signal intensity increased as the protein concentration increased and as the pH decreased. The MTRAPT imaging showed potential value for application in BCa.

Massive bleeding is a great threat to the life safety of patients, which is a challenging clinical problem. Therefore, it is urgent to develop a kind of multifunctional dressing material with hemostatic ability and antibacterial performance to promote wound healing and repair. To resolve this issue, in this study, a carboxymethyl chitosan (CMCS)/sodium alginate (SA)/oxidized dextran (ODE) (CSO) multifunctional hydrogel was developed. The hydrogel could rapidly gel through Schiff base reaction and amide reaction and firmly adhere to the skin at the wound, to realize the fast hemostasis. Importantly, it was verified that the hydrogel could prevent the Staphylococcus aureus-caused wound infection, owing to the antibacterial effect of CMCS and ODE. In addition, the CSO hydrogel had good water retention capacity and was able to mimic the three-dimensional structure of the natural extracellular matrix, thereby promoting wound repair in mice. In vitro whole-blood clotting assay demonstrated that red blood cells could be adhered to the surface of hydrogel, showing good hemostasis in rat liver injury and tail amputation models. Together with the biocompatible feature, CSO hydrogel holds a great application prospect in hemostasis and wound healing.

This paper describes a mild strategy to promote amide arylations. Photoinduced oxidation of a Ni(II) aryl amido intermediate is proposed to facilitate the challenging C-N reductive elimination step at moderate temperatures. Notably, the mildly basic conditions employed facilitate access to a broad scope including protected amino acids, heterocycles, phenols, and sterically hindered substituents. Hence, this work presents an attractive strategy to enable late-stage functionalization of pre-existing amide moieties in commercial drugs and natural products.

To develop a novel 3D abdominal CEST MRI technique at 3 T using MR multitasking, which enables entire-liver coverage with free-breathing acquisition.k-Space data were continuously acquired with repetitive steady-state CEST (ss-CEST) modules. The stack-of-stars acquisition pattern was used for k-space sampling. MR multitasking was used to reconstruct motion-resolved 3D CEST images of 53 frequency offsets with entire-liver coverage and 2.0 × 2.0 × 6.0 mmBoth APT-CEST and glycoCEST signals showed high sensitivity between post-fasting and post-meal acquisitions. APT-CEST and glycoCEST MTRasym signals from post-mean scans were significantly increased (APT-CEST: -0.019 ± 0.017 in post-fasting scans, 0.014 ± 0.021 in post-meal scans, p 0.01; glycoCEST: 0.003 ± 0.009 in post-fasting scans, 0.027 ± 0.021 in post-meal scans, p 0.01).The proposed 3D abdominal steady-state CEST method using MR multitasking can generate CEST images of the entire liver during free breathing.

Human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection worldwide. Until now, there are no licenced vaccines or effective antiviral drugs against RSV infections. In our previous work, we found 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivatives (4-49 C and 1-HB-63) being a novel inhibitor against RSV

Polyhydroxybutyrate (PHB) is a bio-based, biodegradable and biocompatible plastic that has the potential to replace petroleum-based plastics. Lignocellulosic biomass is a promising feedstock for industrial fermentation to produce bioproducts such as polyhydroxybutyrate (PHB). However, the pretreatment processes of lignocellulosic biomass lead to the generation of toxic byproducts, such as furfural, 5-HMF, vanillin, and acetate, which affect microbial growth and productivity. In this study, to reduce furfural toxicity during PHB production from lignocellulosic hydrolysates, we genetically engineered Cupriavidus necator NCIMB 11599, by inserting the nicotine amide salvage pathway genes pncB and nadE to increase the NAD(P)H pool. We found that the expression of pncB was the most effective in improving tolerance to inhibitors, cell growth, PHB production and sugar consumption rate. In addition, the engineered strain harboring pncB showed higher PHB production using lignocellulosic hydrolysates than the wild-type strain. Therefore, the application of NAD salvage pathway genes improves the tolerance of Cupriavidus necator to lignocellulosic-derived inhibitors and should be used to optimize PHB production.

Self-assembled nanotechnology is a promising strategy for improving the effective utilization of pesticides due to its distinct advantages. Herein, an amide-bonded prodrug conjugate based on pyrimethanil (PYR) and butyric acid (BA) was successfully synthesized by the nucleophilic substitution reaction and subsequently self-assembled into spherical nanoparticles (PB NPs) with an average size of 85 nm through the solvent exchange method without using any toxic adjuvant. The results showed that PB NPs based on PYR and BA had a synergistic antimicrobial activity against

Colloidal organo-mineral associations contribute to soil organic matter (OM) preservation and mainly occur in two forms: (i) as water-dispersible colloids that are potentially mobile (free colloids) and (ii) as building units of soil microaggregates that are occluded inside them (occluded colloids). However, the way in which these two colloidal forms differ in terms of textural characteristics and chemical composition, together with the nature of their associated OM, remains unknown. To fill these knowledge gaps, free and occluded fine colloids220 nm were isolated from arable soils with comparable organic carbon (C

Two diastereomers of the protonated diketopiperazine (DKP) dipeptide cyclo(Tyr-Tyr), namely, cyclo(LTyr-LTyr)H

Chemical exchange saturation transfer (CEST) MRI is promising for detecting dilute metabolites and microenvironment properties, which has been increasingly adopted in imaging disorders such as acute stroke and cancer. However, in vivo CEST MRI quantification remains challenging because routine asymmetry analysis (MTRsubasym/sub) or Lorentzian decoupling measures a combined effect of the labile proton concentration and its exchange rate. Therefore, our study aimed to quantify amide proton concentration and exchange rate independently in a cardiac arrest-induced global ischemia rat model.The amide proton CEST (APT) effect was decoupled from tissue water, macromolecular magnetization transfer, nuclear Overhauser enhancement, guanidinium, and amine protons using the image downsampling expedited adaptive least-squares (IDEAL) fitting algorithm on Z-spectra obtained under multiple RF saturation power levels, before and after global ischemia. Omega plot analysis was applied to determine amide proton concentration and exchange rate simultaneously.Global ischemia induces a significant APT signal drop from intact tissue. Using the modified omega plot analysis, we found that the amide proton exchange rate decreased from 29.6 ± 5.6 to 12.1 ± 1.3 ssup-1/sup(P lt; 0.001), whereas the amide proton concentration showed little change (0.241 ± 0.035% vs. 0.202 ± 0.034%, P = 0.074) following global ischemia.Our study determined the labile proton concentration and exchange rate underlying the in vivo APT MRI. The significant change in the exchange rate, but not the concentration of amide proton demonstrated that the pH effect dominates the APT contrast during tissue ischemia.

ConspectusEnantiopure atropisomers have become increasingly important in asymmetric synthesis and catalysis, pharmaceutical science, and material science since the discovery of inherent features of axial chirality originating from rotational restriction. Despite the advances made in this field to date, it remains highly desirable to construct structurally diverse atropisomers with potentially useful functions. We propose superposition to match axial and point chirality as a potentially useful strategy to access structurally complex and diverse building blocks for organic synthesis and pharmaceutical science because merging atropisomeric backbones with one or more extra chiral elements can topologically broaden three-dimensional environments to create complex scaffolds with multiple tunable parameters. Over the past decade, we have successfully implemented a strategic design for the superposition of axial and point chirality to develop a series of enantiopure atropisomers and have utilized the synergistic functions of these molecules to enhance chirality transfer in various catalytic asymmetric transformations.In this Account, we present several novel atropisomers with superposed axial and point chirality developed in our laboratory. In our studies, this superposition strategy was used to design and synthesize both biaryl and non-biaryl atropisomers from commercially available chiral sources. Consequently, these atropisomers were used to demonstrate the importance of the synergetic functions of axial and point chirality in specific enantioselective reactions. For example, aromatic amide-derived atropisomers, simplified as Xing-Phos arrays, were broadly employed in Ag-catalyzed [3 + 2] cycloaddition by a series of reactions of aldiminoesters with activated alkenes and imines, as well as being used as chiral solvating agents for the discrimination of optically active mandelic acid derivatives. Considering the powerful potential of non-biaryl atropisomers for asymmetric catalysis, we also explored the transition-metal-catalyzed enantioselective construction of a novel backbone of non-biaryl atropisomers (Ar-alkene, Ar-N axis) bearing both axial and point chirality for the design and synthesis of chiral ligands and functional molecules.The studies presented herein are expected to stimulate further research efforts on the development of functional atropisomers by superposition of matching axial and point chirality. In addition to tunable electron and stereohindrance effects, the synergy between matching chiral elements of axial/point chirality and functional groups is proven to be a special function that cannot be ignored for promoting reactivity and chirality-transfer efficiency in enantioselective synthesis. Consequently, our novel types of scaffolds with superposed axial and point chirality that are capable of versatile coordination with various metal catalysts in asymmetric catalysis highlight the power of the superposition of matching axial and point chirality for the construction of synthetically useful atropisomers.

A simple, rapid, accurate, and non-destructive method was developed for the determination of cannabinoids, combining principal component analysis and multi-layer perceptron neural network to classify indole and indazole amide synthetic cannabinoids. Under the experimental conditions of this study, 25 experimental samples were successfully classified into two categories as the final classification, which guaranteed 96% correct rate. First, the samples were manually classified and divided into two categories according to the difference in peak position and peak intensity of the differential Raman characteristic peaks at 650-540 cm

The chemo- and site-selective reaction at the particular C─N amide bond among a sea of other amides is a significant and long-standing challenge. Although the use of twisted amides has been demonstrated for modifications of inert C─N amide bonds, none of these methods can selectively activate a particular amide bond for C─C bond formation in the presence of similar amides. Using density functional theory as a guide, we report the first site-selective C─C bond modification of a particular C─N amide bond in polyamides with a low twist angle by combining ground-state steric distortion with electronic activation.

Heba Abdel-Halim,1,*,† Malak Hajar1,†, Luma Hasouneh1,†, Suzanne MA Abdelmalek2,† 1Department of Medicinal Chemistry, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan; 2Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan†Dr Abdel-Halim passed away on July 14, 2022*These authors contributed equally to this workCorrespondence: Suzanne MA Abdelmalek, Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, P.O. Box 961343, Amman, 11196, Jordan, Tel +962-6-5799555 Ext. (8310), Fax +962-65715570, Email sabdelmalek@uop.edu.joPurpose: The development of effective treatments for coronavirus infectious disease 19 (COVID-19) caused by SARS-Coronavirus-2 was hindered by the little data available about this virus at the start of the pandemic. Drug repurposing provides a good strategy to explore approved drugs’ possible SARS-CoV-2 antiviral activity. Moreover, drug synergism is essential in antiviral treatment due to improved efficacy and reduced toxicity. In this work, we studied the effect of approved and investigational drugs on one of SARS-CoV-2 essential proteins, the main protease (Mpro), in search of antiviral treatments and/or drug combinations.Methods: Different possible druggable sites of Mpro were identified and screened against an in-house library of more than 4000 chemical compounds. Molecular dynamics simulations were carried out to explore conformational changes induced by different ligands’ binding. Subsequently, the inhibitory effect of the identified compounds and the suggested drug combinations on the Mpro were established using a 3CL protease (SARS-CoV-2) assay kit.Results: Three potential inhibitors in three different binding sites were identified; favipiravir, cefixime, and carvedilol. Molecular dynamics simulations predicted the synergistic effect of two drug combinations: favipiravir/cefixime, and favipiravir/carvedilol. The in vitro inhibitory effect of the predicted drug combinations was established on this enzyme.Conclusion: In this work, we could study one of the promising SARS-CoV-2 viral protein targets in searching for treatments for COVID-19. The inhibitory effect of several drugs on Mpro was established in silico and in vitro assays. Molecular dynamics simulations showed promising results in predicting the synergistic effect of drug combinations.Keywords: molecular dynamics simulations, ligand docking, multiple binding sites, drug synergy, SARS-CoV-2

In fibroglandular breast tissue, conventional dynamic contrast-enhanced MR-mammography is known to be affected by water content changes during the menstrual cycle. Likewise, amide proton transfer (APT) chemical exchange saturation transfer (CEST)-MRI might be inherently prone to the menstrual cycle, as CEST signals are indirectly detected via the water signal. The purpose of this study was to investigate the influence of the menstrual cycle on APT CEST-MRI in fibroglandular breast tissue.Ten healthy premenopausal women (19-34 years) were included in this IRB approved prospective study and examined twice during their menstrual cycle. Examination one and two were performed during the first half (day 2-8) and the second half (day 15-21) of the menstrual cycle, respectively. As a reference for the APT signal in malignant breast tumor tissue, previously reported data of nine breast cancer patients were included in this study. CEST-MRI (BThe APT signal showed no significant difference in the fibroglandular breast tissue of healthy premenopausal volunteers throughout the menstrual cycle (p = 1.00) (examination 1 vs. examination 2: mean and standard deviation = 3.24 ± 0.68%Hz vs. 3.30 ± 0.73%Hz, median and IQR = 3.36%Hz and 0.87%Hz vs. 3.38%Hz and 0.71%Hz).The present study provides an important basis for the clinical application of APT CEST-MRI as an additional contrast mechanism in MR-mammography, as menstrual cycle-related APT signal fluctuations seem to be negligible compared to the APT signal increase in breast cancer tissue.

A preparative method for the synthesis of optically pure N-(1-phenylethyl)amides of inherently chiral (cR)- and (cS)-dibenzoyloxy-calix[4]arene acetic acids has been developed. Their absolute stereochemical configuration was determined by X-ray diffraction analysis.

Through a modified Kinugasa reaction, a novel method of amidation on terminal oligo alkyne conjugates by copper-promoted oxidation with nitrones has been developed. Unprotected bifunctional carboxylic acid-amine reagents can be transformed directly to the respective amide products under these edited Kinugasa reaction conditions. 3-Cycle DNA-encoded libraries (DELs) can be built in three steps of chemical conversion.

The Protein Data Bank (PDB) file format developed at Brookhaven National Laboratory is the most popular file format to store biological data and is widely supported by many software programs for the editing and visualization of macromolecular structures. Unfortunately, many of these structures have variety of issues ranging from missing side chains and/or atoms to alternate locations (rotamers). To fix these flaws, one has to learn a new program, compile modules, and install libraries. To overcome these challenges, we present Protein Repair and Analysis Server (PRAS), an easy-to-use web server to repair protein structures and add missing atoms. The PRAS program flow has two main sections. In the first section, several subroutines are called to deal with sequence microheterogeneity, rotamers, missing side chains, heavy atoms, or hydrogen atoms. A log file is generated detailing irregularities and their fixes as carried out by the program. In the later section, the program uses the error-corrected protein structure to assign secondary structure elements based on amide-amide interactions of the backbone. Plots of four Ramachandran types (general, glycine, proline, and pre-proline) and percentage of secondary structure elements; a log file and the error-corrected PDB file can be downloaded by clicking on the download link generated by the server. The server is freely available and is accessed through its web address at www.protein-science.com. Alternatively, users can download the source code from the server or install the program on their local machines following the instructions at https://pypi.org/project/Pras-Server/ or https://github.com/osita-sunday-nnyigide/Pras_Server. While the present work focuses on the repair of structural data in the PDB format, the server is capable of fixing similar errors in the extensible and newly adopted mmCIF format.

Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For example, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested

Favipiravir is one of the essential antiviral drugs used for the treatment of coronavirus disease (COVID-19) in some countries. However, there is not enough information about used, especially in pregnancy. Therefore, in this study, it was aimed to determine the developmental toxicity of favipiravir on fetal bone development and embryonic development.In this study, 16 pregnant wistar albino rats were used. The rats were divided into four groups: Control (saline) and Group A (50 mg/kg × 5 days), Group B (50 mg/kg × 1 days + 20 mg/kg × 4 days), Group C (20 mg/kg × 5 days). Solutions were administered to the rats by oral gavage from the 10th to 14th days of pregnancy, twice a day. The skeletal system development of fetuses was examined with double skeletal staining and immunohistochemical staining methods.A total of 72 fetuses from pregnant rats, 18 in each group, were included in the study. As a result, depending on favipiravir dose increase, in experimental groups, it was determined that the statistically significant decrease on the ossification rates of anterior and posterior extremity bones, and length and weight of fetuses.Exposure to favipiravir during pregnancy impairs bone metabolism and bone formation-resorption stages and may cause developmental delay.