Search

OBJECTIVES: Although guidelines recommend antiviral therapy for outpatients with COVID-19 who are at high risk of progressing to severe conditions, such as older adults, many patients do not receive appropriate treatment. Little is known, however, about the physician factors associated with the prescription of guideline-recommended antiviral therapy for patients with COVID-19. DESIGN: A cross-sectional study. SETTING: Data including outpatient visits in primary care clinics in Japan from April to August 2023. PARTICIPANTS: We analysed 30 953 outpatients aged ≥65 years treated with COVID-19 (mean (SD) age, 75.0 (7.6) years; 17 652 women (57.0%)) in 1394 primary care clinics. OUTCOME MEASURES: The primary outcome was the prescription of guideline-recommended antivirals (ie, nirmatrelvir-ritonavir or molnupiravir), adjusted for patient characteristics, months of visits and regions. RESULTS: Antiviral prescriptions were concentrated among a small proportion of physicians; for example, the top 10% of physicians that had the largest number of nirmatrelvir-ritonavir prescriptions accounted for 92.4% of all nirmatrelvir-ritonavir prescriptions. After adjusting for potential confounders, physicians with higher patient volumes were more likely to prescribe guideline-recommended antivirals to their patients (adjusted OR (aOR) for high vs low volume, 1.76; 95% CI 1.31 to 2.38; adjusted p

Organic–inorganic halide perovskite solar cells (PVSCs) are considered a promising emerging photovoltaic technology that offer exceptional optoelectronic properties and the potential for economic solar energy conversion. Additive engineering‐based fabrication processes can achieve highly efficient and stable PVSCs that feature well‐controlled perovskite layers with a dense, uniform, "black" α‐phase crystal structure, as well as large grains and few defects. In this study, several hydroxylamine derivatives are introduced as additives to FAPbI3 precursor solutions to investigate their effects on the performance of PVSCs. The addition of hydroxylamine derivatives suppresses the formation of the unwanted δ‐phase and lead iodide, while the α‐phase cubic structure is preferentially formed without changing the bandgap of FAPbI3. Additionally, the additive‐treated perovskite films show improved stability compared with those without additives. Moreover, using X‐ray diffraction and X‐ray photoelectron spectroscopy analyses, it is discovered that the hydroxylamine‐based additives are not incorporated in the crystal lattices but rather resided on the surface or grain boundaries. Notably, the inverted PVSCs added with N‐methylhydroxylamine exhibit an improved power conversion efficiency, higher stability, and minimal hysteresis. [ABSTRACT FROM AUTHOR]

There has been increasing interest in methods to generate synthetic lipid membranes as key constituents of artificial cells or to develop new tools for remodeling membranes in living cells. However, the biosynthesis of phospholipids involves elaborate enzymatic pathways that are challenging to reconstitute in vitro. An alternative approach is to use chemical reactions to non‐enzymatically generate natural or non‐canonical phospholipids de novo. Previous reports have shown that synthetic lipid membranes can be formed in situ using various ligation chemistries, but these methods lack biocompatibility and/or suffer from slow kinetics at physiological pH. Thus, it would be valuable to develop chemoselective strategies for synthesizing phospholipids from water‐soluble precursors that are compatible with synthetic or living cells Here, we demonstrate that amide‐forming ligations between lipid precursors bearing hydroxylamines and α‐ketoacids (KAs) or potassium acyltrifluoroborates (KATs) can be used to prepare non‐canonical phospholipids at physiological pH conditions. The generated amide‐linked phospholipids spontaneously self‐assemble into cell‐like micron‐sized vesicles similar to natural phospholipid membranes. We show that lipid synthesis using KAT ligation proceeds extremely rapidly, and the high selectivity and biocompatibility of the approach facilitates the in situ synthesis of phospholipids and associated membranes in living cells. [ABSTRACT FROM AUTHOR]

Abstract Organic–inorganic halide perovskite solar cells (PVSCs) are considered a promising emerging photovoltaic technology that offer exceptional optoelectronic properties and the potential for economic solar energy conversion. Additive engineering‐based fabrication processes can achieve highly efficient and stable PVSCs that feature well‐controlled perovskite layers with a dense, uniform, “black” α‐phase crystal structure, as well as large grains and few defects. In this study, several hydroxylamine derivatives are introduced as additives to FAPbI3 precursor solutions to investigate their effects on the performance of PVSCs. The addition of hydroxylamine derivatives suppresses the formation of the unwanted δ‐phase and lead iodide, while the α‐phase cubic structure is preferentially formed without changing the bandgap of FAPbI3. Additionally, the additive‐treated perovskite films show improved stability compared with those without additives. Moreover, using X‐ray diffraction and X‐ray photoelectron spectroscopy analyses, it is discovered that the hydroxylamine‐based additives are not incorporated in the crystal lattices but rather resided on the surface or grain boundaries. Notably, the inverted PVSCs added with N‐methylhydroxylamine exhibit an improved power conversion efficiency, higher stability, and minimal hysteresis.

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Comprehensive Summary: A general and efficient strategy for the synthesis of γ‐lactams has been reported. The hydroxylamines form Lossen rearrangement products of electron‐deficient group migration with base and then undergo [3+2] cycloaddition reaction with vinyl cyclopropane, which could be performed with broad substrate scope, excellent functional group tolerance and high efficiency to produce the desired products. It also allowed further modification to other derivatives of these γ‐lactams. [ABSTRACT FROM AUTHOR]

N−O σ bonds containing compounds are versatile substrates for organic synthesis under transition metal catalysis. Their ability to react through both polar (oxidative addition, formation of metallanitrene, nucleophilic substitution) and radical pathways (single electron transfer, homolytic bond scission) have triggered the development of various synthetic methodologies, particularly toward synthesizing nitrogen‐containing compounds. In this review, we discuss the different modes of activation of N−O bonds in the presence of transition metal catalysts, emphasizing the experimental and computational mechanistic proofs in the literature to help to design new synthetic pathways toward the synthesis of C−N bonds. [ABSTRACT FROM AUTHOR]

BackgroundCoronavirus Disease 2019 (Covid-19) continues to challenge the limits of our knowledge and our healthcare system. Here we sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach.MethodOver 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. An AI-based approach was used to explore the utility of the signature in navigating the uncharted territory of Covid-19, setting therapeutic goals, and finding therapeutic solutions.FindingsThe 166-gene signature was surprisingly conserved across all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determine severity/fatality. Precise therapeutic goals could be formulated; these goals were met in high-dose SARS-CoV-2-challenged hamsters using either neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement or a directly acting antiviral agent, EIDD-2801. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine prognosticated disease severity.InterpretationThe ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.FundingThis work was supported by the National Institutes for Health (NIH) [grants CA151673 and GM138385 (to DS) and AI141630 (to P.G), DK107585-05S1 (SD) and AI155696 (to P.G, D.S and S.D), U19-AI142742 (to S.C, cchiCooperative Centers for Human Immunology)]; Research Grants Program Office (RGPO) from the University of California Office of the President (UCOP) (R00RG2628 & R00RG2642 to P.G, D.S and S.D); the UC San Diego Sanford Stem Cell Clinical Center (to P.G, D.S and S.D); LJI Institutional Funds (to S.C); the VA San Diego Healthcare System Institutional funds (to L.C.A). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists.One sentence summaryThe host immune response in COVID-19.

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.

In this study on perovskite solar cells (PVSCs), we incorporate N-benzylhydroxylamine (N-BzHoA) as an additive into the precursor solution. The addition of N-BzHoA suppressed the formation of unwanted PbI _2 and δ-phase perovskite without affecting the band gap, confirming uniform and large grains in the perovskite film. The fabricated inverted PVSCs exhibited remarkably improved properties compared to the control device, with a power conversion efficiency of 17.49%, reduced hysteresis, and more than 89% retention of the initial capacity after 100 h of light exposure. Thus, this study highlights the effectiveness of N-BzHoA as an effective additive for inverted PVSCs.

An unprecedented oxidative cyclodimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of N,N-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule. The crucial condition for the synthesis of pyrimidines is generation of N,N-diethylhydroxylamine in the reaction mixture in a very low concentration, which is ensured by the slow oxidation of triethylamine with air oxygen. Addition of a radical initiator accelerated the reaction and resulted in higher yields of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized. [ABSTRACT FROM AUTHOR]

As an underrepresented functional group in bioorganic and medicinal chemistry, the hydroxylamine unit has historically received little attention from the synthetic community. Recent developments, however, suggest that hydroxylamines may have broader applications such that a review covering recent developments in the synthesis of this functional group is timely. With this in mind, this review primarily covers developments in the past 15 years in the preparation of di- and trisubstituted hydroxylamines. The mechanism of the reactions and key features and shortcomings are discussed throughout the review. [ABSTRACT FROM AUTHOR]

Oximes and hydroxylamines are a very important class of skeletons that not only widely exist in natural products and drug molecules, but also a class of synthon, which have been widely used in industrial production. Due to weak N-O σ bonds of oximes and hydroxylamines, they can be easily transformed into other functional groups by N-O bond cleavage. Therefore, the synthesis of N-heterocycle by using oximes and hydroxylamines as nitrogen sources has attracted wide attention. Recent advances for the synthesis of N-heterocycle through transition-metal-catalyzed and radical-mediated cyclization classified by the type of nitrogen sources and rings are summarized. In this paper, the recent advances in the N-O bond cleavage of oximes and hydroxylamines are reviewed. We hope that this review provides a new perspective on this field, and also provides a reference to develop environmentally friendly and sustainable methods. [ABSTRACT FROM AUTHOR]

In the presence of CuOAc, a series of unsymmetric ureas can be generated in moderate to good yields under mild reaction conditions (10 mol% of CuOAc, 2 equiv t-BuONa or PhONa, 30 °C), using aryl isocyanides and O-benzoyl hydroxylamines as the readily accessible starting materials. The reactions might undergo a cascade process involving isocyanide insertion into the N-O bond and Mumm-type rearrangement. This work represents a rare example of isocyanide insertion into N-O bonds, which would extend isocyanide insertion chemistry. [ABSTRACT FROM AUTHOR]

The synthesis of many biologically active compounds is not complete without transforming the carbonyl group into an amino group, carried out by the reaction of nucleophilic substitution with hydroxylamine at the carbonyl carbon atom and further reduction of the C–N and N–O bonds. This method eliminates nitrating agents that exhibit oxidizing properties and may cause undesirable effects on other structural fragments of complex molecules. Selective hydrogenation of oximes over heterogeneous catalysts is still one of the most useful and challenging reactions in synthetic organic chemistry to obtain amines and hydroxylamines since the 1920s when the Adam's catalyst was first used for this reaction. In this review, we focused on the application of heterogeneous catalysts for the hydrogenation of oximes in relation to the methods applied for pharmaceutical synthesis. [ABSTRACT FROM AUTHOR]

Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain.

An adaptive catalytic system that provides control over the nitroarene hydrogenation network to prepare a wide range of aniline and hydroxylamine derivatives is presented. This system takes advantage of a delicate interplay between a rhodium(III) center and a Lewis acidic borane introduced in the secondary coordination sphere of the metal. The high chemoselectivity of the catalyst in the presence of various potentially vulnerable functional groups and its readiness to be deployed at a preparative scale illustrate its practicality. Mechanistic studies and density functional theory (DFT) methods were used to shed light on the mode of functioning of the catalyst and elucidate the origin of adaptivity. The competition for interaction with boron between a solvent molecule and a substrate was found crucial for adaptivity. When operating in THF, the reduction network stops at the hydroxylamine platform, whereas the reaction can be directed to the aniline platform in toluene. [ABSTRACT FROM AUTHOR]

Objective: This proof-of-principle pharmacovigilance study used Electronic Health Record (EHR) data to examine the safety of sotrovimab, paxlovid and molnupiravir in prehospital treatment of Covid-19., Method: With NHS England approval, we conducted an observational cohort study using OpenSAFELY-TPP, a secure software-platform which executes analyses across EHRs for 24 million people in England. High-risk individuals with Covid-19 eligible for prehospital treatment were included. Adverse events (AEs) were categorised into events in the drug's Summary of Product Characteristics (SmPC), drug-reactions and immune-mediated. Cox models compared risk across treatments. A pre-pandemic record analysis was performed for comparative purposes., Results: Between 2021-2023, 37,449 patients received sotrovimab, paxlovid or molnupiravir whilst 109,647 patients made up an eligible-but-untreated population. The 28-day rates of AEs were low: SmPC 0.34 per 1000 patient-years (95% CI 0.32-0.36); drug-reactions 0.01 (95% CI 0.01-0.02) and immune-mediated 0.03 (95% CI 0.03-0.04), and similar or lower than the pre-pandemic period. Compared with the eligible but untreated population, sotrovimab and paxlovid associated with a risk of SmPC AE [adjHR 1.36 (95% CI 1.15-1.62) and 1.28 (95% CI 1.05-1.55), respectively], whilst sotrovimab associated with a risk of drug-reactions [adjHR 2.95 (95% CI 1.56-5.55)] and immune-mediated events [adjHR 3.22 (95% CI 1.86-5.57)]., Conclusion: Sotrovimab, paxlovid and molnupiravir demonstrate acceptable safety profiles. Although the risk of AEs was greatest with sotrovimab, event rates were lower than comparative pre-pandemic period., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AG, BMK, BZ, RMS, SB, SN and ZY have no known competing financial interests. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AM is a senior clinical researcher at the University of Oxford in the Bennett Institute, which is funded by contracts and grants obtained from the Bennett Foundation, Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, Mohn-Westlake Foundation, and NHS England. AMe received 3 days of consultancy for https://inductionhealthcare.com/ (last date feb 2022) - paid direct to me. Member of RCGP health informatics group and the NHS Digital GP data Professional Advisory Group that advises on access to GP Data for Pandemic Planning and Research (GDPPR); payment direct to me for the GDPPR role. Last invoiced Dec 2022. BG has received research funding from the Laura and John Arnold Foundation, NIHR, NIHR School of Primary Care Research, NHS England, NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organisation, UKRI MRC, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; he is a Non-Executive Director at NHS Digital; he also receives personal income from speaking and writing for lay audiences on the misuse of science. JBG has received honoraria from Abbvie, Amgen, Celgene, Chugai, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sobi, and UCB, and has research funding from Amgen, Aztra-Zeneca, Gilead, Janssen, Medicago, Novovax and Pfizer. KB has received honoraria from Galapagos, UCB and Viforpharma. MDR has received honoraria from AbbVie, Biogen, Lilly, Galapagos, Menarini, UCB, and Viforpharma., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

During the pandemic, Favipiravir (FVP) and Molnupiravir (MPV) have been widely used for COVID-19 treatment, leading to their presence in the environment. A green synchronous spectrofluorimetric method was developed to simultaneously detect them in environmental water, human plasma, and binary mixtures. Maximum fluorescence intensity was achieved at pH 8, with MPV exhibiting two peaks at 300 and 430 nm, and FVP showing one peak at 430 nm. A fluorescence subtraction method effectively removed interference, enabling direct determination of MPV at 300 nm and FVP at 430 nm. The method showed linearity within 2-13 ng/mL for FVP and 50-600 ng/mL for MPV, with recoveries of 100.35% and 100.12%, respectively. Limits of detection and quantification were 0.19 and 0.57 ng/mL for FVP and 10.52 and 31.88 ng/mL for MPV. Validation according to ICH and FDA guidelines yielded acceptable results. The method demonstrated good recoveries of FVP and MPV in pharmaceuticals, tap water and Nile water (99.62% ± 0.96% and 99.69% ± 0.64%) as per ICH guidelines and spiked human plasma (94.87% ± 2.111% and 94.79% ± 1.605%) following FDA guidelines, respectively. Its environmental friendliness was assessed using Green Analytical Procedure Index (GAPI) and the Analytical Greenness Metric (AGREE) tools., (© 2024 John Wiley & Sons Ltd.)

Objective: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria., Methods: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance., Results: Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%)., Conclusion: Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

Objectives: In this retrospective cohort study, we aimed to assess clinical effectiveness and viral clearance following the use of molnupiravir, azvudine and paxlovid in hospitalized patients with COVID-19 in China dominated by the omicron BA.5.2 and BF.7 subvariant of SARS-CoV-2., Methods: Enrolled patients were assigned to the molnupiravir group or the azvudine group or the paxlovid group or the control group (not taking any antiviral drugs). The primary outcome of the cohort study was viral clearance and viral burden rebound after treatment and the secondary outcome was 28-day all-cause mortality. The four groups were propensity score-matched (1:1). We plotted viral load trends for each antiviral drug intervention using locally weighted regression (LOWESS) smoothed data. Multivariate logistic regression (stepwise algorithm) models were used to determine any risk factors for 28-day mortality., Results: Of the 1537 patients receiving any treatment, 886 (57.6 %) received molnupiravir, 390 (25.4 %) received azvudine, 94 (6.1 %) received paxlovid, and 167 (10.9 %) did not use any antiviral drugs. Our data analysis showed that age (OR = 1.05, 95 % CI: 1.03-1.07, P < 0.001), Charlson comorbidty index (OR = 1.32, 95 % CI: 1.18-1.48, P < 0.001), severity of COVID-19 (P < 0.001), gamma globulin (OR = 2.04, 95 % CI: 1.03-3.99, P = 0.039) and corticosteroids use (OR = 2.3, 95 % CI: 1.19-4.69, P = 0.017) were independent prognostic factors for 28-day mortality in COVID-19 patients. After propensity score matching (PSM), the paxlovid recipients (OR = 0.22, 95 % CI: 0.05-0.83, P = 0.036) or azvudine recipients (OR = 0.27, 95 % CI: 0.07-0.91, P = 0.046) had lower 28-day mortality compared to their matched controls. Viral rebound occurred in the control group around days 9-16, while no viral rebound was found in any of the three oral antiviral groups. We found that molnupiravir group performed comparably in terms of the rate of nucleic acid conversion negative compared with the paxlovid group, while azvudine group performed slightly worse compared with the paxlovid group or molnupiravir group., Conclusions: In our retrospective cohort of hospitalized patients with COVID-19 during the wave of omicron strain, the molnupiravir, paxlovid and azvudine recipients showed a faster and more stable decrease in viral load and rare virus rebound in response to antiviral treatments when compared to the controls. The study supported that initiation treatment with paxlovid and azvudine was associated with significantly lower risk of all-cause death within 28 days., Competing Interests: Declaration of competing interest Authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The clinical benefit of coronavirus disease 2019 (COVID-19) treatments against new circulating variants remains unclear. We sought to describe characteristics and clinical outcomes of highest risk patients with COVID-19 receiving early COVID-19 treatments in Scotland., Methods: Retrospective cohort study of non-hospitalized patients diagnosed with COVID-19 from December 1, 2021-October 25, 2022, using Scottish administrative health data. We included adult patients who met ≥ 1 of the National Health Service highest risk criteria for early COVID-19 treatment and received outpatient treatment with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or no early COVID-19 treatment. Index date was defined as the earliest of COVID-19 diagnosis or early COVID-19 treatment. Baseline characteristics and acute clinical outcomes in the 28 days following index were reported. Values of ≤ 5 were suppressed., Results: In total, 2548 patients were included (492: sotrovimab, 276: nirmatrelvir/ritonavir, 71: molnupiravir, and 1709: eligible highest risk untreated). Patients aged ≥ 75 years accounted for 6.9% (n = 34/492), 21.0% (n = 58/276), 16.9% (n = 12/71) and 13.2% (n = 225/1709) of the cohorts, respectively. Advanced renal disease was reported in 6.7% (n = 33/492) of sotrovimab-treated and 4.7% (n = 81/1709) of untreated patients, and ≤ 5 nirmatrelvir/ritonavir-treated and molnupiravir-treated patients. All-cause hospitalizations were experienced by 5.3% (n = 25/476) of sotrovimab-treated patients, 6.9% (n = 12/175) of nirmatrelvir/ritonavir-treated patients, ≤ 5 (suppressed number) molnupiravir-treated patients and 13.3% (n = 216/1622) of untreated patients. There were no deaths in the treated cohorts; mortality was 4.3% (n = 70/1622) among untreated patients., Conclusions: Sotrovimab was often used by patients who were aged < 75 years. Among patients receiving early COVID-19 treatment, proportions of 28-day all-cause hospitalization and death were low., (© 2024. The Author(s).)

Transition metal-catalyzed diamination by hydroxylamines is a common approach for making three-membered aziridines, while its use for building the larger N-heterocycles is still underdeveloped. Herein, we report an efficient Pd(0)-catalyzed inter-molecular [4+1] annulation of o-bromo(or chloro)-biaryls with bifunctional secondary hydroxylamines for the one-step assembly of synthetically useful carbazoles. Noteworthily, a linchpin for this domino reaction was the judicious selection of both the amino-sources and Pd(0)-catalysts for enabling the prerequisite oxidative addition of aryl halides to Pd(0)-species in the presence of hydroxylamines with a labile N-O bond. [ABSTRACT FROM AUTHOR]

Study questionCan the histone deacetylase inhibitor Scriptaid improve the efficiency of the development of round spermatid injection (ROSI)-fertilized embryos in a mouse model?Summary answerTreatment of ROSI mouse zygotes with Scriptaid increased the expression levels of several development-related genes at the blastocyst stage, resulting in more efficient in vitro development of the blastocyst and an increased birth rate of ROSI-derived embryos.What is known alreadyThe full-term development of embryos derived through ROSI is significantly lower than that following ICSI in humans and other species.Study design, size, durationOocytes, spermatozoa and round spermatids were collected from BDF1 (C57BL/6 × DBA/2) mice. For in vitro development experiments, mouse ROSI-derived zygotes were treated with Scriptaid at different concentrations (0, 125, 250, 500 and 1000 nM) and for different exposure times (0, 6, 10, 16 or 24 h). Next, blastocysts of the optimal Scriptaid-treated group and the non-treated ROSI group were separately transferred into surrogate ICR mice to compare in vivo development with the ICSI group (control). Each experiment was repeated at least three times.Participants/materials, setting, methodsMetaphase II (MII) oocytes, spermatozoa and round spermatids were obtained from sexually mature BDF1 female or male mice. The developmental potential of embryos among the three groups (the ICSI, ROSI and optimal Scriptaid-treated ROSI groups) was assessed based on the rates of obtaining zygotes, two-cell stage embryos, four-cell stage embryos, blastocysts and full-term offspring. In addition, the expression levels of development-related genes (Oct4, Nanog, Klf4 and Sox2) were analysed using real-time PCR, and the methylation states of imprinted genes (H19 and Snrpn) in these three groups were detected using methylation-specific PCR (MS-PCR) sequencing following bisulfite treatment.Main results and the role of chanceThe in vitro experiments revealed that treating ROSI-derived zygotes with 250 nM Scriptaid for 10 h significantly improved the blastocyst formation rate (59%) compared with the non-treated group (38%) and further increased the birth rates of ROSI-derived embryos from 21% to 40% in vivo. Moreover, in ROSI-derived embryos, the expression of the Oct4, Nanog and Sox2 genes at the blastocyst stage was decreased, but the optimal Scriptaid treatment restored expression to a level similar to their ICSI counterparts. In addition, Scriptaid treatment moderately repaired the abnormal DNA methylation pattern in the imprinting control regions (ICRs) of H19 and Snrpn.Large scale dataN/A LIMITATIONS, REASONS FOR CAUTION: Because of the ethics regarding the use of human gametes for ROSI studies, the mouse model was used as an approach to explore the effects of Scriptaid on the developmental potential of ROSI-derived embryos. However, to determine whether these findings can be applied to humans, further investigation will be required.Wider implications of the findingsScriptaid treatment provides a new means of improving the efficiency and safety of clinical human ROSI.Study funding/competing interestsThe study was financially supported through grants from the National Key Research Program of China (No. 2016YFC1304800); the National Natural Science Foundation of China (Nos: 81170756, 81571486); the Natural Science Foundation of Shanghai (Nos: 15140901700, 15ZR1424900) and the Programme for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning. There are no conflicts of interest to declare.

As an underrepresented functional group in bioorganic and medicinal chemistry, the hydroxylamine unit has historically received little attention from the synthetic community. Recent developments, however, suggest that hydroxylamines may have broader applications such that a review covering recent developments in the synthesis of this functional group is timely. With this in mind, this review primarily covers developments in the past 15 years in the preparation of di- and trisubstituted hydroxylamines. The mechanism of the reactions and key features and shortcomings are discussed throughout the review.

Oximes and hydroxylamines are a very important class of skeletons that not only widely exist in natural products and drug molecules, but also a class of synthon, which have been widely used in industrial production. Due to weak N-O σ bonds of oximes and hydroxylamines, they can be easily transformed into other functional groups by N-O bond cleavage. Therefore, the synthesis of N-heterocycle by using oximes and hydroxylamines as nitrogen sources has attracted wide attention. Recent advances for the synthesis of N-heterocycle through transition-metal-catalyzed and radical-mediated cyclization classified by the type of nitrogen sources and rings are summarized. In this paper, the recent advances in the N-O bond cleavage of oximes and hydroxylamines are reviewed. We hope that this review provides a new perspective on this field, and also provides a reference to develop environmentally friendly and sustainable methods.

A metal‐ and oxidant‐free, practical and efficient method for the synthesis of highly versatile and synthetically useful ortho‐trifluoromethanesulfonylated anilines from arylhydroxylamines and trifluoromethanesulfinic chloride was developed. This rapid transformation proceeded smoothly with good yields and excellent ortho‐selectivity in the absence of any metals or ligands. Mechanistically, the reaction comprised a noncanonical O‐trifluoromethanesulfinylation of the arylhydroxylamine, and the subsequent [2,3]‐sigmatropic rearrangement to afford ortho‐trifluoromethanesulfonylated aniline derivatives. The practical application of this reaction was demonstrated by further conversion into a series of functional molecules under different reaction conditions. [ABSTRACT FROM AUTHOR]

The synthesis of many biologically active compounds is not complete without transforming the carbonyl group into an amino group, carried out by the reaction of nucleophilic substitution with hydroxylamine at the carbonyl carbon atom and further reduction of the C–N and N–O bonds. This method eliminates nitrating agents that exhibit oxidizing properties and may cause undesirable effects on other structural fragments of complex molecules. Selective hydrogenation of oximes over heterogeneous catalysts is still one of the most useful and challenging reactions in synthetic organic chemistry to obtain amines and hydroxylamines since the 1920s when the Adam’s catalyst was first used for this reaction. In this review, we focused on the application of heterogeneous catalysts for the hydrogenation of oximes in relation to the methods applied for pharmaceutical synthesis.

Within a multistate clinical cohort, SARS-CoV-2 antiviral prescribing patterns were evaluated from April 2022-June 2023 among nonhospitalized patients with SARS-CoV-2 with risk factors for severe COVID-19. Among 3247 adults, only 31.9% were prescribed an antiviral agent (87.6% nirmatrelvir/ritonavir, 11.9% molnupiravir, 0.5% remdesivir), highlighting the need to identify and address treatment barriers., Competing Interests: Potential conflicts of interest. M. E. L., V. C., L. M. M., D. W., A. D. R., H. D., M. I., N. L. W., T. B., K. T., J. N., J. R., E. S., W. L., J. L., and S. L. are employees of Helix, Inc. M. E. L., M. I., and S. L. report contracted research from Pfizer. M. E. L., M. I., W. L., and S. L. report contracted research from the Centers for Disease Control and Prevention (CDC). M. I., M. E. L., J. L., D. W., and S. L. report support for attending meetings and/or travel from Helix. M. I., M. E. L., W. L., A. D. R., J. L., D. W., and N. L. W. report stock or stock options from Helix. M. E. L. reports contracted research and travel support from Novavax. E. B. is an employee of Janssen Pharmaceuticals and a prior employee of Helix, Inc. P. R. H. reports contracted research from Seegene USA and Helix, Inc. J. G. is employed by the University of Nevada, Reno, and Renown Health, and reports a professional relationship with the Desert Research Institute and research funding from Gilead Sciences and the National Institute of Environmental Health Sciences (NIEHS); reports consulting fees from Renown Health; and US Patent Application 63/467,250 “Dynamic risk management for breast cancer based on multi-factor genetic testing” with Dr. Alexandre Bolze. J. D. G. reports contracted research from Helix, Gilead, Eli Lilly, and Regeneron; grants from Merck (BARDA) and Gilead; speaking honoraria and personal fees from Gilead Sciences, Inc, and Eli Lilly & Co; and collaborative services agreements with Adaptive Biotechnologies, Monogram Biosciences, and LabCorp; and serving as a speaker or advisory board member for Gilead and Eli Lilly. J. G., M. I., N. L. W., and S. L. report patents pending or issued to Helix, Inc (M. I. and S. L.: US-11776694-B2 and US-20230178236-A1). P. A. P. reports no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect., Methods: This retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥ 10 6 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥ 10 6 copies/ml. Therapeutic strategies and risk groups were compared using odds ratios and Fisher's tests or Kaplan-Meier analysis and long-rank tests. Multivariable regression analysis was performed., Results: 144 patients were included with a median duration of SARS-CoV-2 viral load ≥ 10 6 copies/ml of 8.0 days (IQR 6.0-15.3). Underlying haematological malignancies (HM) (p = 0.03) and treatment initiation later than five days after diagnosis (p < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% (n = 21/144), particularly in patients with underlying HM (OR 3.5; 95% CI 1.2-9.9; p = 0.02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially related to combination treatment., Conclusion: Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients., (© 2023. The Author(s).)

In the presence of CuOAc, a series of unsymmetric ureas can be generated in moderate to good yields under mild reaction conditions (10 mol% of CuOAc, 2 equiv t-BuONa or PhONa, 30 °C), using aryl isocyanides and O-benzoyl hydroxylamines as the readily accessible starting materials. The reactions might undergo a cascade process involving isocyanide insertion into the N-O bond and Mumm-type rearrangement. This work represents a rare example of isocyanide insertion into N-O bonds, which would extend isocyanide insertion chemistry.

Host targeting antiviral drugs (HTA) are directed against cellular mechanisms which can be exploited by viruses. These mechanisms are essential for viral replication, because missing functions cannot be compensated by the virus. However, this assumption needs experimental proof. Here we compared the HTA Zapnometinib (ZMN), with direct acting antivirals (DAA) (Remdesivir (RDV), Molnupiravir (MPV), Nirmatrelvir (NTV), Ritonavir (RTV), Paxlovid PAX)), in terms of their potency to induce reduced drug susceptibilities in SARS-CoV-2. During serial passage of δ-B1.617.2 adaptation to all DAAs occurred, while the inhibitory capacity of ZMN was not altered. Known single nucleotide polymorphisms (SNPs) responsible for partial resistances were found for RDV, NTV and PAX. Additionally, the high mutagenic potential of MPV was confirmed and decreased drug efficacies were found for the first time. Reduced DAA efficacy did not alter the inhibitory potential of ZMN. These results show that ZMN confers a high barrier towards the development of viral resistance and has the potential to act against partially DAA-insensitive viruses., Competing Interests: Declaration of competing interest SL and OP are cofounders, shareholders and advisory board members of Atriva Therapeutics GmbH, Tübingen, Germany, a biotech company that develops hosttargeted antivirals to hyperinflammatory respiratory virus infections. The company was not involved in design or funding of the present study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Partial nitrification is a key aspect of efficient nitrogen removal, although practically it suffers from long start-up cycles and unstable long-term operational performance. To address these drawbacks, this study investigated the effect of low intensity ultrasound treatment combined with hydroxylamine (NH 2 OH) on the performance of partial nitrification. Results show that compared with the control group, low-intensity ultrasound treatment (0.10 W/mL, 15 min) combined with NH 2 OH (5 mg/L) reduced the time required for partial nitrification initiation by 6 days, increasing the nitrite accumulation rate (NAR) and ammonia nitrogen removal rate (NRR) by 20.4% and 6.7%, respectively, achieving 96.48% NRR. Mechanistic analysis showed that NH 2 OH enhanced ammonia oxidation, inhibited nitrite-oxidizing bacteria (NOB) activity and shortened the time required for partial nitrification initiation. Furthermore, ultrasonication combined with NH 2 OH dosing stimulated EPS (extracellular polymeric substances) secretion, increased carbonyl, hydroxyl and amine functional group abundances and enhanced mass transfer. In addition, 16S rRNA gene sequencing results showed that ultrasonication-sensitive Nitrospira disappeared from the ultrasound + NH 2 OH system, while Nitrosomonas gradually became the dominant group. Collectively, the results of this study provide valuable insight into the enhancement of partial nitrification start-up during the process of wastewater nitrogen removal., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023. Published by Elsevier B.V.)

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (M pro ) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 μM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 M pro . In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate., Competing Interests: Competing interests statement:Yale University has filed a patent application covering Mpro61.

The role of monoclonal antibodies as vehicles to deliver payloads has evolved as a powerful tool in cancer therapy in recent years. The clinical development of therapeutic antibody conjugates with precise payloads holds great promise for targeted therapeutic interventions. The use of affinity-peptide mediated functionalization of native off-the-shelf antibodies offers an effective approach to selectively modify IgG antibodies with a drug-antibody ratio (DAR) of 2. Here, we report the traceless, peptide-directed attachment of two hydroxylamines to native IgGs followed by chemoselective potassium acyltrifluoroborate (KAT) ligation with quinolinium acyltrifluoroborates (QATs), which provide enhanced ligation rates with hydroxylamines under physiological conditions. By applying KAT ligation to the modified antibodies, conjugation of small molecules, proteins, and oligonucleotides to off-the-shelf IgGs proceeds efficiently, in good yields, and with simultaneous cleavage of the affinity peptide-directing moiety., (© 2024 Wiley‐VCH GmbH.)

A comparative analysis of molecularly imprinted polymers based on different synthesis techniques was performed for the recognition of molnupiravir (MOL). The polymerizations were performed with 3-thienyl boronic acid (3-TBA) as a functional monomer by electropolymerization (EP) and with guanine methacrylate (GuaM) as a functional monomer by photopolymerization (PP). Morphological and electrochemical characterizations of the developed sensors were investigated to verify the constructed sensors. Moreover, quantum chemical calculations were used to evaluate changes on the electrode surface at the molecular and electronic levels. The dynamic linear range of both designed sensors under optimized experimental conditions was found to be 7.5 × 10 -12 -2.5 × 10 -10  M and 7.5 × 10 -13 -2.5 × 10 -11  M for EP and PP, respectively. The effect of various interfering agents on MOL peak current was assessed for the selectivity of the study. In the presence of 100 times more interfering agents, the RSD and recovery values were determined. The RSD values of GuaM/MOL@MIP/GCE and poly(Py-co-3-PBA)/MOL@MIP/GCE sensors were found to be 1.99% and 1.72%, respectively. Furthermore, the recovery values of the MIP-based sensors were 98.18-102.69% and 98.05-103.72%, respectively. In addition, the relative selectivity coefficient (k') of the proposed sensor was evaluated, and it exhibited good selectivity for MOL with respect to the NIP sensor. The prepared sensor was successfully applied to determine MOL in commercial serum samples and capsule form. In conclusion, the developed sensors provided excellent reproducibility, repeatability, high sensitivity, and selectivity against the MOL molecule., (© 2024. The Author(s).)

The exogenous hydroxylamine dosing has been proven to enhance nitrite supply for anammox bacteria. In this study, exogenous hydroxylamine was fed into a sequencing batch reactor to investigate its long-term effect on anammox granular sludge. The results showed that hydroxylamine enhanced the reactor's performance with an increase in total nitrogen removal rate from 0.23 to 0.52 kg N/m 3 /d and an increase in bacterial activity from 11.65 to 78.24 mg N/g VSS/h. Meanwhile, hydroxylamine promoted granulation by eluting flocs. And higher anammox activity and granulation were supported by extracellular polymeric substances (EPS) characteristics. Moreover, Candidatus Brocadia's abundance increased from 1.10 % to 3.03 %, and its symbiosis with heterotrophic bacteria was intensified. Additionally, molecular docking detailed the mechanism of the hydroxylamine effect. Overall, this study would provide new insights into the hydroxylamine dosing strategy application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could ha ve appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Kidney transplant recipients (KTRs) are at risk of severe coronavirus disease 2019 (COVID-19), and even now that Omicron subvariants have become dominant, cases of severe disease are certain to occur. The aims of this retrospective study were to evaluate the efficacy of antiviral treatment for COVID-19 and to identify risk factors for severe disease in KTRs during Omicron subvariant-dominant periods., Methods: A total of 65 KTRs diagnosed with COVID-19 who received antiviral treatment between July 2022 and September 2023 were analyzed. Mild cases received oral molnupiravir (MP) as outpatient therapy, while moderate or worse cases received intravenous remdesivir (RDV) as inpatient therapy. In principle, mycophenolate mofetil was withdrawn and switched to everolimus. We investigated the efficacy of antiviral treatment and compared the clinical parameters of mild/moderate and severe/critical cases to identify risk factors for severe COVID-19., Results: Among 65 cases, 49 were mild, 6 were moderate, 9 were severe, and 1 was of critical severity. MP was administered to 57 cases; 49 (86%) improved and 8 (14%) progressed. RDV was administered to 16 cases; 14 (87%) improved and 2 (13%) progressed. Seventeen (26%) cases required hospitalization, and none died. Comparisons of the severe/critical group (n = 10) with the mild/moderate group (n = 55) demonstrated that the severe/critical group had a significantly higher median age (64 vs. 53 years, respectively; p = 0.0252), prevalence of diabetes (70% vs. 22%, respectively; p = 0.0047) and overweight/obesity (40% vs. 11%, respectively; p = 0.0393), as well as a significantly longer median time from symptom onset to initial antiviral therapy (3 days vs. 1 day, respectively; p = 0.0026). Multivariate analysis showed that a longer time from symptom onset to initial antiviral treatment was an independent risk factor for severe COVID-19 (p = 0.0196, odds ratio 1.625, 95% confidence interval 1.081-2.441)., Conclusion: These findings suggest that a longer time from symptom onset to initial antiviral treatment is associated with a higher risk of severe COVID-19 in KTRs. Initiating antiviral treatment as early as possible is crucial for preventing severe outcomes; this represents a valuable insight into COVID-19 management in KTRs., (© 2024. The Author(s).)

Cupin/methionyl-tRNA synthetase (MetRS)-like didomain enzymes catalyze nitrogen-nitrogen (N-N) bond formation between Nω-hydroxylamines and amino acids to generate hydrazines, key biosynthetic intermediates of various natural products containing N-N bonds. While the combination of these two building blocks leads to the creation of diverse hydrazine products, the full extent of their structural diversity remains largely unknown. To explore this, we herein conducted phylogeny-guided genome-mining of related hydrazine biosynthetic pathways consisting of two enzymes: flavin-dependent Nω-hydroxylating monooxygenases (NMOs) that produce Nω-hydroxylamine precursors and cupin/MetRS-like enzymes that couple the Nω-hydroxylamines with amino acids via N-N bonds. A phylogenetic analysis identified the largely unexplored sequence spaces of these enzyme families. The biochemical characterization of NMOs demonstrated their capabilities to produce various Nω-hydroxylamines, including those previously not known as precursors of N-N bonds. Furthermore, the characterization of cupin/MetRS-like enzymes identified five new hydrazine products with novel combinations of building blocks, including one containing non-amino acid building blocks: 1,3-diaminopropane and putrescine. This study substantially expanded the variety of N-N bond forming pathways mediated by cupin/MetRS-like enzymes., (© 2024 Wiley‐VCH GmbH.)

Despite the great potential of electrochemical nitrate reduction as a hydroxylamine production method, this strategy has not been sufficiently examined, and the effects of electrode material type on the selectivity and efficiency of this reduction remain underexplored. To bridge this gap, the present study evaluated six metals (Ag, Cu, Ni, Sn, Ti, and Zn) as cathode materials for the electrochemical reduction of nitrate to hydroxylamine, showing that the selectivity of hydroxylamine production was maximal for Sn, while the corresponding faradaic and energy utilization efficiencies were maximal for Ti. Although all tested materials favored nitrate reduction over hydrogen evolution, the disparity in the onset potentials of these reactions did not adequately explain the variations in nitrate removal efficiency, which was found to be influenced by material resistance and charge-transfer properties. The rate constants of elementary nitrate reduction steps determined from the time-dependent concentrations of nitrate and its reduction products (nitrous acid, hydroxylamine, and ammonium) were used to calculate the selectivity and efficiency of hydroxylamine production for each electrode. In turn, these selectivities and efficiencies were correlated with the density functional theory-computed adsorption energies of a key hydroxylamine precursor on different electrodes to afford a volcano-type plot with Ti and Sn at its pinnacle. Thus, this study introduces valuable descriptors and methods for the further screening of electrocatalysts for hydroxylamine generation and the establishment of more environmentally friendly hydroxylamine production techniques utilizing sustainable electricity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This article describes the aza-Piancatelli rearrangement with hydroxylamines to 4-aminocyclopentenones and subsequent transformations that highlight the versatility of the cyclopentene scaffold and the value of the hydroxylamine nucleophile in this transformation.