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Chemical & Pharmaceutical Bulletin 2022Knoevenagel condensation, an olefin-forming reaction from active methyl/methylene-containing compounds and aldehydes, is a fundamental and useful synthetic method....
Knoevenagel condensation, an olefin-forming reaction from active methyl/methylene-containing compounds and aldehydes, is a fundamental and useful synthetic method. Benzothiazoles are, however, out of the scope of Knoevenagel condensation. Here, we report that Knoevenagel condensation between aldehydes and 2-methyl-thiazolo[4,5-b]pyrazines (MeTPy), a fused ring structure comprising pyrazine and thiazole, proceeded smoothly, despite minor structural differences from benzothiazoles. This finding will be useful for short synthesis of MeTPy-containing functional molecules, such as a tau probe analog 1.
Topics: Aldehydes; Alkenes; Molecular Structure; Pyrazines
PubMed: 34980738
DOI: 10.1248/cpb.c21-00780 -
The Lancet. Respiratory Medicine May 2023COVID-19 has overwhelmed health services globally. Oral antiviral therapies are licensed worldwide, but indications and efficacy rates vary. We aimed to evaluate the... (Randomized Controlled Trial)
Randomized Controlled Trial
Favipiravir in patients hospitalised with COVID-19 (PIONEER trial): a multicentre, open-label, phase 3, randomised controlled trial of early intervention versus standard care.
BACKGROUND
COVID-19 has overwhelmed health services globally. Oral antiviral therapies are licensed worldwide, but indications and efficacy rates vary. We aimed to evaluate the safety and efficacy of oral favipiravir in patients hospitalised with COVID-19.
METHODS
We conducted a multicentre, open-label, randomised controlled trial of oral favipiravir in adult patients who were newly admitted to hospital with proven or suspected COVID-19 across five sites in the UK (n=2), Brazil (n=2) and Mexico (n=1). Using a permuted block design, eligible and consenting participants were randomly assigned (1:1) to receive oral favipiravir (1800 mg twice daily for 1 day; 800 mg twice daily for 9 days) plus standard care, or standard care alone. All caregivers and patients were aware of allocation and those analysing data were aware of the treatment groups. The prespecified primary outcome was the time from randomisation to recovery, censored at 28 days, which was assessed using an intention-to-treat approach. Post-hoc analyses were used to assess the efficacy of favipiravir in patients aged younger than 60 years, and in patients aged 60 years and older. The trial was registered with clinicaltrials.gov, NCT04373733.
FINDINGS
Between May 5, 2020 and May 26, 2021, we assessed 503 patients for eligibility, of whom 499 were randomly assigned to favipiravir and standard care (n=251) or standard care alone (n=248). There was no significant difference between those who received favipiravir and standard care, relative to those who received standard care alone in time to recovery in the overall study population (hazard ratio [HR] 1·06 [95% CI 0·89-1·27]; n=499; p=0·52). Post-hoc analyses showed a faster rate of recovery in patients younger than 60 years who received favipiravir and standard care versus those who had standard care alone (HR 1·35 [1·06-1·72]; n=247; p=0·01). 36 serious adverse events were observed in 27 (11%) of 251 patients administered favipiravir and standard care, and 33 events were observed in 27 (11%) of 248 patients receiving standard care alone, with infectious, respiratory, and cardiovascular events being the most numerous. There was no significant between-group difference in serious adverse events per patient (p=0·87).
INTERPRETATION
Favipiravir does not improve clinical outcomes in all patients admitted to hospital with COVID-19, however, patients younger than 60 years might have a beneficial clinical response. The indiscriminate use of favipiravir globally should be cautioned, and further high-quality studies of antiviral agents, and their potential treatment combinations, are warranted in COVID-19.
FUNDING
LifeArc and CW+.
Topics: Adult; Humans; Middle Aged; Aged; COVID-19; SARS-CoV-2; Treatment Outcome; Pyrazines
PubMed: 36528039
DOI: 10.1016/S2213-2600(22)00412-X -
Chemical Biology & Drug Design Oct 2021Parasitic diseases are a public health problem, especially in developing countries where millions of people are affected every year. Current treatments have several... (Review)
Review
Parasitic diseases are a public health problem, especially in developing countries where millions of people are affected every year. Current treatments have several drawbacks: emerging resistance to the existing drugs, lack of efficacy, and toxic side effects. Therefore, new antiparasitic drugs are urgently needed to treat and control diseases that affect human health, such as malaria, Chagas disease, leishmaniasis, amebiasis, giardiasis schistosomiasis, and filariasis, among others. Quinoxaline is a compound containing a benzene ring and a pyrazine ring. The oxidation of both pyrazine ring nitrogens allows the obtention of quinoxaline 1,4-di-N-oxides (QdNOs) derivatives. By modifying the chemical structure of these compounds, it is possible to obtain a wide variety of biological properties. This review investigated the activity of quinoxaline derivatives and QdNOs against different protozoan parasites and helminths. We also cover the structure-activity relationship (SAR) and summarize the main findings related to their mechanisms of action from published works in recent years. However, further studies are needed to determine specific molecular targets. This review aims to highlight the new development of antiparasitic drugs with better pharmacological profiles than current treatments.
Topics: Animals; Antiparasitic Agents; Benzene; Chagas Disease; Humans; Leishmaniasis; Malaria; Oxidation-Reduction; Oxides; Pyrazines; Quinoxalines; Structure-Activity Relationship
PubMed: 34289242
DOI: 10.1111/cbdd.13921 -
Journal of Medicinal Chemistry Sep 2020Pyrazine-based compounds are of great importance in medicinal chemistry. Due to their heteroaromatic nature, they uniquely combine properties of heteroatoms (polar... (Review)
Review
Pyrazine-based compounds are of great importance in medicinal chemistry. Due to their heteroaromatic nature, they uniquely combine properties of heteroatoms (polar interactions) with the properties of aromatic moieties (nonpolar interactions). This review summarizes results of a systematic analysis of RCSB PDB database focused on important binding interactions of pyrazine-based ligands cocrystallized in protein targets. The most frequent interaction of pyrazine was hydrogen bond to pyrazine nitrogen atom as an acceptor, followed by weak hydrogen bond with pyrazine hydrogen as donor. We also identified intramolecular hydrogen bonds within pyrazine ligands, π-interactions, coordination to metal ions, and few halogen bonds in chloropyrazines. In many cases the binding mode of the pyrazine fragment was complex, involving a combination of several interactions. We conclude that pyrazine as a molecular fragment should not be perceived as a simple aromatic isostere but rather as a readily interacting moiety of drug-like molecules with high potential for interactions to proteins.
Topics: Amino Acyl-tRNA Synthetases; Binding Sites; Databases, Protein; Humans; Hydrogen Bonding; Ligands; Metals; Molecular Dynamics Simulation; Proteins; Pyrazines
PubMed: 32275822
DOI: 10.1021/acs.jmedchem.9b02021 -
European Journal of Medicinal Chemistry Dec 2022A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid,...
A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b, 1c, 2b, 2c, and 8) were found to be preferentially and highly cytotoxic (IC ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c, 2b, and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26-28 gained activities of IC 0.026-0.043 μM against K562 cells. Compounds 1b, 8, 21, 22, 23, and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF-CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b, 8, and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b, 1c, 2b, 2c, 24, and 26-28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs.
Topics: Humans; Prodrugs; Pyrazines; Membrane Potential, Mitochondrial; Antineoplastic Agents, Phytogenic; HeLa Cells; Drug Resistance, Neoplasm; Cell Line, Tumor; Triterpenes; Antineoplastic Agents; Pyridines
PubMed: 36174412
DOI: 10.1016/j.ejmech.2022.114777 -
Chemistry, An Asian Journal Nov 2019Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other... (Review)
Review
Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3-deazaneplanocin A, galidesivir, GS-6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS-6620, remdesivir and pyrazofurin) are C-nucleosides, and two of them (GS-6620, remdesivir) also contain a phosphoramidate part. The C-nucleoside and phosphoramidate (and for the adenine analogues the 1'-cyano group as well) may be considered as essential attributes for their antiviral activity.
Topics: Adenine; Adenosine; Alanine; Amides; Antiviral Agents; Base Pairing; Ebolavirus; Guanine; Hemorrhagic Fevers, Viral; Humans; Nucleotides; Phosphoric Acids; Pyrazines; Triazines
PubMed: 31389664
DOI: 10.1002/asia.201900841 -
Food Chemistry Jan 2024Pyrazines are a class of active aromatic substances existing in various foods. The accumulation of pyrazines has an impact on flavor and quality of food products. This... (Review)
Review
Pyrazines are a class of active aromatic substances existing in various foods. The accumulation of pyrazines has an impact on flavor and quality of food products. This review encompasses the formation mechanisms and control strategies of pyrazines via Maillard reaction (MR), including the new reactants and emerging techniques. Pyrazines characteristics are better understood through the developed sample pretreatments and detection methods. Herein, an in-depth review of pretreatments and analysis methods since 2010 is presented to explore the simple, fast, green, and effective strategies. Sample preparation methods include liquid phase extraction, solid phase extraction, supercritical fluid extraction, and microextraction methods such as liquid phase microextraction, and solid phase microextraction, etc. Detections are made by chromatographic methods, and sensors, etc. Advantages and limitations are discussed and compared for providing insights to further studies.
Topics: Pyrazines; Solid Phase Extraction; Liquid-Liquid Extraction; Solid Phase Microextraction; Chromatography, Supercritical Fluid
PubMed: 37566982
DOI: 10.1016/j.foodchem.2023.137086 -
Critical Reviews in Food Science and... 2023Natural pyrazines, mainly methyl- or ethyl-substituted forms, are commonly applied as flavor ingredients in raw and roasted food. Meanwhile alkylpyrazines are used as... (Review)
Review
Natural pyrazines, mainly methyl- or ethyl-substituted forms, are commonly applied as flavor ingredients in raw and roasted food. Meanwhile alkylpyrazines are used as food preservatives due to their effective antimicrobial action. These natural pyrazines are widely distributed in several biological systems such as plants, animals, and insects; each with respective physiological role. Besides, pyrazines are formed in food via thermal treatment and fermentation. This review presents the most comprehensive overview of pyrazines with correlation to their chemical structures and different applications with emphasis on their food applications. The major part deals with pyrazines generated in thermally treated food, reaction mechanisms highlighting factors and optimum conditions affecting their production. Additionally, the several metabolic reactions mediating for pyrazines metabolism in humans and excretion via the kidney are discussed and on context to their effects. Lastly, a review of the different techniques applied for pyrazines isolation, detection and quantitation is presented. The study provides future considerations and direction of research on this important dietary component and their applications. Pyrazines multifunctional chemistry is of value to the food sector, by presenting the best practices for their production whilst the detrimental effects are minimized.
Topics: Humans; Animals; Pyrazines; Food
PubMed: 34933625
DOI: 10.1080/10408398.2021.2017260 -
Biomolecules Oct 2021Alkyl-methoxypyrazines are an important class of odor-active molecules that contribute green, 'unripe' characters to wine and are considered undesirable in most wine... (Review)
Review
Alkyl-methoxypyrazines are an important class of odor-active molecules that contribute green, 'unripe' characters to wine and are considered undesirable in most wine styles. They are naturally occurring grape metabolites in many cultivars, but can also be derived from some Coccinellidae species when these 'ladybugs' are inadvertently introduced into the must during harvesting operations. The projected impacts of climate change are discussed, and we conclude that these include an altered alkyl-methoxypyrazine composition in grapes and wines in many wine regions. Thus, a careful consideration of how to manage them in both the vineyard and winery is important and timely. This review brings together the relevant literatures on viticultural and oenological interventions aimed at mitigating alkyl-methoxypyrazine loads, and makes recommendations on their management with an aim to maintaining wine quality under a changing and challenging climate.
Topics: Climate Change; Food Contamination; Fruit; Gas Chromatography-Mass Spectrometry; Humans; Odorants; Pyrazines; Vitis; Wine
PubMed: 34680154
DOI: 10.3390/biom11101521 -
EBioMedicine Oct 2021Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality, however with no effective therapy available. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality, however with no effective therapy available.
METHODS
The effect of favipiravir (FPV) in treating SFTS was evaluated by an integrated analysis on data collected from a single-arm study (n=428), a surveillance study (n=2350) and published data from a randomized controlled trial study (n=145). A 1:1 propensity score matching was performed to include 780 patients: 390 received FPV and 390 received supportive therapy only. Case fatality rates (CFRs), clinical progress, and adverse effects were compared.
FINDINGS
FPV treatment had significantly reduced CFR from 20.0% to 9.0% (odds ratio 0.38, 95% confidence interval 0.23-0.65), however showing heterogeneity when patients were grouped by age, onset-to-admission interval, initial viral load and therapy duration. The effect of FPV was significant only among patients aged ≤70 years, with onset-to-admission interval ≤5 days, therapy duration ≥5 days or baseline viral load ≤1 × 10 copies/mL. Age-stratified analysis revealed no benefit in the aging group >70 years, regardless of their sex, onset-to-admission interval, therapy duration or baseline viral load. However, for both ≤60 and 60-70 years groups, therapy duration and baseline viral load differentially affected FPV therapy efficiency. Hyperuricemia and thrombocytopenia, as the major adverse response of FPV usage, were observed in >70 years patients.
INTERPRETATION
FPV was safe in treating SFTS patients but showed no benefit for those aged >70 years. Instant FPV therapy could highly benefit SFTS patients aged 60-70 years.
FUNDING
China Natural Science Foundation (No. 81825019, 82073617 and 81722041) and China Mega-project for Infectious Diseases (2018ZX10713002 and 2015ZX09102022).
Topics: Aged; Amides; Antiviral Agents; Female; Humans; Male; Middle Aged; Pyrazines; Severe Fever with Thrombocytopenia Syndrome; Treatment Outcome; Viral Load
PubMed: 34563924
DOI: 10.1016/j.ebiom.2021.103591