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Bioorganic & Medicinal Chemistry Letters Nov 2015The emergence of multidrug-resistant bacterial strains has heightened the need for new antimicrobial agents based on novel chemical scaffolds that are able to circumvent...
The emergence of multidrug-resistant bacterial strains has heightened the need for new antimicrobial agents based on novel chemical scaffolds that are able to circumvent current modes of resistance. We recently developed a whole-animal drug-screening methodology in pursuit of this goal and now report the discovery of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC) as a novel antibacterial effective against resistant nosocomial pathogens. The minimum inhibitory concentrations (MIC) of PSPC against Staphylococcus aureus and Enterococcus faecium were 4 μg/mL and 8 μg/mL, respectively, whereas the MICs were higher against the Gram-negative bacteria Klebsiella pneumoniae (64 μg/mL), Acinetobacter baumannii (32 μg/mL), Pseudomonas aeruginosa (>64 μg/mL), and Enterobacter spp. (>64 μg/mL). However, co-treatment of PSPC with the efflux pump inhibitor phenylalanine arginyl β-naphthylamide (PAβN) or with sub-inhibitory concentrations of the lipopeptide antibiotic polymyxin B reduced the MICs of PSPC against the Gram-negative strains by >4-fold. A sulfide analog of PSPC (PSPC-1S) showed no antibacterial activity, whereas the sulfoxide analog (PSPC-6S) showed identical activity as PSPC across all strains, confirming structure-dependent activity for PSPC and suggesting a target-based mechanism of action. PSPC displayed dose dependent toxicity to both Caenorhabditis elegans and HEK-293 mammalian cells, culminating with a survival rate of 16% (100 μg/mL) and 8.5% (64 μg/mL), respectively, at the maximum tested concentration. However, PSPC did not result in hemolysis of erythrocytes, even at a concentration of 64 μg/mL. Together these results support PSPC as a new chemotype suitable for further development of new antibiotics against Gram-positive and Gram-negative bacteria.
Topics: Animals; Anti-Bacterial Agents; Caenorhabditis elegans; Dipeptides; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; HEK293 Cells; High-Throughput Screening Assays; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Polymyxin B; Pyrazines; Sheep; Vancomycin
PubMed: 26459212
DOI: 10.1016/j.bmcl.2015.09.066 -
Expert Review of Anti-infective Therapy Apr 2022The role of favipiravir (FVP) as a COVID-19 treatment is recognized but not fully elucidated. We aimed to evaluate whether FVP has definite clinical efficacy and safety... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The role of favipiravir (FVP) as a COVID-19 treatment is recognized but not fully elucidated. We aimed to evaluate whether FVP has definite clinical efficacy and safety in the treatment of COVID-19.
METHODS
International and Chinese databases were searched for randomized controlled clinical trials evaluating FVP for the treatment of COVID-19. A meta-analysis was performed and published literature was synthesized to evaluate the corresponding therapeutic effects.
RESULTS
We included 13 studies (1430 patients in total). Meta-analysis showed that patients with mild-to-moderate disease treated with FVP had a significantly higher viral clearance rate than those in the control group 10 and 14 days after initiation of treatment [RR: 1.13 (95% CI: 1.00, 1.28), P = 0.04; I = 39% for day 10 and RR: 1.16 (95% CI: 1.04, 1.30), P = 0.008; I = 38% for day 14] and a significantly shorter hospital stay [MD: -1.52 (95% CI: -2.82, -0.23), P = 0.02; I = 0%].
CONCLUSIONS
FVP significantly promotes viral clearance and reduces the hospitalization duration in mild-to-moderate COVID-19 patients, which can reduce the risk of severe disease outcomes in patients. However, more importantly, the results showed no benefit of FVP in severe patients, and caution should be taken regarding the treatment options of FVP in severe patients.
Topics: Amides; Humans; Pyrazines; Randomized Controlled Trials as Topic; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 34846960
DOI: 10.1080/14787210.2022.2012155 -
Molecules (Basel, Switzerland) Jul 2021Ladybug taint (also known as ladybird taint) is a relatively recently recognized fault that has been identified in wines from a wide range of terroirs.... (Review)
Review
Ladybug taint (also known as ladybird taint) is a relatively recently recognized fault that has been identified in wines from a wide range of terroirs. Alkyl-methoxypyrazines-particularly 2-isopropyl-3-methoxypyrazine-have been determined as the causal compounds, and these are introduced into grape must during processing, when specific species of vineyard-dwelling Coccinellidae are incorporated into the harvested fruit. , and especially the invasive , are the beetles implicated, and climate change is facilitating wider dispersal and survivability of in viticultural regions worldwide. Affected wines are typically characterized as possessing excessively green, bell pepper-, and peanut-like aroma and flavor. In this paper, we review a range of vineyard practices that seek to reduce Coccinellidae densities, as well as both "standard" and novel wine treatments aimed at reducing alkyl-methoxypyrazine load. We conclude that while prevention of ladybug taint is preferable, there are several winery interventions that can remediate the quality of wine affected by this taint, although they vary in their relative efficacy and specificity.
Topics: Animals; Coleoptera; Food Contamination; Fruit; Odorants; Pyrazines; Vitis; Wine
PubMed: 34299616
DOI: 10.3390/molecules26144341 -
Molecules (Basel, Switzerland) Apr 2022Class I histone deacetylases, HDAC1, HDAC2, and HDAC3, represent potential targets for cancer treatment. However, the development of isoform-selective drugs for these...
Class I histone deacetylases, HDAC1, HDAC2, and HDAC3, represent potential targets for cancer treatment. However, the development of isoform-selective drugs for these enzymes remains challenging due to their high sequence and structural similarity. In the current study, we applied a computational approach to predict the selectivity profile of developed inhibitors. Molecular docking followed by MD simulation and calculation of binding free energy was performed for a dataset of 2-aminobenzamides comprising 30 previously developed inhibitors. For each HDAC isoform, a significant correlation was found between the binding free energy values and in vitro inhibitory activities. The predictive accuracy and reliability of the best preforming models were assessed on an external test set of newly designed and synthesized inhibitors. The developed binding free-energy models are cost-effective methods and help to reduce the time required to prioritize compounds for further studies.
Topics: Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Molecular Docking Simulation; Protein Isoforms; Pyrazines; Reproducibility of Results
PubMed: 35458724
DOI: 10.3390/molecules27082526 -
British Journal of Clinical Pharmacology Jul 2022This prospective observational study describes the pharmacokinetic characteristics of favipiravir in adult patients hospitalized for mild to moderate COVID-19 with a... (Observational Study)
Observational Study
This prospective observational study describes the pharmacokinetic characteristics of favipiravir in adult patients hospitalized for mild to moderate COVID-19 with a positive RT-PCR test. Favipiravir was administered for 5 days, with a loading dose of 3200 mg and a maintenance dose of 1200 mg/day. Serial blood samples were collected on Day 2 and Day 4 of the therapy. Laboratory findings of the patients (n = 21) and in-hospital mortality were recorded. Favipiravir concentrations exhibited substantial variability and a significant decrease during the treatment of COVID-19. The median favipiravir trough concentration (C ) on Day 2 was 21.26 (interquartile range [IQR], 8.37-30.78) μg/mL, whereas it decreased significantly to 1.61 (IQR, 0.00-6.41) μg/mL on Day 4, the area under the concentration-time curve decreased by 68.5%. Day 2 C of female patients was higher than male patients. Our findings indicate that favipiravir concentrations show significant variability during the treatment of COVID-19 and therapeutic drug monitoring may be necessary to maintain targeted concentrations.
Topics: Adult; Amides; Antiviral Agents; Female; Humans; Male; Pyrazines; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 35014080
DOI: 10.1111/bcp.15227 -
Molecules (Basel, Switzerland) Mar 2020According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people...
According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino--phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against H37Ra and four other mycobacterial strains (, , , ) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, -(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)--(-tolyl)pyrazine-2-carboxamide (, MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the genus.
Topics: Antitubercular Agents; Drug Design; Drug Development; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Pyrazines; Structure-Activity Relationship
PubMed: 32231166
DOI: 10.3390/molecules25071561 -
Clinical Cardiology Feb 2024While the GRIPHON study and others have confirmed the efficacy and safety of selexipag with single, dual, and initial triple combination therapy for patients with...
BACKGROUND
While the GRIPHON study and others have confirmed the efficacy and safety of selexipag with single, dual, and initial triple combination therapy for patients with pulmonary arterial hypertension (PAH), multicenters studies concerning diverse triple oral combination therapies based on selexipag are limited.
HYPOTHESIS
This study was conducted to evaluate the effects of various sequential triple oral combination therapies on PAH outcomes.
METHODS
A retrospective study was carried out involving 192 patients from 10 centers, who were receiving sequential triple oral combination therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase 5 inhibitor (PDE5i)/riociguat and selexipag. Clinical parameters, event-free survival, and all-cause survival were assessed and analyzed at baseline and posttreatment.
RESULTS
Among the 192 patients, 37 were treated with ERA + riociguat + selexipag, and 155 patients received ERA + PDE5i + selexipag. Both sequential triple oral combination therapies improved the World Health Organization functional class and raised the count of low-risk parameters. As a result of the larger patients' population in the ERA + PDE5i + selexipag group, these individuals exhibited significant increases in 6-minute walking distance (6MWD), pulmonary arterial systolic pressure, pulmonary arterial pressure, right ventricle, and eccentricity index, and significant decreases in N-terminal probrain natriuretic peptide after 6 months of treatment. Nevertheless, both sequential triple oral combination therapy groups demonstrated similar shifts in these clinical parameters between baseline and 6 months. Baseline 6MWD and mean pulmonary arterial pressure were independent predictors of survival in patients undergoing ERA + PDE5i + selexipag therapy. Importantly, no significant differences were found in 6-month event-free survival and all-cause survival between two groups.
CONCLUSIONS
Different oral sequential triple combination therapies based on selexipag could comparably improve outcomes in patients with PAH.
Topics: Humans; Pulmonary Arterial Hypertension; Retrospective Studies; Acetamides; Pyrazines
PubMed: 38402556
DOI: 10.1002/clc.24245 -
Blood Advances Mar 2023
Topics: Humans; Neoplasm Recurrence, Local; Aniline Compounds; Pyrazines; Leukemia, Myeloid, Acute
PubMed: 36583677
DOI: 10.1182/bloodadvances.2022008991 -
Molecules (Basel, Switzerland) Nov 2020Pulcherriminic acid is a cyclic dipeptide found mainly in and yeast. Due to the ability of pulcherriminic acid to chelate Fe to produce reddish brown pulcherrimin,... (Review)
Review
Pulcherriminic acid is a cyclic dipeptide found mainly in and yeast. Due to the ability of pulcherriminic acid to chelate Fe to produce reddish brown pulcherrimin, microorganisms capable of synthesizing pulcherriminic acid compete with other microorganisms for environmental iron ions to achieve bacteriostatic effects. Therefore, studying the biosynthetic pathway and their enzymatic catalysis, gene regulation in the process of synthesis of pulcherriminic acid in can facilitate the industrial production, and promote the wide application in food, agriculture and medicine industries. After initially discussing, this review summarizes current research on the synthesis of pulcherriminic acid by , which includes the crystallization of key enzymes, molecular catalytic mechanisms, regulation of synthetic pathways, and methods to improve efficiency in synthesizing pulcherriminic acid and its precursors. Finally, possible applications of pulcherriminic acid in the fermented food, such as Chinese Baijiu, applying combinatorial biosynthesis will be summarized.
Topics: Anti-Bacterial Agents; Bacillus; Biosynthetic Pathways; Pyrazines
PubMed: 33260656
DOI: 10.3390/molecules25235611 -
Scientific Reports Feb 2018Ants use pheromones to coordinate their communal activity. Volatile pyrazines, for instance, mediate food resource gathering and alarm behaviors in different ant...
Ants use pheromones to coordinate their communal activity. Volatile pyrazines, for instance, mediate food resource gathering and alarm behaviors in different ant species. Here we report that leaf-cutter ant-associated bacteria produce a family of pyrazines that includes members previously identified as ant trail and alarm pheromones. We found that L-threonine induces the bacterial production of the trail pheromone pyrazines, which are common for the host leaf-cutter ants. Isotope feeding experiments revealed that L-threonine along with sodium acetate were the biosynthetic precursors of these natural products and a biosynthetic pathway was proposed.
Topics: Animals; Ants; Ecosystem; Gas Chromatography-Mass Spectrometry; Pheromones; Pyrazines; Serratia marcescens; Sodium Acetate; Threonine
PubMed: 29416082
DOI: 10.1038/s41598-018-20953-6