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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 -
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 -
Pharmacology & Therapeutics Jul 2024In recent decades, natural products have attracted worldwide attention and become one of the most important resources for pharmacological industries and medical sciences... (Review)
Review
In recent decades, natural products have attracted worldwide attention and become one of the most important resources for pharmacological industries and medical sciences to identify novel drug candidates for disease treatment. Tetramethylpyrazine (TMP) is an alkaloid extracted from Ligusticum chuanxiong Hort., which has shown great therapeutic potential in cardiovascular and cerebrovascular diseases, liver and renal injury, as well as cancer. In this review, we analyzed 1270 papers published on the Web of Science Core Collection from 2002 to 2022 and found that TMP exerted significant protective effects on ischemia-reperfusion (I/R) injury that is the cause of pathological damages in a variety of conditions, such as ischemic stroke, myocardial infarction, acute kidney injury, and liver transplantation. TMP is limited in clinical applications to some extent due to its rapid metabolism, a short biological half-life and poor bioavailability. Obviously, the structural modification, administration methods and dosage forms of TMP need to be further investigated in order to improve its bioavailability. This review summarizes the clinical applications of TMP, elucidates its potential mechanisms in protecting I/R injury, provides strategies to improve bioavailability, which presents a comprehensive understanding of the important compound. Hopefully, the information and knowledge from this review can help researchers and physicians to better improve the applications of TMP in the clinic.
Topics: Pyrazines; Humans; Reperfusion Injury; Animals; Ligusticum
PubMed: 38735486
DOI: 10.1016/j.pharmthera.2024.108656 -
Journal of Agricultural and Food... Sep 2022In this study, it was found that extra-added cysteine (Cys) became involved in volatile compound formation during the Maillard reaction of the glycine-ribose Amadori...
Formation Priority of Pyrazines and 2-Acetylthiazole Dependent on the Added Cysteine and Fragments of Deoxyosones during the Thermal Process of the Glycine-Ribose Amadori Compound.
In this study, it was found that extra-added cysteine (Cys) became involved in volatile compound formation during the Maillard reaction of the glycine-ribose Amadori rearrangement product (GR-ARP). The priority of the Cys reaction with different α-dicarbonyls and its dependence on the Cys dosage were investigated. At the same concentrations of methylglyoxal (MGO) and glyoxal (GO), it was found that 2-acetylthiazole was the dominant product when the molar ratio of Cys to MGO was 1:1, while formation of pyrazines was improved when the Cys percentage increased. Cys preferentially reacted with MGO first rather than GO to exclusively generate 2-acetylthiazole at a high yield. The concentration of 2-acetylthiazole quickly increased up to a plateau and remained stable during further heat treatment. When MGO was totally consumed, remaining Cys began to react with GO through the predominant pathway where the keto form of carbonylcysteimine derived from Cys and GO was hydrolyzed to recover GO with cysteamine formation, whereas the hydrolysis reactivity of enolized carbonylcysteimine as the Strecker pathway for generation of pyrazines was relatively low. During the heat treatment of GR-ARP, the constantly lower ratios of α-dicarbonyls to Cys led to inhibited formation of 2-aminopropanal, which accounted for the decreased methylpyrazine yields.
Topics: Cysteamine; Cysteine; Glycine; Glyoxal; Magnesium Oxide; Maillard Reaction; Pyrazines; Pyruvaldehyde; Ribose; Thiazoles
PubMed: 36070497
DOI: 10.1021/acs.jafc.2c04874 -
Current Organic Synthesis Aug 20222,3-Diaminomaleonitrile (DAMN), a tetramer of hydrogen cyanide, displays weakly basic properties and has reactivity comparable to o-phenylenediamine. It has emerged as a... (Review)
Review
2,3-Diaminomaleonitrile (DAMN), a tetramer of hydrogen cyanide, displays weakly basic properties and has reactivity comparable to o-phenylenediamine. It has emerged as a versatile, cheap as well as a readily accessible building block towards the synthesis of a variety of organic compounds. The present review focuses on the applications of 2,3-diaminomaleonitrile for the synthesis of Schiff's base, imidazoles, pyrazines, quinoxolines, benzodiazocines, 1,4-diazepines, purines, pyrimidines, pyrazine-tetrazole hybrids, triazoles, thiadiazole, thiazolidines, porphyrazines, formamidines, 1,3,5-triazepines, pyrrolo[3,4-b][1,4]diazepin-6(3H)-ones, triaza[22]annulenes, pyrrolo[3,4-f][1,3,5]triazepines, spiro compounds, pyrazoles and 2,3-dicyano-5,7- bismethylthieno[3,4-b]pyrazine.
Topics: Chemistry Techniques, Synthetic; Nitriles; Pyrazines; Pyrazoles
PubMed: 34994313
DOI: 10.2174/1570179419666220107155346 -
Molecules (Basel, Switzerland) Nov 2023Infectious diseases pose a major challenge to human health, and there is an urgent need to develop new antimicrobial agents with excellent antibacterial activity. A...
Infectious diseases pose a major challenge to human health, and there is an urgent need to develop new antimicrobial agents with excellent antibacterial activity. A series of novel triazolo[4,3-]pyrazine derivatives were synthesized and their structures were characterized using various techniques, such as melting point, H and C nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. All the synthesized compounds were evaluated for in vitro antibacterial activity using the microbroth dilution method. Among all the tested compounds, some showed moderate to good antibacterial activities against both Gram-positive and Gram-negative strains. In particular, compound exhibited superior antibacterial activities (MICs: 32 μg/mL against and 16 μg/mL against ), which was comparable to the first-line antibacterial agent ampicillin. In addition, the structure-activity relationship of the triazolo[4,3-]pyrazine derivatives was preliminarily investigated.
Topics: Humans; Pyrazines; Anti-Bacterial Agents; Anti-Infective Agents; Escherichia coli; Structure-Activity Relationship; Staphylococcal Infections; Microbial Sensitivity Tests; Molecular Structure
PubMed: 38067606
DOI: 10.3390/molecules28237876 -
Food Research International (Ottawa,... Jul 2023Theanine is a distinctive amino acid in tea that plays a vital role in tea flavor during the roasting process. Model thermal reactions of total amino acids and sugars...
Theanine is a distinctive amino acid in tea that plays a vital role in tea flavor during the roasting process. Model thermal reactions of total amino acids and sugars with different roasting conditions (low-fire, middle-fire, and high-fire) showed theanine competitively inhibited the formation of indole, skatole, 4-hydroxy-2,5-dimethyl-3(2H)-furanone, and Strecker aldehydes, while greatly stimulated the production of roasty pyrazines. In addition, highest amounts of pyrazines were obtained under high-fire degree. Quantification of these reaction products in Wuyi rock tea (WRT) was realized in different roasted Dahongpao teas by means of sensomics approach. The quantitative data revealed the biggest influence of roasting temperatures on the formation of reaction products among indole, lipid oxidation products, and pyrazines, while other reaction products were only slightly affected. The findings of this study provide a fresh perspective on the impact of theanine on aroma formation during the roasting process, which will help to explore the formation of key odorants during tea production.
Topics: Odorants; Temperature; Amino Acids; Tea; Pyrazines
PubMed: 37254434
DOI: 10.1016/j.foodres.2023.112860 -
European Journal of Medicinal Chemistry Jan 2022GYH2-18 is a type II HBV CAM with 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamine (DPPC) skeleton discovered by Roche INC. A series of GYH2-18 derivatives were...
GYH2-18 is a type II HBV CAM with 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamine (DPPC) skeleton discovered by Roche INC. A series of GYH2-18 derivatives were designed, synthesized and evaluated for their anti-HBV activity. Two compounds 2f and 3k exhibited excellent anti-HBV activity, low cytotoxicity and accepted oral PK profiles. Chiral separation of 2f and 3k was conducted successfully, and (6S)-cyclopropyl DPPC isomers 2f-1, 2f-3, 3k-1 and 3k-3 were identified to be much more active than the corresponding (6R)-ones. The preliminary structure-activity relationship, particle gel assay and molecular modeling studies were also discussed, which provide useful indications for guiding the further rational design of new (6S)-cyclopropyl DPPC analogues.
Topics: Antiviral Agents; Capsid Proteins; Dose-Response Relationship, Drug; Hepatitis B virus; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pyrazines; Structure-Activity Relationship; Virus Replication
PubMed: 34772528
DOI: 10.1016/j.ejmech.2021.113974 -
Journal of Managed Care & Specialty... Oct 2021Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and confirmed feline McDonough sarcoma (FMS)-like tyrosine kinase 3 gene mutations () have a...
Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and confirmed feline McDonough sarcoma (FMS)-like tyrosine kinase 3 gene mutations () have a poor prognosis and limited effective treatment options. Gilteritinib is the first targeted therapy approved in the United States and Europe for R/R AML with significantly improved efficacy compared with existing treatments. To evaluate gilteritinib against salvage chemotherapy (SC) and best supportive care (BSC) over a lifetime horizon among adult patients with R/R AML from a US third-party payer's perspective. The model structure of this cost-effectiveness analysis included a decision tree to stratify patients based on their hematopoietic stem cell transplantation (HSCT) status, followed by 2 separate 3-state partitioned survival models to predict the long-term health status conditional on HSCT status. The ADMIRAL trial data and literature were used to predict probabilities of patients being in different health states until a conservative cure point at year 3. Afterwards, living patients followed the survival outcomes of long-term survivors with AML. Model inputs for utilities, medical resource use, and costs were based on the ADMIRAL trial, published literature, and public sources. All costs were inflated to 2019 US dollars (USD). Total incremental costs (in 2019 USD), life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Deterministic sensitivity analyses and probabilistic sensitivity analyses were performed. Over a lifetime horizon with a 3.0% annual discount rate, the base-case model estimated that gilteritinib led to an increase of 1.29 discounted QALYs at an additional cost of $148,106 vs SC, corresponding to an ICER of $115,192 per QALY; for BSC, results were an increase of 2.32 discounted QALYs, $249,674, and $107,435, respectively. The base-case findings were robust in sensitivity analyses. The estimated probabilities of gilteritinib being cost-effective vs SC and BSC were 90.5% and 99.8%, respectively, in the probabilistic sensitivity analyses, based on a willingness-to-pay threshold of $150,000 per QALY. Gilteritinib is a cost-effective novel treatment for patients with R/R AML in the United States. This work was supported by Astellas Pharma, Inc., which was involved in all stages of the research and manuscript development. Garnham, Pandya, and Shah are employees of Astellas and hold stock/stock options. Zeidan consulted and received personal fees/honoraria and research funding from Astellas. Zeidan also has received research funding from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff Oncology, Incyte, Takeda, Novartis, Amgen, Aprea, and ADC Therapeutics; has participated in advisory boards; has consulted with and/or received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Daiichi Sankyo, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Syndax, Gilead, Kura, Aprea, Lox Oncology, Genentech, Servier, Jasper, Tyme, and Epizyme; has served on clinical trial committees for Novartis, Abbvie, Geron, Gilead, Kura, Lox Oncology, BioCryst, and Celgene/BMS; and has received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. Qi and Yang are employees of Analysis Group, Inc., which received consulting fees from Astellas for work on this study. Part of this material was presented at the American Society of Hematology (ASH) Annual Meeting; December 7-10, 2019; Orlando, FL.
Topics: Aniline Compounds; Cost-Benefit Analysis; Humans; Leukemia, Myeloid, Acute; Pyrazines; Quality-Adjusted Life Years; Recurrence; Survival Analysis; fms-Like Tyrosine Kinase 3
PubMed: 34595955
DOI: 10.18553/jmcp.2021.27.10.1469