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Journal of Medicinal Chemistry Mar 2021Flaviviruses, including Zika, dengue, and West Nile viruses, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral...
Flaviviruses, including Zika, dengue, and West Nile viruses, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screening, followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile viruses, and their inhibitory activities are correlated. The most potent compounds and potently inhibited Zika virus replication in cells with EC values of 300-600 nM and in a mouse model of Zika infection. These compounds represent novel pharmacological leads for drug development against Flavivirus infections.
Topics: Allosteric Regulation; Animals; Antiviral Agents; Cell Line, Tumor; Dengue Virus; Humans; Mice; Molecular Structure; Pyrazines; Serine Endopeptidases; Serine Proteinase Inhibitors; Structure-Activity Relationship; Viral Nonstructural Proteins; Viral Proteins; Virus Replication; West Nile virus; Zika Virus; Zika Virus Infection
PubMed: 33596380
DOI: 10.1021/acs.jmedchem.0c02070 -
Molecular Cancer Research : MCR May 2021Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases...
Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the () fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation-positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinib-mediated growth inhibitory effects on NPM1-ALK-driven ALCL cells. We utilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G-G-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion-driven hematologic or solid malignancies. IMPLICATIONS: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK-driven ALCL cells and pave a path for developing future clinical trials. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/5/913/F1.large.jpg.
Topics: Anaplastic Lymphoma Kinase; Aniline Compounds; Humans; Lymphoma, Large-Cell, Anaplastic; Pyrazines
PubMed: 33514657
DOI: 10.1158/1541-7786.MCR-20-0738 -
Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis.Nature Chemistry May 2021Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores,...
Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.
Topics: Chemistry Techniques, Synthetic; Humans; Pyrazines; Pyrazoles; Solid-Phase Synthesis Techniques
PubMed: 33875818
DOI: 10.1038/s41557-021-00662-w -
PloS One 2022Atherosclerosis(AS) is widely recognized as a risk factor for incident cardiovascular and cerebrovascular diseases. Tetramethylpyrazine (TMP) is the active ingredient of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atherosclerosis(AS) is widely recognized as a risk factor for incident cardiovascular and cerebrovascular diseases. Tetramethylpyrazine (TMP) is the active ingredient of Ligusticum wallichii that possesses a variety of biological activities against atherosclerosis.
OBJECTIVE
This systematic review and meta-analysis sought to study the impact of and mechanism of tetramethylpyrazine for atherosclerosis in animal models.
METHODS
A systematic search was conducted of PubMed, Embase, Cochrane Library, Web of Science database, Chinese Biomedical (CBM) database, China National Knowledge Infrastructure (CNKI), WanFang data, and Vip Journal Integration Platform, covering the period from the respective start date of each database to December 2021. We used SYRCLE's 10-item checklist and Rev-Man 5.3 software to analyze the data and the risk of bias.
RESULTS
Twelve studies, including 258 animals, met the inclusion criteria. Compared with the control group, TMP significantly reduced aortic atherosclerotic lesion area, and induced significant decreases in levels of TC (SMD = -2.67, 95% CI -3.68 to -1.67, P < 0.00001), TG (SMD = -2.43, 95% CI -3.39 to -1.47, P < 0.00001), and LDL-C (SMD = -2.87, 95% CI -4.16 to -1.58, P < 0.00001), as well as increasing HDL-C (SMD = 2.04, 95% CI 1.05 to 3.03, P = 0.001). TMP also significantly modulated plasma inflammatory responses and biological signals associated with atherosclerosis. In subgroup analysis, the groups of high-dose TMP (≥50 mg/kg) showed better results than those of the control group. No difference between various durations of treatment groups or various assessing location groups.
CONCLUSION
TMP exerts anti-atherosclerosis functions in an animal model of AS mediated by anti-inflammatory action, antioxidant action, ameliorating lipid metabolism disorder, protection of endothelial function, antiplatelet activity, reducing the proliferation and migration of smooth muscle cells, inhibition of angiogenesis, antiplatelet aggregation. Due to the limitations of the quantity and quality of current studies, the above conclusions need to be verified by more high-quality studies.
TRIAL REGISTRATION NUMBER
PROSPERO registration no.CRD42021288874.
Topics: Animals; Aortic Diseases; Atherosclerosis; Disease Models, Animal; Humans; Pyrazines
PubMed: 35500001
DOI: 10.1371/journal.pone.0267968 -
Molecules (Basel, Switzerland) May 2024Ligustrazine (TMP) is the main active ingredient extracted from , which is used in the treatment of cardiovascular and cerebrovascular diseases, with the drawback of...
Ligustrazine (TMP) is the main active ingredient extracted from , which is used in the treatment of cardiovascular and cerebrovascular diseases, with the drawback of being unstable and readily sublimated. Cocrystal technology is an effective method to improve the stability of TMP. Three benzoic acid compounds including P-aminobenzoic acid (PABA), 3-Aminobenzoic acid (MABA), and 3,5-Dinitrobenzoic acid (DNBA) were chosen for co-crystallization with TMP. Three novel cocrystals were obtained, including TMP-PABA (1:2), TMP-MABA (1.5:1), and TMP-DNBA (0.5:1). Hygroscopicity was characterized by the dynamic vapor sorption (DVS) method. Three cocrystals significantly improved the hygroscopicity stability, and the mass change in TMP decreased from 25% to 1.64% (TMP-PABA), 0.12% (TMP-MABA), and 0.03% (TMP-DNBA) at 90% relative humidity. The melting points of the three cocrystals were all higher than TMP, among which the TMP-DNBA cocrystal had the highest melting point and showed the best stability in reducing hygroscopicity. Crystal structure analysis shows that the mesh-like structure formed by the O-H⋯N hydrogen bond in the TMP-DNBA cocrystal was the reason for improving the stability of TMP.
Topics: Pyrazines; Crystallization; Wettability; Drug Stability; Hydrogen Bonding; Crystallography, X-Ray; Molecular Structure; X-Ray Diffraction
PubMed: 38792070
DOI: 10.3390/molecules29102208 -
Molecules (Basel, Switzerland) Jun 2022Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activity, the changes of which can be easily detected by a substituent effect...
Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activity, the changes of which can be easily detected by a substituent effect or a change in the functional group. The present studies combined theoretical research with the density functional theory (DFT) approach (B3LYP/6-311+G**) and experimental (potentiometric and spectrophotometric) analysis for a thorough understanding of the structure of chlorohydrazinopyrazine, its physicochemical and cytotoxic properties, and the site and nature of interaction with DNA. The obtained results indicated that 2-chloro-3-hydrazinopyrazine (2Cl3HP) displayed the highest affinity to DNA. Cytotoxicity studies revealed that the compound did not exhibit toxicity toward human dermal keratinocytes, which supported the potential application of 2Cl3HP in clinical use. The study also attempted to establish the possible equilibria occurring in the aqueous solution and, using both theoretical and experimental methods, clearly showed the hydrophilic nature of the compound. The experimental and theoretical results of the study confirmed the quality of the compound, as well as the appropriateness of the selected set of methods for similar research.
Topics: Anti-Bacterial Agents; Antineoplastic Agents; DNA; Humans; Pyrazines; Water
PubMed: 35744829
DOI: 10.3390/molecules27123704 -
Haematologica Oct 2007
Topics: Amyloidosis; Animals; Boronic Acids; Bortezomib; Humans; Kidney; Plasma Cells; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Treatment Outcome
PubMed: 18024367
DOI: 10.3324/haematol.12136 -
Journal of Medicinal Chemistry Dec 2020Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole...
Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure-activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.
Topics: Animals; Antiprotozoal Agents; Antitubercular Agents; Blood Proteins; Cell Survival; Drug Design; Half-Life; Humans; Mice; Microbial Sensitivity Tests; Microsomes; Mycobacterium; Nitroimidazoles; Protein Binding; Pyrazines; Solubility; Structure-Activity Relationship; Trypanosoma brucei brucei
PubMed: 33151678
DOI: 10.1021/acs.jmedchem.0c01372 -
Molecules (Basel, Switzerland) Jun 2022This study describes the synthesis, theoretical investigations, and photocatalytic degradational properties of a new...
This study describes the synthesis, theoretical investigations, and photocatalytic degradational properties of a new (pyrazine)(meso-tetrakis(4-tert-methoxyphenyl)-porphyrinato)-cadmium (II) ([Cd(TMPP)-Pyz]) complex (). The new penta-coordinated Cd porphyrin complex () was characterized by various spectroscopic techniques, including FT-IR, NMR, UV-visible absorption, fluorescence emission, and singlet oxygen, while its molecular structure was studied using single crystal X-ray diffraction. The UV-Vis spectroscopic study highlighted the redshift of the absorption bands after the insertion of the Cd(II) metal ion into the TMPP ring. The co-coordination of the pyrazine axial ligand enhanced this effect. A fluorescence emission spectroscopic study showed a significant blueshift in the Q bands, accompanied by a decrease in the fluorescence emission intensity and quantum yields of Φ = 0.084, Φ = 0.06 and Φ = 0.03 for H-TMPP free-base porphyrin, [Cd(TMPP)] and [Cd(TMPP)(Pyz)] () respectively. Singlet oxygen revealed that the H-TMPP porphyrin produced the most efficient singlet oxygen quantum yield of (Φ = 0.73) compared to [CdTMPP] (Φ = 0.57) and [Cd(TMPP)(Pyz)] () (Φ = 0.13). In the crystal lattice, the [Cd(TMPP)Pyz] was stabilized through non-covalent intermolecular interactions (NCI), such as the hydrogen bonds C-H···N and C-H···Cg. Additionally, crystal explorer software was then utilized to measure the quantitative analysis of the intermolecular interactions in the unit cell of the crystal structure and established that the C-H···π interaction dominated. The Natural bond orbital (NBO) analysis revealed that each molecule is stabilized by hyperconjugation and charge delocalization. As a photocatalyst, the coordination complex showed excellent photocatalytic activity toward the degradation of Levafix Blue CA reactive dye (i.e., dye photo-degradation of 80%).
Topics: Cadmium; Porphyrins; Pyrazines; Singlet Oxygen; Spectroscopy, Fourier Transform Infrared
PubMed: 35744951
DOI: 10.3390/molecules27123833 -
Journal of Pharmacy & Pharmaceutical... 2009To evaluate the pharmacokinetic interaction between oltipraz and silymarin after intravenous and oral administration of both drugs to male Sprague-Dawley rats.
PURPOSE
To evaluate the pharmacokinetic interaction between oltipraz and silymarin after intravenous and oral administration of both drugs to male Sprague-Dawley rats.
METHODS
Oltipraz (single doses of 10 and 30 mg/kg for intravenous and oral administration, respectively), silymarin (single doses of 50 and 100 mg/kg for intravenous and oral administration, respectively, and 14 days oral administration of 100 mg/kg), alone and together were administered to control rats.
RESULTS
The pharmacokinetic parameters of oltipraz did not significantly altered by silymarin. However, after intravenous administration of the drugs together, the AUCs of unconjugated, conjugated, and total (unconjugated plus conjugated) silibinin were significantly different (32.7% decrease, and 32.1% and 27.2% increase, respectively), and total and (CL) and non-renal (CL NR ) clearance of unconjugated silibinin were significantly faster (49.4% and 61.1% increase, respectively) than those of silymarin alone (without oltipraz). After oral administration of silymarin with or without oltipraz, however, the pharmacokinetic parameters of unconjugated, conjugated, and total silibinin were comparable.
CONCLUSIONS
After single intravenous administration of the drugs together, the AUC of unconjugated silibinin was significantly smaller, but that of both conjugated and total silibinin was significantly greater. This could have been due to an increase in the formation of conjugates (glucuronidation and sulfation) of silibinin as induced by oltipraz. After simultaneous oral administration of the drugs, however, the AUCs (or AUC 0-12 h) of unconjugated, conjugated, and total silibinin were comparable.
Topics: Administration, Oral; Animals; Anticarcinogenic Agents; Area Under Curve; Drug Interactions; Injections, Intravenous; Male; Metabolic Clearance Rate; Microsomes, Liver; Pyrazines; Rats; Rats, Sprague-Dawley; Silybin; Silymarin; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Thiones; Thiophenes; Tissue Distribution
PubMed: 19470289
DOI: 10.18433/j38c7w