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Molecules (Basel, Switzerland) Aug 2023On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF were designed and synthesized. Their...
On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF were designed and synthesized. Their chemical structures were characterized by H and C nuclear magnetic resonance and high-resolution mass spectrometry. These compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi by the mycelium growth rate method. Most of the compounds showed some activity against each of the fungi at 100 μg/mL. Compounds and exhibited higher activity against all the tested fungi, and displayed the highest activity against with an EC value of 0.0530 μM, which was comparable with commercial pyraclostrobin. Structure-activity relationship analysis showed that, with respect to the R substituent, the straight chain or cycloalkyl ring moiety was a key structural moiety for the activity, and the R substituent on the pyrazole ring could have significant effects on the activity. Simple and readily available pyrazoles with potent antifungal activity were obtained, which are ready for further elaboration to serve as a pharmacophore in new potential antifungal agents.
Topics: Antifungal Agents; Pyrazoles; Mass Spectrometry; Mycelium
PubMed: 37687108
DOI: 10.3390/molecules28176279 -
The Journal of Pain Jul 2023Approximately half of patients with alcohol use disorder report pain and this can be severe during withdrawal. Many questions remain regarding the importance of...
Approximately half of patients with alcohol use disorder report pain and this can be severe during withdrawal. Many questions remain regarding the importance of biological sex, alcohol exposure paradigm, and stimulus modality to the severity of alcohol withdrawal-induced hyperalgesia. To examine the impact of sex and blood alcohol concentration on the time course of the development of mechanical and heat hyperalgesia, we characterized a mouse model of chronic alcohol withdrawal-induced pain in the presence or absence the alcohol dehydrogenase inhibitor, pyrazole. Male and female C57BL/6J mice underwent chronic intermittent ethanol vapor ± pyrazole exposure for 4 weeks, 4 d/wk to induce ethanol dependence. Hind paw sensitivity to the plantar application of mechanical (von Frey filaments) and radiant heat stimuli were measured during weekly observations at 1, 3, 5, 7, 24, and 48 hours after cessation of ethanol exposure. In the presence of pyrazole, males developed mechanical hyperalgesia after the first week of chronic intermittent ethanol vapor exposure, peaking at 48 hours after cessation of ethanol. By contrast, females did not develop mechanical hyperalgesia until the fourth week; this also required pyrazole and did not peak until 48 hours. Heat hyperalgesia was consistently observed only in females exposed to ethanol and pyrazole; this developed after the first weekly session and peaked at 1 hour. We conclude that Chronic alcohol withdrawal-induced pain develops in a sex-, time-, and blood alcohol concentration-dependent manner in C57BL/6J mice. PERSPECTIVE: Alcohol withdrawal-induced pain is a debilitating condition in individuals with AUD. Our study found mice experience alcohol withdrawal-induced pain in a sex and time course specific manor. These findings will aid in elucidating mechanisms of chronic pain and AUD and will help individuals remain abstinent from alcohol.
Topics: Mice; Male; Female; Animals; Hyperalgesia; Ethanol; Blood Alcohol Content; Alcoholism; Substance Withdrawal Syndrome; Hot Temperature; Mice, Inbred C57BL; Pain; Pyrazoles
PubMed: 36868488
DOI: 10.1016/j.jpain.2023.02.024 -
International Journal of Molecular... May 2023Some new Bis-pyrazoline hybrids with dual EGFR and BRAF inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer...
Some new Bis-pyrazoline hybrids with dual EGFR and BRAF inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds , , and demonstrated strong antiproliferative activity with GI values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAF. Compounds , , and inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound is the most potent inhibitor of cancer cell proliferation and BRAF. Compounds and induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds , , and have the potential to be dual EGFR/BRAF inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, and , were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.
Topics: Humans; Apoptosis; Cell Line; Cell Proliferation; Cell Survival; Density Functional Theory; Drug Design; ErbB Receptors; Molecular Docking Simulation; Proto-Oncogene Proteins B-raf; Pyrazoles; Static Electricity; Structure-Activity Relationship; Antineoplastic Agents
PubMed: 37240450
DOI: 10.3390/ijms24109104 -
Current Hematologic Malignancy Reports Dec 2014Considerable clinical experience regarding the long-term efficacy and safety of ruxolitinib has been gathered since the drug was approved in the USA for patients with... (Review)
Review
Considerable clinical experience regarding the long-term efficacy and safety of ruxolitinib has been gathered since the drug was approved in the USA for patients with intermediate or high-risk myelofibrosis (MF) in November 2011. Findings from the pivotal phase 3 COMFORT studies showed that ruxolitinib-associated reductions in MF-related splenomegaly and symptom burden occur rapidly and in the majority of patients. Two- and 3-year follow-up data further suggest that the benefits of ruxolitinib are durable and associated with a survival advantage compared with conventional therapies. However, careful management of treatment-related thrombocytopenia and anemia with dose modifications and supportive care is critical to allow chronic therapy. Based on preliminary evidence, ruxolitinib also allows spleen size and symptom reduction before allogeneic stem cell transplantation without negative effect on engraftment or outcomes. In recent studies, ruxolitinib provided effective management of hematologic parameters and symptoms in patients with polycythemia vera refractory to or intolerant of hydroxyurea.
Topics: Disease Management; Humans; Myeloproliferative Disorders; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines
PubMed: 25145552
DOI: 10.1007/s11899-014-0229-y -
Cells Jan 2022In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue...
In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.
Topics: Caspases; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Enzyme Activation; Exocytosis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Membrane Potential, Mitochondrial; Microtubules; Neoplasm Invasiveness; Neoplasm Proteins; Phosphatidylserines; Phosphorylation; Poly(ADP-ribose) Polymerases; Pyrazoles; Reactive Oxygen Species; Signal Transduction; Spindle Apparatus; Triple Negative Breast Neoplasms; Tubulin
PubMed: 35053370
DOI: 10.3390/cells11020254 -
Angewandte Chemie (International Ed. in... Nov 2019C-Nucleosides are characterized by a C-C rather than a C-N linkage between the heterocyclic base and the ribofuranose ring. While the biosynthesis of...
C-Nucleosides are characterized by a C-C rather than a C-N linkage between the heterocyclic base and the ribofuranose ring. While the biosynthesis of pseudouridine-C-nucleosides has been studied, less is known about the pyrazole-C-nucleosides such as the formycins and pyrazofurin. Herein, genome screening of Streptomyces candidus NRRL 3601 led to the discovery of the pyrazofurin biosynthetic gene cluster pyf. In vitro characterization of gene product PyfQ demonstrated that it is able to catalyze formation of the C-glycoside carboxyhydroxypyrazole ribonucleotide (CHPR) from 4-hydroxy-1H-pyrazole-3,5-dicarboxylic acid and phosphoribosyl pyrophosphate (PRPP). Similarly, ForT, the PyfQ homologue in the formycin pathway, can catalyze the coupling of 4-amino-1H-pyrazole-3,5-dicarboxylic acid and PRPP to form carboxyaminopyrazole ribonucleotide. Finally, PyfP and PyfT are shown to catalyze amidation of CHPR to pyrazofurin 5'-phosphate thereby establishing the latter stages of both pyrazofurin and formycin biosynthesis.
Topics: Amides; Bacterial Proteins; Formycins; Glycosides; Multigene Family; Nucleosides; Pyrazoles; Ribonucleosides; Ribose; Streptomyces
PubMed: 31518483
DOI: 10.1002/anie.201910356 -
Nature Mar 2019Carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds are the main constituents of organic matter. Recent advances in C-H functionalization technology have vastly expanded...
Carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds are the main constituents of organic matter. Recent advances in C-H functionalization technology have vastly expanded our toolbox for organic synthesis. By contrast, C-C activation methods that enable editing of the molecular skeleton remain limited. Several methods have been proposed for catalytic C-C activation, particularly with ketone substrates, that are typically promoted by using either ring-strain release as a thermodynamic driving force or directing groups to control the reaction outcome. Although effective, these strategies require substrates that contain highly strained ketones or a preinstalled directing group, or are limited to more specialist substrate classes. Here we report a general C-C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone and transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules.
Topics: Acylation; Carbon; Hydrazines; Iridium; Ketones; Phosphines; Pyrazoles
PubMed: 30758326
DOI: 10.1038/s41586-019-0926-8 -
Scientific Reports Apr 2023Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and...
Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and synthesis of a series of novel pyridine sulfonamide-pyrazole hybrid scaffold mimicking dual-tail inhibitors of CA IX. A library of 15 compounds was synthesized and assessed for their potential cytotoxic effects against colorectal cancer cells. Compounds 3, and 11 induced potential cytotoxic effects against the three cancer cell lines (HCT-116, HT-29, and SW-620) with ICs' of 45.88, 28.27, and 16.57 uM, 25.01, 8.99, and 3.27 µM, respectively. Both compounds induced cellular apoptosis on HCT-116 and SW-620 cells, while compound 3 induced necrosis as well. In addition, both compounds induced cell cycle arrest on G0/G1, and S phases. Also, compound 11 showed potential autophagy induction on both colon cancer cell lines (HCT-116, and HT-29), and a little bit on metastatic type. Both compounds were less cytotoxic than the reference drug on normal epithelial cell. The migration rates of HCT-116 and the metastatic one SW-620 were reduced by both compounds. Finally, molecular docking of compounds 3 and 11 into the active site of CA IX confirmed in vitro inhibitory activity for both compounds.
Topics: Humans; Structure-Activity Relationship; Molecular Docking Simulation; Carbonic Anhydrase IX; Sulfonamides; Antineoplastic Agents; Colonic Neoplasms; Apoptosis; Pyrazoles; Molecular Structure; Cell Proliferation
PubMed: 37031294
DOI: 10.1038/s41598-023-32820-0 -
Molecules (Basel, Switzerland) Jun 2022An efficient synthetic route to construct diverse pyrazole-based chalcones from 1-phenyl-1-pyrazol-3-ols bearing a formyl or acetyl group on the C4 position of pyrazole...
An efficient synthetic route to construct diverse pyrazole-based chalcones from 1-phenyl-1-pyrazol-3-ols bearing a formyl or acetyl group on the C4 position of pyrazole ring, employing a base-catalysed Claisen-Schmidt condensation reaction, is described. Isomeric chalcones were further reacted with -hydroxy-4-toluenesulfonamide and regioselective formation of 3,5-disubstituted 1,2-oxazoles was established. The novel pyrazole-chalcones and 1,2-oxazoles were characterized by an in-depth analysis of NMR spectral data, which were obtained through a combination of standard and advanced NMR spectroscopy techniques.
Topics: Chalcone; Chalcones; Magnetic Resonance Spectroscopy; Oxazoles; Pyrazoles
PubMed: 35744875
DOI: 10.3390/molecules27123752 -
Chemical Biology & Drug Design Oct 2021N-formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a...
N-formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4-(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6-membered compounds, all exhibiting the same 4-bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five-membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.
Topics: Acetamides; Binding Sites; Humans; Models, Molecular; Neutrophils; Oxazoles; Protein Binding; Pyrazoles; Pyrazolones; Pyridones; Receptors, Formyl Peptide; Structure-Activity Relationship; Triazoles
PubMed: 34148303
DOI: 10.1111/cbdd.13913