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Two 3-(p-substituted phenyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazoles were synthesized by 1,3-dipolar cycloaddition of the corresponding nitrile oxides with cycloheptatriene. Two endoperoxides were synthesized as facially selective and single products in high yields (93%-95%) from the reactions of isoxazole derivatives with singlet oxygen. The exact configurations of the endoperoxide with a methyl group in the phenyl ring and the diol synthesized from it were confirmed by X-ray analysis. To elucidate the mechanism, the formation energy of the endoperoxide was investigated by simulations using the software package Gaussian 09 and density functional theory calculations via the M06-2X/6-311+G(d,p) level method in dichloromethane. The results were consistent with experimental findings showing the formation of isoxazole products.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects the elderly population globally and there is an urgent demand for developing novel anti-AD agents. In this study, a new series of indole-isoxazole carbohydrazides were designed and synthesized. The structure of all compounds was elucidated using spectroscopic methods including FTIR, 1H NMR, and 13C NMR as well as mass spectrometry and elemental analysis. All derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Out of all synthesized compounds, compound 5d exhibited the highest potency as AChE inhibitor with an IC50 value of 29.46 ± 0.31 µM. It showed significant selectivity towards AChE, with no notable inhibition against BuChE. A kinetic study on AChE for compound 5d indicated a competitive inhibition pattern. Also, 5d exhibited promising BACE1 inhibitory potential with an IC50 value of 2.85 ± 0.09 µM and in vitro metal chelating ability against Fe3+. The molecular dynamic studies of 5d against both AChE and BACE1 were executed to evaluate the behavior of this derivative in the binding site. The results showed that the new compounds deserve further chemical optimization to be considered potential anti-AD agents.
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Acetilcolinesterasa , Enfermedad de Alzheimer , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Indoles , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/química , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Humanos , Simulación del Acoplamiento Molecular , Isoxazoles/química , Isoxazoles/farmacología , Isoxazoles/síntesis química , Relación Estructura-Actividad , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Modelos Moleculares , Sitios de Unión , Simulación de Dinámica Molecular , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Cinética , HidrazinasRESUMEN
Electrochemical transformations are considered a green alternative to classical redox chemistry as it eliminates the necessity for toxic and waste producing redox reagents. Typical electrochemical reactions require the addition of a so-called supporting electrolyte - a salt bridge - and other additives, such as hexafluorisopropanol, to enhance conductivity and reaction outcomes, respectively. However, this is often accompanied by an increase in the amount of produced waste. Here, we report an "in-situ electrolyte" concept for facile, transition-metal-free, additive-free one-pot electrochemical preparation of isoxazol(in)es, important scaffolds for biologically active natural and synthetic molecules, from the respective aldehydes. The protocol utilizes no halogenated solvents and no external oxidants, while salt side-products provide the ionic conductivity necessary for the electrosynthesis. The electrolysis is performed in an undivided cell, using the state-of-the-art electrodes for the chlor-alkali industry dimensionally stable and scalable mixed metal oxide anode and platinized titanium anode of high durability. The cascade transformation comprises the condensation of aldehyde to oxime followed by its anodic oxidation and subsequent intra- and/or intermolecular [3+2] cycloadditions with an appropriate dipolarophile. Chemical yields up to 97%, and good Faradaic efficiency, scalability, and stability are observed for most substrates in a broad scope.
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Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells.
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Alcaloides , Antineoplásicos , Glioma , Simulación del Acoplamiento Molecular , Animales , Glioma/tratamiento farmacológico , Glioma/patología , Ratas , Alcaloides/química , Alcaloides/farmacología , Alcaloides/síntesis química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Urea/química , Urea/farmacología , Urea/análogos & derivados , Proliferación Celular/efectos de los fármacosRESUMEN
This work describes the synthesis, characterization, and in vitro and in silico evaluation of the biological activity of new functionalized isoxazole derivatives. The structures of all new compounds were analyzed by IR and NMR spectroscopy. The structures of 4c and 4f were further confirmed by single crystal X-ray and their compositions unambiguously determined by mass spectrometry (MS). The antibacterial effect of the isoxazoles was assessed in vitro against Escherichia coli, Bacillus subtilis, and Staphylococcusaureus bacterial strains. Isoxazole 4a showed significant activity against E. coli and B. subtilis compared to the reference antibiotic drugs while 4d and 4f also exhibited some antibacterial effects. The molecular docking results indicate that the synthesized compounds exhibit strong interactions with the target proteins. Specifically, 4a displayed a better affinity for E. coli, S. aureus, and B. subtilis in comparison to the reference drugs. The molecular dynamics simulations performed on 4a strongly support the stability of the ligand-receptor complex when interacting with the active sites of proteins from E. coli, S. aureus, and B. subtilis. Lastly, the results of the Absorption, Distribution, Metabolism, Excretion and Toxicity Analysis (ADME-Tox) reveal that the molecules have promising pharmacokinetic properties, suggesting favorable druglike properties and potential therapeutic agents.
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Antibacterianos , Isoxazoles , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Isoxazoles/química , Isoxazoles/farmacología , Bacillus subtilis/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Escherichia coli/efectos de los fármacos , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Compounds with a heterocyclic isoxazole ring are well known for their diverse biologic activities encompassing antimicrobial, antipsychotic, immunosuppressive, antidiabetic and anticancer effects. Recent studies on hematological malignancies have also shown that some of the isoxazole-derived compounds feature encouraging cancer selectivity, low toxicity to normal cells and ability to overcome cancer drug resistance of conventional treatments. These characteristics are particularly promising because patients with hematological malignancies face poor clinical outcomes caused by cancer drug resistance or relapse of the disease. This review summarizes the knowledge on isoxazole-derived compounds toward hematological malignancies and provides clues on their mechanism(s) of action (apoptosis, cell cycle arrest, ROS production) and putative pharmacological targets (c-Myc, BET, ATR, FLT3, HSP90, CARM1, tubulin, PD-1/PD-L1, HDACs) wherever known.
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Antineoplásicos , Neoplasias Hematológicas , Isoxazoles , Humanos , Neoplasias Hematológicas/tratamiento farmacológico , Isoxazoles/farmacología , Isoxazoles/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Terapia Molecular DirigidaRESUMEN
The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines. Compound C11, which features a 2-methyl substitution at the quinoline and carries an isoxazole ring, emerged as the most promising, with 48 h IC50s of less than 20 nmol/L against two ESCC cell lines. The findings from EBI competitive assay, CETA, and in vitro tubulin polymerization assay of C11 are consistent with those of the positive control colchicine, demonstrating the clear affinity of compound C11 to the colchicine binding site. The subsequent cellular-based mechanism studies revealed that C11 significantly inhibited ESCC cell proliferation, arrested cell cycle at the M phase, induced apoptosis, and impeded migration. Experiments conducted in vivo further confirmed that C11 effectively suppressed the growth of ESCC without showing any toxicity towards the selected animal species. Overall, our research suggests that the tubulin polymerization inhibitor incorporating quinoline and the isoxazole ring may deserve consideration for cancer therapy.
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Antineoplásicos , Proliferación Celular , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Isoxazoles , Moduladores de Tubulina , Tubulina (Proteína) , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Isoxazoles/farmacología , Isoxazoles/química , Isoxazoles/síntesis química , Estructura Molecular , Polimerizacion/efectos de los fármacos , Quinolinas/farmacología , Quinolinas/química , Quinolinas/síntesis química , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/químicaRESUMEN
Novel isoxazole-triazole conjugates have been efficiently synthesized using 3-formylchromone as starting material according to a multi-step synthetic approach. The structures of the target conjugates and intermediate products were characterized by standard spectroscopic techniques (1H NMR and 13C NMR) and confirmed by mass spectrometry (MS). The all-synthesized compounds were screened for their antibacterial activity against three ATCC reference strains, namely Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC BAA-44, and Escherichia coli ATCC 25922 as well as one strain isolated from the hospital environment Pseudomonas aeruginosa. The findings indicate that conjugate 7b exhibits a stronger antibacterial response against the tested Escherichia coli ATCC 25922 and Pseudomonas aeruginosa pathogenic strains compared to the standard antibiotics. Furthermore, hybrid compound 7b proved to have a bactericidal action on the Escherichia coli ATCC 25922 strain, as evidenced by the results of the MBC determination. Moreover, the ADMET pharmacokinetic characteristics revealed a favorable profile for the examined compound, as well as a good level of oral bioavailability. Molecular docking and molecular dynamics simulations were performed to explore the inhibition mechanism and binding energies of conjugate 7b with the proteins of Escherichia coli and Pseudomonas aeruginosa bacterial strains. The in silico results corroborated the data observed in the in vitro evaluation for compound 7b.
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Antibacterianos , Escherichia coli , Isoxazoles , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Pseudomonas aeruginosa , Triazoles , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Pseudomonas aeruginosa/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Isoxazoles/química , Isoxazoles/farmacología , Isoxazoles/síntesis química , Staphylococcus aureus/efectos de los fármacos , Diseño de Fármacos , Simulación de Dinámica Molecular , Estructura Molecular , Relación Estructura-Actividad , Simulación por ComputadorRESUMEN
The ionotropic glutamate receptors (iGluRs) are comprised of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate receptor, kainate, and delta subtypes and are pivotal in neuronal plasticity. Recent structural studies on AMPA receptors reveal intricate conformational changes during activation and desensitization elucidating the steps from agonist binding to channel opening and desensitization. Additionally, interactions with auxiliary subunits, including transmembrane AMPA-receptor regulatory proteins, germ-cell-specific gene 1-like protein, and cornichon homologs, intricately modulate AMPA receptors. We discuss the recent high-resolution structures of these complexes that unveil stoichiometry, subunit positioning, and differences in specific side-chain interactions that influence these functional modulations.
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Receptores AMPA , Receptores AMPA/metabolismo , Receptores AMPA/química , Humanos , Animales , Activación del Canal Iónico , Conformación Proteica , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Modelos MolecularesRESUMEN
Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.
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Adenilil Ciclasas , Colforsina , Giro del Cíngulo , Potenciación a Largo Plazo , Animales , Ratones , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/metabolismo , Colforsina/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Masculino , Receptores AMPA/metabolismo , Ratones Endogámicos C57BL , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Calcio/metabolismoRESUMEN
BACKGROUND: Inhibiting receptor-tyrosine-kinase (RTK) signalling pathways has emerged as a key focus of novel cancer therapy development. Vascular endothelial growth factor receptor (VEGFR) is a member of the RTK family and is required for vasculogenesis and angiogenesis. Because VEGFR 2 is the subtype responsible for cellular angiogenesis and vasculogenesis, blocking it will impair tumour cell blood supply, reducing their development, proliferation, and metastasis. AIM & OBJECTIVE: The aim of this study is to obtain an optimised pharmacophore as a VEGFR2 inhibitor using QSAR investigations. This aids in determining the link between structure and activity in new chemical entities (NCEs). MATERIALS AND METHODS: The multi-linear regression approach (MLR) method was utilised to generate the QSAR Model using the programme QSARINS v.2.2.4. RESULTS AND DISCUSSION: For 2D QSAR, the best models produced has correlation coefficients of R2= 0.9396. The 3D-QSAR model obtained with R2= 0.9121 and Q2 = 0.8377. Taking docking observations, pharmacological behaviour, and toxicity analyses into account, most of the derivatives demonstrated VEGFR2 inhibitory competence. CONCLUSION: According to QSAR studies, more electron-donating groups on the benzene ring linked to the isoxazole were shown to be necessary for activity. In molecular docking studies, most compounds have shown stronger affinity for the crucial amino acids Cys:919, Asp:1046, and Glu:885, which are found in typical drugs. All NCEs passed the Lipinski screening.
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CONTEXT: In the present work, the influence of aromatic ring substitution on a series of small-donor organic molecules (A, B, C, D, and E) with isoxazole cores was investigated for photovoltaic applications in organic solar cells. Frontier molecular orbital analysis, chemical reactivity descriptors, dipole moment, and population analysis showed that all the organic materials have intramolecular charge transfer abilities capable of donating electrons to the acceptor material (PCBM). The required photovoltaic parameters such as Voc, FF, Jsc, LHE, and other associated optoelectronic parameters are reported. The results demonstrate that aromatic ring substitution influences charge transfer and power conversion efficiencies of solar cells. That is, an increase in the aromatic character of a material increases its charge transfer, and as a result, its photovoltaic properties are increased. Additionally, all the investigated derivatives are good charge transporters with suitable electron reorganization energies, which are beneficial for minimizing energy loss. Hence, these organic derivatives with isoxazole backbones are promising materials and may provide fresh insights into the design of new materials for organic solar cell applications. METHOD: All calculations were performed using DFT and the ORCA 4.1.0 program package as the main tool for geometry optimization and frequency calculations. The Avogadro 1.2.1 visualization tool was used to prepare all input files executed by ORCA 4.1.0. The BP86, B3LYP, and wB97M series of functionals coupled with the def2/TZVP basis set were employed for geometry optimization. All energy-related calculations were carried out using the M06-2x functional. Multiwfn version 3.7 was used for aromaticity and population analysis. Excited state and UV-visible spectra were simulated using the TD-DFT method at the CAM-B3LYP-D3, wB97X-D3, and PBE0-D3 coupled with the ma-def2-TZVP basis set. Moreover, solvent effects were incorporated using the SMD scheme as incorporated in the ORCA software. Lastly, the RIJCOSX approximations were used to speed up calculations while maintaining accuracy.
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CONTEXT: The corrosion of mild steel is a significant issue in various industries, prompting the need for effective corrosion inhibitors. This study focuses on understanding the corrosion inhibition properties of organic compounds derived from isoxazole, namely series Iso(a), Iso(b), Iso(c), Iso(d), Iso(e), Iso(f), Iso(g), and Iso(h), which could have implications for materials science and industrial applications. By investigating the influence of different substitutions on these compounds, valuable insights can be gained into designing better corrosion inhibitors for practical use. METHODS: Theoretical studies were conducted using density functional theory (DFT) with the B3LYP functional and the 6-31G (d,p) basis set. These calculations enabled the evaluation of various parameters including frontier orbital energies (EHOMO, ELUMO), energy gap (∆E), electronegativity (χ), absolute hardness (η), softness (σ), fraction of transferred electrons (∆N), as well as local properties such as natural atomic populations and Fukui indices. Additionally, molecular dynamics simulations were performed to study the adsorption behavior of the inhibitors on the surface of Fe (110). The simulations were conducted using Materials Studio version 8.0 software package using COMPASS force field to understand the impact of different functional groups on the inhibitors before and after adsorption on the iron surface.
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Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC50 value of 0.13 µM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC50 = 2.93 µM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.
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Ácidos Carboxílicos , Diseño de Fármacos , Inhibidores Enzimáticos , Isoxazoles , Xantina Oxidasa , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Isoxazoles/química , Isoxazoles/farmacología , Isoxazoles/síntesis química , Ácidos Carboxílicos/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Estructura Molecular , Humanos , Simulación del Acoplamiento Molecular , Indoles/farmacología , Indoles/química , Indoles/síntesis química , Relación Dosis-Respuesta a DrogaRESUMEN
In this study, a new series of Isoxazole-carboxamide derivatives were synthesized and characterized via HRMS, 1H-, 13CAPT-NMR, and MicroED. The findings revealed that nearly all of the synthesized derivatives exhibited potent inhibitory activities against both COX enzymes, with IC50 values ranging from 4.1 nM to 3.87 µM. Specifically, MYM1 demonstrated the highest efficacy among the compounds tested against the COX-1, displaying an IC50 value of 4.1 nM. The results showed that 5 compounds possess high COX-2 isozyme inhibitory effects with IC50 value in range 0.24-1.30 µM with COX-2 selectivity indexes (2.51-6.13), among these compounds MYM4 has the lowest IC50 value against COX-2, with selectivity index around 4. Intriguingly, this compound displayed significant antiproliferative effects against CaCo-2, Hep3B, and HeLa cancer cell lines, with IC50 values of 10.22, 4.84, and 1.57 µM, respectively, which was nearly comparable to that of doxorubicin. Compound MYM4 showed low cytotoxic activities on normal cell lines LX-2 and Hek293t with IC50 values 20.01 and 216.97 µM respectively, with safer values than doxorubicin. Furthermore, compound MYM4 was able to induce the apoptosis, suppress the colonization of both HeLa and HepG2 cells. Additionally, the induction of Reactive oxygen species (ROS) production could be the mechanism underlying the apoptotic effect and the cytotoxic activity of the compound. In the 3D multicellular tumor spheroid model, results revealed that MYM4 compound hampered the spheroid formation capacity of Hep3B and HeLa cancer cells. Moreover, the molecular docking of MYM4 compound revealed a high affinity for the COX2 enzyme, with energy scores (S) -7.45 kcal/mol, which were comparable to celecoxib (S) -8.40 kcal/mol. Collectively, these findings position MYM4 as a promising pharmacological candidate as COX inhibitor and anticancer agent.
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Antineoplásicos , Proliferación Celular , Inhibidores de la Ciclooxigenasa , Ensayos de Selección de Medicamentos Antitumorales , Isoxazoles , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Isoxazoles/farmacología , Isoxazoles/química , Isoxazoles/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Esferoides Celulares/efectos de los fármacos , Modelos Moleculares , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Línea Celular TumoralRESUMEN
In this paper, we report the synthesis of quinoxaline-isoxazole-piperazine conjugates. The anticancer activity was evaluated against three human cancer cell lines, including MCF-7 (breast), HepG-2 (liver), and HCT-116 (colorectal). The outcomes of the tested compounds 5d, 5e, and 5f have shown more potent activity when compared to the standard drug erlotinib. In a cell survivability test (MCF-10A), three potent compounds (5d, 5e, and 5f) were evaluated against the normal breast cell line, although neither of them displayed any significant cytotoxicity with IC50 values greater than 84 µM. Furthermore, the compounds 5d, 5e, and 5f were tested for tyrosine kinase EGFR inhibitory action using erlotinib as the reference drug and compound 5e was shown to be more potent in inhibiting the tyrosine kinase EGFR than sorafenib. In addition to this, molecular docking studies of compounds 5d, 5e, and 5f demonstrated that these compounds had more EGFR-binding interactions. The potent compounds 5d, 5e, and 5f were subjected to in silico pharmacokinetic assessment by SWISS, ADME, and pkCSM. While the compounds 5d, 5e, and 5f followed Lipinski, Veber, Egan, and Muegge rules without any deviation.
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Antineoplásicos , Quinoxalinas , Humanos , Simulación del Acoplamiento Molecular , Clorhidrato de Erlotinib/farmacología , Quinoxalinas/farmacología , Antineoplásicos/farmacología , Isoxazoles , Piperazina , Proteínas Tirosina Quinasas , Receptores ErbBRESUMEN
A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3-H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N-O fragment donor.
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STAT3 is a crucial member within a family of seven essential transcription factors. Elevated STAT3 levels have been identified in various cancer types, notably in breast cancer (BC). Consequently, inhibiting STAT3 is recognized as a promising and effective strategy for therapeutic intervention against breast cancer. We herein synthesize a library of isoxazole (PAIs) from piperic acid [2E, 4E)-5-(2H-1,3-Benzodioxol-5-yl) penta-2,4-dienoic acid] on treatment with propargyl bromide followed by oxime under prescribed reaction conditions. Piperic acid was obtained by hydrolysis of piperine extracted from Piper nigrum. First, we checked the binding potential of isoxazole derivatives with breast cancer target proteins by network pharmacology, molecular docking, molecular dynamic (MD) simulation and cytotoxicity analysis as potential anti-breast cancer (BC) agents. The multi-source databases were used to identify possible targets for isoxazole derivatives. A network of protein-protein interactions (PPIs) was generated by obtaining 877 target genes that overlapped gene symbols associated with isoxazole derivatives and BC. Molecular docking and MD modelling demonstrated a strong affinity between isoxazole derivatives and essential target genes. Further, the cell viability studies of isoxazole derivatives on the human breast carcinoma cell lines showed toxicity in all breast cancer cell lines. In summary, our study indicated that the isoxazole derivative showed the significant anticancer activity. The results highlight the prospective utility of isoxazole derivatives as new drug candidates for anticancer chemotherapy, suggesting route for the continued exploration and development of drugs suitable for clinical applications.
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Ácidos Grasos Insaturados , Isoxazoles , Simulación del Acoplamiento Molecular , Factor de Transcripción STAT3 , Neoplasias de la Mama Triple Negativas , Humanos , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Isoxazoles/farmacología , Isoxazoles/química , Línea Celular Tumoral , Estructura Molecular , Ácidos Grasos Insaturados/farmacología , Ácidos Grasos Insaturados/aislamiento & purificación , Ácidos Grasos Insaturados/química , Farmacología en Red , Simulación de Dinámica Molecular , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificaciónRESUMEN
Hypoxia-inducible factor-2 (HIF-2) serves as the pivotal transcription factor in cellular responses to low oxygen levels, particularly concerning the regulation of erythropoietin (EPO) production. A docking-based virtual screening on crystal structures of HIF-2α inhibitors unexpectedly identified 3-phenyl-5-methyl-isoxazole-4-carboxamide derivative v19 as a hit of HIF-2α agonist. Further structural optimizations of compound v19 led to the discovery of a series of HIF-2α agonists with novel scaffolds. The most promising compounds 12g and 14d exhibited potent HIF-2α agonistic activities in vitro with EC50 values of 2.29 µM and 1.78 µM, respectively. Molecular dynamics simulations have revealed their capacity to allosterically enhance HIF-2 dimerization, which shed light on their mechanism of action. Moreover, compound 14d demonstrated a favorable pharmacokinetic (PK) profile, boasting an impressive oral bioavailability value of 68.71 %. These findings strongly suggest that compound 14d is an auspicious lead compound for the treatment of renal anemia.
Asunto(s)
Anemia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Humanos , Factores de Transcripción/metabolismo , Regulación de la Expresión Génica , Oxígeno , Subunidad alfa del Factor 1 Inducible por HipoxiaRESUMEN
BACKGROUND: The prevalence of heart failure is constantly increasing, and the prognosis of patients remains poor. New treatment strategies to preserve cardiac function and limit cardiac hypertrophy are therefore urgently needed. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used as an experimental platform for cardiac in vitro studies. However, in contrast to adult cardiomyocytes, hiPSC-CMs display immature morphology, contractility, gene expression and metabolism and hence express a naive phenotype that resembles more of a foetal cardiomyocyte. METHODS: A library of 14 novel compounds was synthesized in-house and screened for GATA4-NKX2-5 reporter activity and cellular toxicity. The most potent compound, 3i-1262, along with previously reported GATA4-acting compounds, were selected to investigate their effects on hypertrophy induced by endothelin-1 or mechanical stretch. Morphological changes and protein expression were characterized using immunofluorescence staining and high-content analysis. Changes in gene expression were studied using qPCR and RNA sequencing. RESULTS: The prototype compound 3i-1262 inhibited GATA4-NKX2-5 synergy in a luciferase reporter assay. Additionally, the isoxazole compound 3i-1262 inhibited the hypertrophy biomarker B-type natriuretic peptide (BNP) by reducing BNP promoter activity and proBNP expression in neonatal rat ventricular myocytes and hiPSC-CMs, respectively. Treatment with 3i-1262 increased metabolic activity and cardiac troponin T expression in hiPSC-CMs without affecting GATA4 protein levels. RNA sequencing analysis revealed that 3i-1262 induces gene expression related to metabolic activity and cell cycle exit, indicating a change in the identity and maturity status of hiPSC-CMs. The biological processes that were enriched in upregulated genes in response to 3i-1262 were downregulated in response to mechanical stretch, and conversely, the downregulated processes in response to 3i-1262 were upregulated in response to mechanical stretch. CONCLUSIONS: There is currently a lack of systematic understanding of the molecular modulation and control of hiPSC-CM maturation. In this study, we demonstrated that the GATA4-interfering compound 3i-1262 reorganizes the cardiac transcription factor network and converts hypertrophic signalling towards enhanced cardiomyocyte identity and maturity. This conceptually unique approach provides a novel structural scaffold for further development as a modality to promote cardiomyocyte specification and maturity.