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BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown. AIM: To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model. METHODS: ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays. RESULTS: The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and ß-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation. CONCLUSION: EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.
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Chalconas , Modelos Animales de Enfermedad , Mucosa Intestinal , Cirrosis Hepática , Hepatopatías Alcohólicas , Ratones Endogámicos C57BL , PPAR alfa , Animales , Ratones , Humanos , Femenino , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/prevención & control , Hepatopatías Alcohólicas/etiología , Hepatopatías Alcohólicas/tratamiento farmacológico , PPAR alfa/metabolismo , PPAR alfa/agonistas , Chalconas/farmacología , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Células CACO-2 , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Etanol/toxicidad , Apoptosis/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , PPAR delta/agonistas , PPAR delta/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , PropionatosRESUMEN
Aim: A series of isocoumarin-chalcone hybrids were prepared and assays for the inhibition of four isoforms of human carbonic anhydrase (hCA; EC 4.2.1.1), hCA I, II, IX and XII. Materials & methods: Isocoumarin-chalcone hybrids were synthesized by condensing acetyl-isocoumarin with aromatic aldehydes. They did not significantly inhibit off-target cytosolic isoforms hCA I and II (KI >100 µM) but acted as low micromolar or submicromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Results & conclusion: Our work provides insights into a new and scarcely investigated chemotype which provides interesting tumor-associated CA inhibitors, considering that some such derivatives like sulfonamide SLC-0111 are in advanced clinical trials for the management of metastatic advanced solid tumors.
A series of isocoumarinchalcone hybrids was prepared and assays for the inhibition of four isoforms of the metalloenzyme carbonic anhydrase (CA; EC 4.2.1.1), i.e., human (h) isoforms hCA I, II, IX and XII. Isocoumarins were less investigated as inhibitors of this enzyme. Here we show that the isocoumarinchalcone hybrids do not significantly inhibit the off-target cytosolic isoforms hCA I and II (KIs >100 µM) but act as low micromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Our work thus provides insights into a new and scarcely investigated chemotype which may provide interesting tumor-associated CA inhibitors, because some such compounds, e.g., the sulfonamide SLC-0111, are presently in advanced clinical trials for the management of metastatic advanced solid tumors.
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Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Isocumarinas , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Humanos , Anhidrasas Carbónicas/metabolismo , Isocumarinas/química , Isocumarinas/farmacología , Isocumarinas/síntesis química , Chalcona/química , Chalcona/farmacología , Relación Estructura-Actividad , Isoenzimas/metabolismo , Isoenzimas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Estructura Molecular , Chalconas/química , Chalconas/farmacología , Chalconas/síntesis químicaRESUMEN
Nasopharyngeal carcinoma (NPC) is prevalent in Asia and exhibits highly metastatic characteristics, leading to uncontrolled disease progression. Isoliquiritigenin (ISL) have attracted attention due to their diverse biological and pharmacological properties, including anticancer activities. However, the impact of ISL on the invasive and migratory ability of NPC remains poorly understood. Hence, this study aimed to investigate the in vitro anti-metastatic effects of ISL on NPC cells and elucidate the underlying signalling pathways. Human NPC cell NPC-39 and NPC-BM were utilized as cell models. Migratory and invasive capabilities were evaluated through wound healing and invasion assays, respectively. Gelatin zymography was employed to demonstrate matrix metalloproteinase-2 (MMP-2) activity, while western blotting was conducted to analyse protein expression levels and explore signalling cascades. Overexpression of signal transducer and activator of transcription 3 (STAT3) was carried out by transduction of STAT3-expressing vector. Our findings revealed that ISL effectively suppressed the migration and invasion of NPC cells. Gelatin zymography and Western blotting assays demonstrated that ISL treatment led to a reduction in MMP-2 enzyme activity and protein expression. Investigation of signalling cascades revealed that ISL treatment resulted in the inhibition of STAT3 phosphorylation. Moreover, overexpression of STAT3 restored the migratory ability of NPC cells in the presence of ISL. Collectively, these findings indicate that ISL inhibits the migration and invasion of NPC cells associating with MMP-2 downregulation through suppressing STAT3 activation. This suggests that ISL has an anti-metastatic effect on NPC cells and has potential therapeutic benefit for NPC treatment.
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Movimiento Celular , Chalconas , Metaloproteinasa 2 de la Matriz , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Invasividad Neoplásica , Factor de Transcripción STAT3 , Transducción de Señal , Humanos , Factor de Transcripción STAT3/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Chalconas/farmacología , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/genética , Transducción de Señal/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
BACKGROUND: Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. METHODS: ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 µmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot. RESULTS: ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury. CONCLUSION: ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury.
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Proteínas Quinasas Activadas por AMP , Homólogo de la Proteína 1 Relacionada con la Autofagia , Autofagia , Chalconas , Modelos Animales de Enfermedad , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Ratas Sprague-Dawley , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/prevención & control , Autofagia/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Chalconas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Línea Celular , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/metabolismo , Masculino , Ratas , Función Ventricular Izquierda/efectos de los fármacos , Infarto del Miocardio/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/enzimología , Apoptosis/efectos de los fármacos , FibrosisRESUMEN
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 µΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
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Cumarinas , Gutatión-S-Transferasa pi , Simulación del Acoplamiento Molecular , Sulfonamidas , Humanos , Cumarinas/química , Cumarinas/farmacología , Gutatión-S-Transferasa pi/antagonistas & inhibidores , Gutatión-S-Transferasa pi/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Línea Celular Tumoral , Chalcona/química , Chalcona/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Chalconas/química , Chalconas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Células MCF-7RESUMEN
Phenol soluble modulins (PSMs) are small amphipathic peptides involved in a series of biological functions governing staphylococcal pathogenesis, primarily by facilitating the formation of an extracellular fibril structure with amyloid-like properties. This fibrillar architecture stabilizes the staphylococcal biofilm making it resilient to antibiotic treatment. Our study aims to abrogate the amyloid fibrillation of PSM α1 with novel insights on the amyloid modulatory potential of a prenylated chalcone, Isobavachalcone (IBC). A combination of biophysical and computational assays to address the amyloid modulatory effect of IBC has been undertaken to arrive at a model for the inhibition of PSM α1 fibrillation. ThT kinetics studies indicated that IBC must be stably interacting with the amyloidogenic core of PSM α1 monomers or it may be inhibiting the pre-fibrillar aggregates populated at the early stages of amyloid transformation kinetics. This heteromolecular association further inhibits the amyloid transformation corroborated by a â¼ 94% and â¼ 91% reduction in the ThT maxima, even at sub-stoichiometric concentrations. Transmission electron microscopy (TEM) of end-stage aggregates (â¼ 55 h) depict mature, inter-twined, laterally stacked amyloid fibrils in untreated PSM α1 samples while this fibrillar load is remarkably reduced in the presence of IBC. The inhibitory effect of IBC on the ß-sheet transitions of PSM α1 were also validated using far-UV CD spectra. Molecular dynamics simulation studies with PSM aggregates (PSM-A) have also suggested that IBC disrupts the hydrogen bonding interactions and corroborates the inhibition of alpha to beta transitions of PSM-A. Collectively, our data proposes a novel structural motif for the rational discovery of non-toxic therapeutic agents targeting the functional amyloids which have slowly emerged as potent factors, consolidating the antibiotic resistant staphylococcal biofilm assembly.
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Amiloide , Chalconas , Staphylococcus aureus , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/metabolismo , Chalconas/farmacología , Chalconas/química , Chalconas/metabolismo , Amiloide/metabolismo , Amiloide/química , Simulación de Dinámica Molecular , Cinética , Prenilación , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Biopelículas/efectos de los fármacos , Toxinas BacterianasRESUMEN
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by oxidative stress and neuroinflammation. Sofalcone (SFC), a chalcone derivative known for its antioxidative and anti-inflammatory properties, is widely used clinically as a gastric mucosa protective agent. However, its therapeutic potential in PD remains to be fully explored. In this study, we investigated the neuroprotective effects of SFC in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. METHODS AND RESULTS: We found that SFC ameliorated MPTP-induced motor impairments in mice, as assessed by the rotarod and wire tests. Moreover, SFC administration prevented the loss of dopaminergic neurons and striatal degeneration induced by MPTP. Subsequent investigations revealed that SFC reversed MPTP-induced downregulation of NRF2, reduced elevated levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and increased total antioxidant capacity (TAOC). Furthermore, SFC suppressed MPTP-induced activation of microglia and astrocytes, downregulated the pro-inflammatory cytokine TNF-α, and upregulated the anti-inflammatory cytokine IL-4. Additionally, SFC ameliorated the MPTP-induced downregulation of phosphorylation of Akt at Ser473. CONCLUSIONS: This study provides evidence for the neuroprotective effects of SFC, highlighting its antioxidative and anti-inflammatory properties and its role in Akt activation in the PD model. These findings underscore SFC's potential as a promising therapeutic candidate for PD, warranting further clinical investigation.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Chalconas , Modelos Animales de Enfermedad , Fármacos Neuroprotectores , Estrés Oxidativo , Animales , Estrés Oxidativo/efectos de los fármacos , Ratones , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Chalconas/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Antioxidantes/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Antiinflamatorios/farmacologíaRESUMEN
Senolytics are drugs that specifically target senescent cells. Flavonoids such as quercetin and fisetin possess selective senolytic activities. This study aims to investigate if chalcones exhibit anti-senescence activities. Anti-senescence effect of 11 chalcone derivatives on the replicative senescence human aortic endothelial cells (HAEC) and human fetal lung fibroblasts (IMR90) was evaluated. Compound 2 (4-methoxychalcone) and compound 4 (4-bromo-4'-methoxychalcone) demonstrated increased cytotoxicity in senescent HAEC compared to young HAEC, with significant differences on IC50 values. Their anti-senescence effects on HAEC exceeded fisetin. Higher selectivity of compound 4 toward HAEC over IMR90 could be attributed to 4-methoxy (4-OMe) substitution at ring A (R1). Chalcone derivatives have potentials as senolytics in mitigating replicative senescence, warranting further research and development on chalcones as anti-senescent agent.
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Senescencia Celular , Chalconas , Células Endoteliales , Fibroblastos , Humanos , Senescencia Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Chalconas/farmacología , Fibroblastos/efectos de los fármacos , Células Cultivadas , Senoterapéuticos/farmacología , Concentración 50 Inhibidora , Aorta/efectos de los fármacos , Aorta/citología , Relación Estructura-Actividad , Línea CelularRESUMEN
4'-dihydrochalcones are secondary metabolites isolated from many medicinal plants and from the resin known as 'dragon's blood'. Due to their biological potential, our research objective was to determine the possibilities of using biocatalysis processes carried out in deep eutectic solvents (DESs) to obtain 4'-dihydrochalcones as a model compound. The processes were carried out in a culture of the yeast Yarrowia lipolytica KCh 71 and also in cultures of strains of the genera Rhodotorula and Debaryomyces. Based on the experiments carried out, an optimum process temperature of 35 °C was chosen, and the most suitable DES contained glycerol as a hydrogen bond donor (HBD). For a medium with 30% water content (DES 11), the conversion observed after 24 h exceeded 70%, while increasing the amount of water to 50% resulted in a similar level of conversion after just 1 h. A fivefold increase in the amount of added substrate resulted in a reduction in conversion, which reached 30.3%. Of the other yeast strains tested, Rhodotorula marina KCh 77 and Rhodotorula rubra KCh 4 also proved to be good biocatalysts for the bioreduction process. For these strains, the conversion reached 95.4% and 95.1%, respectively. These findings highlight the potential of yeast as a biocatalyst for the selective reduction of α,ß-unsaturated ketones and the possibility of using a DESs as a reaction medium in this process.
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Chalconas , Disolventes Eutécticos Profundos , Oxidación-Reducción , Rhodotorula , Rhodotorula/metabolismo , Chalconas/metabolismo , Chalconas/química , Disolventes Eutécticos Profundos/metabolismo , Disolventes Eutécticos Profundos/química , Yarrowia/metabolismo , Levaduras/metabolismo , Temperatura , BiocatálisisRESUMEN
A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone ß-carbon with the furanyl moiety and structural modification of the α,ß-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII-X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays.
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Antineoplásicos , Hidroquinonas , Simulación del Acoplamiento Molecular , Pirazoles , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Hidroquinonas/química , Hidroquinonas/farmacología , Hidroquinonas/síntesis química , Células MCF-7 , Proliferación Celular/efectos de los fármacos , Chalcona/química , Chalcona/farmacología , Células HT29 , Chalconas/química , Chalconas/farmacología , Chalconas/síntesis química , Relación Estructura-Actividad , Línea Celular Tumoral , AnimalesRESUMEN
Butin and butein are significant bioactive flavanones derived from plants, existing as tautomers of each other. However, their physicochemical attributes, such as their spectral profiles under varying experimental conditions in aqueous solutions and established chromatographic methods for distinguishing between them, remain undetermined. In this study, we determined the basic properties of butin and butein using conventional spectroscopic, reversed-phase, and chiral HPLC analyses. The spectra of the synthesized butin and butein were analyzed using a UV-Vis spectrophotometer in several solvents with different polarities as well as in aqueous solutions at various pH values. Furthermore, the behavior of the measured spectra was reproduced by calculations to reveal the effects of the solvent and pH on the spectra of butin and butein in organic and aqueous solutions. Subsequently, we assessed the structural stability of butin and butein using reversed-phase HPLC, which revealed that butein is unstable compared with butin in a general culture medium. The synthesized butin was effectively separated into R- and S-isomers with positive and negative Cotton effects, respectively, via HPLC using a chiral column. These findings will aid in uncovering the individual properties of both butin and butein that may have been concealed by their tautomerism and enable the synthesis of S-butin, which is typically challenging and time-consuming to isolate.
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Chalconas , Cromatografía Líquida de Alta Presión , Chalconas/química , Chalconas/síntesis química , Espectrofotometría Ultravioleta , Estructura Molecular , Concentración de Iones de Hidrógeno , Flavanonas/química , Flavanonas/síntesis química , Flavanonas/análisis , Estereoisomerismo , Solventes/químicaRESUMEN
Malaria is an intracellular protozoan parasitic disease caused by Plasmodium species with significant morbidity and mortality in endemic regions. The complex lifecycle of the parasite and the emergence of drug-resistant Plasmodium falciparum have hampered the efficacy of current anti-malarial agents. To circumvent this situation, the present study attempts to demonstrate the blood-stage anti-plasmodial action of 26 hybrid compounds containing the three privileged bioactive scaffolds (sulfonamide, chalcone, and nitro group) with synergistic and multitarget action. These three parent scaffolds exhibit divergent activities, such as antibacterial, anti-malarial, anti-fungal, anti-inflammatory, and anticancer. All the synthesised compounds were characterised using various spectroscopic techniques. The in vitro blood-stage inhibitory activity of 26 hybrid compounds was evaluated against mixed-stage culture (asynchronize) of human malarial parasite P. falciparum, Pf 3D7 at different concentrations ranging from 25.0 µg/mL to 0.78 µg/mL using SYBR 1 green assay, with IC50 values determined after 48 h of treatment based on the drug-response curves. Two potent compounds (11 and 10), with 2-Br and 2,6-diCl substitutions, showed pronounced activity with IC50 values of 5.4 µg/mL and 5.6 µg/mL, whereas others displayed varied activity with IC50 values ranging from 7.0 µg/mL to 22.0 µg/mL. Both 11 and 10 showed greater susceptibility towards mature-stage trophozoites than ring-stage parasites. The hemolytic and in vitro cytotoxicity assays revealed that compounds 11 and 10 did not cause any toxic effects on host red blood cells (uninfected), human-derived Mo7e cells, and murine-derived BA/F3 cells. The in vitro observations are consistent with the in silico studies using P. falciparum-dihydrofolate reductase, where 11 and 10 showed a binding affinity of -10.4 Kcal/mol. This is the first report of the hybrid scaffold, 4-nitrobenzenesulfonamide chalcones, demonstrating its potential as an anti-plasmodial agent.
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Antimaláricos , Chalconas , Diseño de Fármacos , Plasmodium falciparum , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Chalconas/farmacología , Chalconas/síntesis química , Chalconas/química , Humanos , Simulación del Acoplamiento Molecular , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Simulación por Computador , Relación Estructura-Actividad , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
Imidazole-chalcone compounds are recognised for their broad-spectrum antimicrobial properties. Probiotic-friendly, selective new-generation antimicrobials prove to be more efficient in combating gastrointestinal system pathogens. The aim of this study is to identify imidazole-chalcone derivatives that probiotics tolerate and evaluate their in vitro synergistic antimicrobial effects on pathogens. In this study, fifteen previously identified imidazole-chalcone derivatives were analyzed for their in vitro antimicrobial properties against gastrointestinal microorganisms. Initially, the antimicrobial activity of pathogens was measured using the agar well diffusion method, while the susceptibility of probiotics was determined by microdilution. The chosen imidazole-chalcone derivatives were assessed for synergistic effects using the checkerboard method. Four imidazole-chalcone derivatives to which probiotic bacteria were tolerant exhibited antibacterial and antifungal activity against the human pathogens tested. To our knowledge, this study is the first to reveal the fractional inhibitory concentration (FIC) of combinations of imidazole-chalcone derivatives. Indeed, the minimum inhibitory concentrations (MIC) for morpholinyl- (ZDO-3f) and 4-ethylpiperazinyl- (ZDO-3 m) imidazole-chalcones were notably low when tested against E. coli and B. subtilis, with values of 31.25 µg/mL and 125 µg/mL, respectively. The combination of morpholinyl- and 4-ethylpiperazinyl derivatives demonstrated an indifferent effect against E. coli, but an additive effect was observed for B. subtilis. Additionally, it was observed that imidazole-chalcone derivatives did not exhibit any inhibitory effects on probiotic organisms like Lactobacillus fermentum (CECT-5716), Lactobacillus rhamnosus (GG), and Lactobacillus casei (RSSK-591). This study demonstrates that imidazole-chalcone derivatives that are well tolerated by probiotics can potentially exert a synergistic effect against gastrointestinal system pathogens.
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Sinergismo Farmacológico , Imidazoles , Pruebas de Sensibilidad Microbiana , Probióticos , Probióticos/farmacología , Imidazoles/farmacología , Imidazoles/química , Chalcona/farmacología , Chalcona/química , Chalcona/análogos & derivados , Antibacterianos/farmacología , Antibacterianos/química , Chalconas/farmacología , Chalconas/química , Tracto Gastrointestinal/microbiología , Humanos , Bacterias/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/químicaRESUMEN
A highly selective bis thiophene-based chalcone as a chemosensor for detecting Fe3+ metal ions in DMF: H2O (9:1). This sensor was selective toward ferric ions over other metal ions with a detection limit in micromolar range.
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Espectrometría de Fluorescencia , Tiofenos , Tiofenos/química , Hierro/análisis , Hierro/química , Estructura Molecular , Compuestos Férricos/química , Compuestos Férricos/análisis , Chalconas/química , Chalconas/análisis , Chalcona/química , Colorantes Fluorescentes/químicaRESUMEN
Diabetes mellitus type 2 (T2DM) is a common chronic condition that presents as unsettled hyperglycemia (HG) and results from insulin resistance (IR) and ß-cell dysfunction. T2DM is marked by an increased risk of microvascular and macrovascular complications, all of which can be the cause of increasing mortality. Diabetic nephropathy (DNE), neuropathy (DNU), and retinopathy (DR) are the most common complications of diabetic microangiopathy, while diabetic cardiomyopathy (DCM) and peripheral vascular diseases are the major diabetic macroangiopathy complications. Chalcones (CHs) are in the flavonoid family and are commonly found in certain plant species as intermediate metabolites in the biosynthesis of flavonoids and their derivatives. Natural CHs with different substituents exert diverse therapeutic activities, including antidiabetic ones. However, the therapeutic mechanisms of natural CHs through influencing genes and/or signaling pathways in T2DM complications remain unknown. Therefore, this review summarizes the existing results from experimental models which highlight the mechanisms of natural CHs as therapeutic agents for T2DM complications.
Asunto(s)
Chalconas , Diabetes Mellitus Tipo 2 , Transducción de Señal , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Transducción de Señal/efectos de los fármacos , Animales , Chalconas/uso terapéutico , Chalconas/farmacología , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/genética , Complicaciones de la Diabetes/metabolismo , Chalcona/farmacología , Chalcona/análogos & derivados , Chalcona/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/genéticaRESUMEN
Ovarian cancer ranks among the most severe forms of cancer affecting the female reproductive organs, posing a significant clinical challenge primarily due to the development of resistance to conventional therapies. This study investigated the effects of the chalcone derivative 1C on sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines. Our findings revealed that 1C suppressed cell viability, induced cell cycle arrest at the G2/M phase, and triggered apoptosis in both cell lines. These effects are closely associated with generating reactive oxygen species (ROS). Mechanistically, 1C induced DNA damage, modulated the activity of p21, PCNA, and phosphorylation of Rb and Bad proteins, as well as cleaved PARP. Moreover, it modulated Akt, Erk1/2, and NF-κB signaling pathways. Interestingly, we observed differential effects of 1C on Nrf2 levels between sensitive and resistant cells. While 1C increased Nrf2 levels in sensitive cells after 12 h and decreased them after 48 h, the opposite effect was observed in resistant cells. Notably, most of these effects were suppressed by the potent antioxidant N-acetylcysteine (NAC), underscoring the crucial role of ROS in 1C-induced antiproliferative activity. Moreover, we suggest that modulation of Nrf2 levels can, at least partially, contribute to the antiproliferative effect of chalcone 1C.
Asunto(s)
Apoptosis , Chalconas , Resistencia a Antineoplásicos , Puntos de Control de la Fase G2 del Ciclo Celular , Neoplasias Ováricas , Especies Reactivas de Oxígeno , Humanos , Especies Reactivas de Oxígeno/metabolismo , Femenino , Apoptosis/efectos de los fármacos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Chalconas/farmacología , Antineoplásicos/farmacología , Chalcona/farmacología , Chalcona/análogos & derivados , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Daño del ADN/efectos de los fármacosRESUMEN
Non-enzyme-catalyzed thiol addition onto the α,ß-unsaturated carbonyl system is associated with several biological effects. Kinetics and diastereoselectivity of non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) and N-acetylcysteine (NAC) to the six-membered cyclic chalcone analogs 2a and 2b were investigated at different pH values (pH 3.2, 7.4 and 8.0). The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended both on the substitution and the pH. The stereochemical outcome of the reactions was evaluated using high-pressure liquid chromatography with UV detection (HPLC-UV). The structures of the formed thiol-conjugates and the retro-Michael products (Z)-2a and (Z)-2b were confirmed by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Frontier molecular orbitals and the Fukui function calculations were carried out to investigate their effects on the six-membered cyclic analogs. Data were compared with those obtained with the open-chain (1) and the seven-membered (3) analogs. The observed reactivities do not directly relate to the difference in in vitro cancer cell cytotoxicity of the compounds.
Asunto(s)
Chalconas , Compuestos de Sulfhidrilo , Humanos , Chalconas/química , Chalconas/farmacología , Compuestos de Sulfhidrilo/química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Cromatografía Líquida de Alta Presión , Glutatión/metabolismo , Glutatión/química , Cinética , Compuestos de Bencilideno/químicaRESUMEN
Neohesperidin dihydrochalcone (NHDC) is a citrus-originated, seminatural sweetener. There is no investigation concerning the effect of NHDC on ulcerative colitis. The purpose of this study was to determine the therapeutic and protective effects of NHDC in Wistar Albino rats. NHDC was given for 7 days after or before colitis induction. The results showed that NHDC significantly reduced the interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels. Catalase levels did not show a significant difference between the groups. NHDC provided a remarkable decrease in the expression levels of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and nuclear factor kappa B (NF-κB). Total antioxidant status (TAS) levels were significantly elevated in NHDC treatment groups, while total oxidant status (TOS) and oxidative stress index (OSI) levels were significantly decreased. NHDC provided remarkable improvement in histological symptoms such as epithelial erosion, edema, mucosal necrosis, inflammatory cell infiltration, and hemorrhage. Also, caspase-3 expression levels were statistically decreased in NHDC treatment groups. The results indicated that NHDC might be a protection or alternative treatment for ulcerative colitis.
Asunto(s)
Antiinflamatorios , Antioxidantes , Apoptosis , Chalconas , Hesperidina , FN-kappa B , Ratas Wistar , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/administración & dosificación , Ratas , Antioxidantes/farmacología , Masculino , Apoptosis/efectos de los fármacos , Chalconas/farmacología , Chalconas/administración & dosificación , Hesperidina/análogos & derivados , Hesperidina/farmacología , Hesperidina/administración & dosificación , FN-kappa B/genética , FN-kappa B/metabolismo , Humanos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inducido químicamente , Malondialdehído/metabolismo , Peroxidasa/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Interferón gamma/inmunología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Acute kidney injury (AKI) is a common clinical syndrome worldwide, with no effective treatment strategy. Renal ischemia-reperfusion (IR) injury is one of the main AKI features, and the excessive reactive oxygen species (ROS) production during reperfusion causes severe oxidative damage to the kidney. Loureirin C (LC), an active ingredient in the traditional Chinese medicine Chinese dragon's blood, possesses excellent antioxidative properties, but its role in renal IR injury is not clear. In this study, we evaluated the protective effects of LC against renal IR injury in vivo and in vitro by establishing a mice renal IR injury model and a human proximal renal tubular epithelial cell (HK-2) hypoxia/reoxygenation (HR) model. We found that LC ameliorated renal function and tissue structure injury and inhibited renal oxidative stress and ferroptosis in vivo. In vitro, LC scavenged ROS and attenuated mitochondrial dysfunction in HK-2 cells, thereby inhibiting oxidative cellular injury. Furthermore, we found that LC effectively promoted nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation and activated downstream target genes heme oxygenase 1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) to enhance cellular antioxidant function. Moreover, NRF2 knockdown and pharmacological inhibition of NRF2 partially eliminated the protective effect of LC. These results confirm that LC can effectively inhibit renal IR injury, and the mechanism may be associated with NRF2 activation by LC.
Asunto(s)
Ratones Endogámicos C57BL , Mitocondrias , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Daño por Reperfusión , Animales , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , Estrés Oxidativo/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones , Masculino , Línea Celular , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Especies Reactivas de Oxígeno/metabolismo , Ferroptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Hemo-Oxigenasa 1/metabolismo , ChalconasRESUMEN
Background: Our previous studies in vitro and in vivo have shown anti-severe acute respiratory syndrome coronavirus 2 activity of fingerroot extract (Boesenbergia rotunda) and its phytochemical panduratin A. Aim of Study: Therefore, the objective of this study was to determine the pharmacokinetic profiles of panduratin A, as a pure compound and in fingerroot extract, in rats. Materials and Methods: Male rats were randomly divided into four groups. Rats underwent intravenous administration of 4.5 mg/kg panduratin A, a single oral administration of 45 mg/kg panduratin A, or a multiple oral administration of 45 mg/kg panduratin A-consisted fingerroot extract for 7 consecutive days. The concentrations of panduratin A in plasma, tissues, and excreta were measured by using LCMS with a validated method. Results: The rats showed no change in health status after receiving all test preparations. The absolute oral bioavailability of panduratin A administered as pure panduratin A and fingerroot extract were approximately 9% and 6%, respectively. The peak concentrations for the single oral doses of 45 mg/kg panduratin A and fingerroot extract, were 4833 ± 659 and 3269 ± 819 µg/L, respectively. Panduratin A was mostly distributed in gastrointestinal organs, with the highest tissue-to-plasma ratio in the stomach. Approximately 20-30% of unchanged panduratin A from the administered dose was detected in feces while a negligible amount was found in urine. The major metabolites of administered panduratin A were identified in feces as oxidation and dioxidation products. Conclusion: Panduratin A from fingerroot extract showed low oral bioavailability, good tissue distribution, and partially biotransformed before excretion via feces. These findings will assist in developing fingerroot extract as a phytopharmaceutical product for COVID-19 treatment.