RESUMEN
Interest in the extraction of phytochemical bioactive compounds, especially polyphenols from biomass, has recently increased due to their valuable biological potential as natural sources of antioxidants, which could be used in a wide range of applications, from foods and pharmaceuticals to green polymers and bio-based materials. The present research study aimed to provide a comprehensive chemical characterization of the phytochemical composition of forest biomass (bark and needles) of softwood species (Picea abies L., H. Karst., and Abies alba Mill.) and to investigate their in vitro antioxidant and antimicrobial activities to assess their potential in treating and healing infected chronic wounds. The DPPH radical-scavenging method and P-LD were used for a mechanistic explanation of the biomolecular effects of the investigated bioactive compounds. (+)-Catechin, epicatechin, rutin, myricetin, 4 hydroxybenzoic and p-cumaric acids, kaempherol, and apigenin were the main quantified polyphenols in coniferous biomass (in quantities around 100 µg/g). Also, numerous phenolic acids, flavonoids, stilbenes, terpenes, lignans, secoiridoids, and indanes with antioxidant, antimicrobial, anti-inflammatory, antihemolytic, and anti-carcinogenic potential were identified. The Abies alba needle extract was more toxic to microbial strains than the eukaryotic cells that provide its active wound healing principles. In this context, developing industrial upscaling strategies is imperative for the long-term success of biorefineries and incorporating them as part of a circular bio-economy.
RESUMEN
Antipsychotic drugs or neuroleptics are widely used in the treatment of psychosis as a manifestation of schizophrenia and bipolar disorder. However, their effectiveness largely depends on the blood-brain barrier (BBB) permeation (pharmacokinetics) and drug-receptor pharmacodynamics. Therefore, in this study, we developed and implemented the in silico pipeline to design novel compounds (n = 260) as leads using the standard drug scaffolds with improved PK/PD properties from the standard scaffolds. As a result, the best candidates (n = 3) were evaluated in molecular docking to interact with serotonin and dopamine receptors. Finally, haloperidol (HAL) derivative (1-(4-fluorophenyl)-4-(4-hydroxy-4-{4-[(2-phenyl-1,3-thiazol-4-yl)methyl]phenyl}piperidin-1-yl)butan-1-one) was identified as a "magic shotgun" lead compound with better affinity to the 5-HT2A, 5-HT1D, D2, D3, and 5-HT1B receptors than the control molecule. Additionally, this hit substance was predicted to possess similar BBB permeation properties and much lower toxicological profiles in comparison to HAL. Overall, the proposed rational drug design platform for novel antipsychotic drugs based on the BBB permeation and receptor binding might be an invaluable asset for a medicinal chemist or translational pharmacologist.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Antipsicóticos , Antipsicóticos/farmacología , Barrera Hematoencefálica , Serotonina , Simulación del Acoplamiento Molecular , Haloperidol/farmacología , Haloperidol/metabolismoRESUMEN
Background and objectives: Cancer represents the miscommunication between and within the body cells. The mutations of the oncogenes encoding the MAPK pathways play an important role in the development of tumoral diseases. The mutations of KRAS and BRAF oncogenes are involved in colorectal cancer and melanoma, while the NRAS mutations are associated with melanoma. Thiazolidine-2,4-dione is a versatile scaffold in medicinal chemistry and a useful tool in the development of new antitumoral compounds. The aim of our study was to predict the pharmacokinetic/pharmacodynamic properties, the drug-likeness and lead-likeness of two series of synthetic 5-arylidene(chromenyl-methylene)-thiazolidinediones, the molecular docking on the oncoproteins K-Ras, N-Ras and B-Raf, and to investigate the cytotoxicity of the compounds, in order to select the best structural profile for potential anticancer agents. Materials and Methods: In our paper we studied the cytotoxicity of two series of thiazolidine-2,4-dione derivatives, their ADME-Tox properties and the molecular docking on a mutant protein of K-Ras, two isoforms of N-Ras and an isoform of B-Raf with 16 mutations. Results: The heterocyclic compounds strongly interact with K-Ras and N-Ras right after their posttranslational processing and/or compete with GDP for the nucleotide-binding site of the two GTPases. They are less active against the GDP-bound states of the two targets. All derivatives have a similar binding pattern in the active site of B-Raf. Conclusions: The data obtained encourage the further investigation of the 5-arylidene(chromenyl-methylene)-thiazolidinediones as potential new agents against the oncoproteins K-Ras, N-Ras and B-Raf.
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Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Proteína Oncogénica p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Tiazolidinedionas/química , Tiazolidinedionas/uso terapéutico , Animales , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Descubrimiento de Drogas , GTP Fosfohidrolasas/química , Guanosina Difosfato/química , Humanos , Melanoma Experimental/tratamiento farmacológico , Ratones , Simulación del Acoplamiento Molecular/métodos , Mutación , Proteína Oncogénica p21(ras)/genética , Unión Proteica , Estructura Secundaria de Proteína , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Tiazolidinedionas/síntesis químicaRESUMEN
The rapid emergence of bacterial resistance to antibiotics currently available for treating infectious diseases requires effective antimicrobial agents with new structural profiles and mechanisms of action. Twenty-three thiazolin-4-one derivatives were evaluated for their antibacterial activity by determining the growth inhibition zone diameter, the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC), against gram-positive and gram-negative bacteria. Compounds 3a-c, 3e-h, 6b-c and 9a-c expressed better MIC values than moxifloxacin, against Staphylococcus aureus. Compounds 3h and 9b displayed similar effect to indolmycin, a tryptophanyl-tRNA ligase inhibitor. Due to their structural analogy to indolmycin, all compounds were subjected to molecular docking on tryptophanyl-tRNA synthetase. Compounds 3a-e, 6a-e, 8 and 9a-e exhibited better binding affinities towards the target enzymes than indolmycin. The antioxidant potential of the compounds was evaluated by four spectrophotometric methods. Thiazolin-4-ones 3e, 6e and 9e presented better antiradical activity than ascorbic acid, trolox and BHT, used as references.
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Antibacterianos/farmacología , Antioxidantes/farmacología , Inhibidores Enzimáticos/farmacología , Tiazoles/farmacología , Triptófano-ARNt Ligasa/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Simulación del Acoplamiento Molecular , Picratos/antagonistas & inhibidores , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Triptófano-ARNt Ligasa/metabolismoRESUMEN
Cardioprotective effects of dietary anthocyanins are partly attributed to their ability to maintain endothelial function. However, the underlying cellular and molecular mechanisms of action are not fully understood. This study aimed to evaluate the effect of anthocyanins and their gut metabolites, at physiologically-relevant conditions, on endothelial cell (EC) function and decipher the underlying molecular mechanisms of action using integrated omics approaches. Primary EC were treated with a mixture of 0.1⯵M cyanidin-3-arabinoside, 0.1⯵M cyanidin-3-galactoside, 0.1⯵M cyanidin-3-glucoside, 0.1⯵M delphinidin-3-glucoside, 0.1⯵M peonidin-3-glucoside and 0.5⯵M 4-hydroxybenzaldehyde for 3â¯h or a mixture of gut metabolites: 0.2⯵M protocatechuic, 2⯵M vanillic, 1⯵M ferulic and 2⯵M hippuric acids for 18â¯h. Also, successive exposure of EC to both mixtures was performed to mimic anthocyanin pharmacokinetics following their intake. Inflammatory stress was induced using TNFα and monocytes added to assess adhesion and transmigration. Effects of these mixtures on gene, miRNA expression and their potential interaction with cell signalling were investigated. Anthocyanins and their gut metabolites significantly reduced monocyte adhesion and transendothelial migration. Gene expression analysis, using macroarrays, showed that tested compounds modulated the expression of genes involved in cell-cell adhesion, cytoskeleton organisation or focal adhesion. Bioinformatics analyses of gene expression data identified potential transcription factors involved in the observed nutrigenomic effects and signalling proteins regulating their activity. Molecular docking revealed cell signalling proteins to which these bioactives may bind to and potentially affect their activity and the activation of downstream signalling, effects that were in agreement with the results of Western blot analyses. Microarray analysis showed that anthocyanins and their gut metabolites affected miRNA expression in EC, especially those involved in regulation of EC permeability, contributing to the observed changes in EC function. Integration of these results revealed endothelial-protective properties of anthocyanins and their gut metabolites and deciphered new underlying multi-target and multi-layered mode of action.
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Antocianinas/farmacología , Permeabilidad Capilar/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Monocitos/efectos de los fármacos , Migración Transendotelial y Transepitelial/efectos de los fármacos , Antocianinas/metabolismo , Adhesión Celular/efectos de los fármacos , Adhesión Celular/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , NutrigenómicaRESUMEN
The global spread of bacterial resistance to drugs used in therapy requires new potent and safe antimicrobial agents. DNA gyrases represent important targets in drug discovery. Schiff bases, thiazole, and triazole derivatives are considered key scaffolds in medicinal chemistry. Fifteen thiazolyl-triazole Schiff bases were evaluated for their antibacterial activity, measuring the growth inhibition zone diameter, the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC), against Gram-positive (Staphylococcus aureus, Listeria monocytogenes) and Gram-negative (Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa) bacteria. The inhibition of S. aureus and S. typhimurium was modest. Compounds B1, B2, and B9 showed a similar effect as ciprofloxacin, the antimicrobial reference, against L. monocytogenes. B10 displayed a better effect. Derivatives B1, B5-7, B9, and B11-15 expressed MIC values lower than the reference, against L. monocytogenes. B5, B6, and B11-15 strongly inhibited the growth of P. aeruginosa. All compounds were subjected to an in silico screening of the ADMET (absorption, distribution, metabolism, elimination, toxicity) properties. Molecular docking was performed on the gyrA and gyrB from L. monocytogenes. The virtual screening concluded that thiazolyl-triazole Schiff base B8 is the best drug-like candidate, satisfying requirements for both safety and efficacy, being more potent against the bacterial gyrA than ciprofloxacin.
Asunto(s)
Antibacterianos/farmacología , Simulación del Acoplamiento Molecular , Tiazoles/química , Inhibidores de Topoisomerasa II/farmacología , Triazoles/química , Antibacterianos/química , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Sitios de Unión , Girasa de ADN/química , Girasa de ADN/metabolismo , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Bases de Schiff/química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Curcumin is a phenolic compound that exhibits beneficial properties for cardiometabolic health. We previously showed that curcumin reduced the infiltration of immune cells into the vascular wall and prevented atherosclerosis development in mice. This study aimed to investigate the effect of curcumin on monocyte adhesion and transendothelial migration (TEM) and to decipher the underlying mechanisms of these actions. Human umbilical vein endothelial cells (HUVECs) were exposed to curcumin (0.5-1µM) for 3h prior to their activation by Tumor Necrosis Factor alpha (TNF-α). Endothelial permeability, monocyte adhesion and transendothelial migration assays were conducted under static condition and shear stress that mimics blood flow. We further investigated the impact of curcumin on signaling pathways and on the expression of genes using macroarrays. Pre-exposure of endothelial cells to curcumin reduced monocyte adhesion and their transendothelial migration in both static and shear stress conditions. Curcumin also prevented changes in both endothelial permeability and the area of HUVECs when induced by TNF-α. We showed that curcumin modulated the expression of 15 genes involved in the control of cytoskeleton and endothelial junction dynamic. Finally, we showed that curcumin inhibited NF-κB signaling likely through an antagonist interplay with several kinases as suggested by molecular docking analysis. Our findings demonstrate the ability of curcumin to reduce monocyte TEM through a multimodal regulation of the endothelial cell dynamics with a potential benefit on the vascular endothelial function barrier.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Curcumina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Fenómenos Biomecánicos , Adhesión Celular/efectos de los fármacos , Técnicas de Cocultivo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Cámaras de Difusión de Cultivos , Perfilación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Quinasas Quinasa Quinasa PAM/química , Quinasas Quinasa Quinasa PAM/genética , Análisis por Micromatrices , Simulación del Acoplamiento Molecular , FN-kappa B/antagonistas & inhibidores , FN-kappa B/química , FN-kappa B/genética , Permeabilidad/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/química , Proteínas Proto-Oncogénicas c-akt/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Reología , Transducción de Señal , Células THP-1 , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Twenty-three thiazolin-4-ones were synthesized starting from phenylthioamide or thiourea derivatives by condensation with α-monochloroacetic acid or ethyl α-bromoacetate, followed by substitution in position 5 with various arylidene moieties. All the synthesized compounds were physico-chemically characterized and the IR (infrared spectra), ¹H NMR (proton nuclear magnetic resonance), 13C NMR (carbon nuclear magnetic resonance) and MS (mass spectrometry) data were consistent with the assigned structures. The synthesized thiazolin-4-one derivatives were tested for antifungal properties against several strains of Candida and all compounds exhibited efficient anti-Candida activity, two of them (9b and 10) being over 500-fold more active than fluconazole. Furthermore, the compounds' lipophilicity was assessed and the compounds were subjected to in silico screening for prediction of their ADME-Tox properties (absorbtion, distribution, metabolism, excretion and toxicity). Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme. The results of the in vitro antifungal activity screening, docking study and ADME-Tox prediction revealed that the synthesized compounds are potential anti-Candida agents that might act by inhibiting the fungal lanosterol 14α-demethylase and can be further optimized and developed as lead compounds.
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Inhibidores de 14 alfa Desmetilasa/farmacología , Antifúngicos/farmacología , Diseño de Fármacos , Tiazoles/farmacología , Inhibidores de 14 alfa Desmetilasa/síntesis química , Inhibidores de 14 alfa Desmetilasa/química , Antifúngicos/síntesis química , Antifúngicos/química , Candida/clasificación , Candida/efectos de los fármacos , Candida/crecimiento & desarrollo , Proteínas Fúngicas/antagonistas & inhibidores , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Dominios Proteicos , Espectrofotometría Infrarroja , Esterol 14-Desmetilasa/química , Esterol 14-Desmetilasa/metabolismo , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
Various thiosemicarbazones (TSCs) and their heterocyclic thiadiazolines (TDZ) possess important biological effects. In addition, chromenyl derivatives exhibit a wide range of pharmacological activities. Based on these findings and as a continuation of our research on nitrogen and sulfur containing compounds, we investigated a series of previously reported chromenyl-TSCs (1a-j) and chromenyl-TDZs (2a-j) for their in vitro antimicrobial activities against two bacterial and four fungal strains. MIC and MBC/MFC (µg/mL) values of these compounds were evaluated and compared to those of Spectinomycin, Moxifloxacin and Fluconazole, used as reference drugs. For a better understanding of the drug-receptor interactions, all the compounds were further subjected to molecular docking against four targets that were chosen based on the specific mechanism of action of the reference drugs used in the antimicrobial screening. All compounds tested showed equal or higher antibacterial/antifungal activities relative to the used reference drugs. In silico studies (molecular docking) revealed that all the investigated compounds showed good binding energies towards four receptor protein targets and supported their antimicrobial properties.
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Antiinfecciosos/química , Antiinfecciosos/farmacología , Benzopiranos/química , Benzopiranos/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Bacterias/efectos de los fármacos , Simulación por Computador , Hongos/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Simulación del Acoplamiento Molecular , ARN/efectos de los fármacos , ARN/metabolismo , Receptores de Droga/química , Receptores de Droga/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacologíaRESUMEN
Lipophilicity, as one of the most important physicochemical parameters of bioactive molecules, was investigated for twenty-two thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles. The determination was carried out by reversed-phase thin-layer chromatography, using a binary isopropanol-water mobile phase. Chromatographically obtained lipophilicity parameters were correlated with calculated log P and log D and with some biological parameters, determined in order to evaluate the anti-inflammatory and antioxidant potential of the investigated compounds, by using principal component analysis (PCA). The PCA grouped the compounds based on the nature of their substituents (X, R and Y), indicating that their nature, electronic effects and molar volumes influence the lipophilicity parameters and their anti-inflammatory and antioxidant effects. Also, the results of the PCA analysis applied on all the experimental and computed parameters show that the best anti-inflammatory and antioxidant compounds were correlated with medium values of the lipophilicity parameters. On the other hand, the knowledge of the grouping patterns of the tested variables allows the reduction of the number of parameters, determined in order to establish the biological activity.
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Antiinflamatorios/química , Antioxidantes/química , Semicarbacidas/química , Tiazoles/química , Tionas/química , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Fagocitosis/efectos de los fármacos , Análisis de Componente Principal , Ratas , Semicarbacidas/farmacología , Relación Estructura-Actividad , Tiazoles/farmacología , Tionas/farmacología , TrementinaRESUMEN
The objective of this study was to investigate the anti-inflammatory and antioxidant activity of new thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azole derivatives as potential iNOS inhibitors. The in vivo anti-inflammatory effects of the new thiazole compounds were studied in a turpentine oil induced inflammation model. Their anti-inflammatory activity was assessed by evaluating the acute phase bone marrow response, phagocytes' activity, NO synthesis and antioxidant capacity. The new thiazole compounds have anti-inflammatory effects by lowering bone marrow acute phase response and oxidative stress. The best anti-inflammatory and antioxidant effect was found for thiazolyl-carbonyl-thiosemicarbazides Th-1-8, thiazolyl-1,3,4-oxadiazole Th-20 and thiazolyl-1,3,4-thiadiazole Th-21. Virtual screening of thiazole derivatives against the oxygenase domain of chain A from 2Y37 revealed that all twenty-two compounds bind the active site of inducible nitric oxide synthase (iNOS). Based on the virtual screening and on the results obtained above, the activity may be due to their capacity to reduce the NO synthesis by blocking the bind of L-Arg in the active site of iNOS, the compounds binding the synthase by hydrogen bonds between the NH (2 and/or 4) of thiosemicarbazide fragment (Th-2-8) or N2/N3 from azole cycles and by the thiol function (Th-9-22).