Essential amino acids interacting with flavonoids: A theoretical approach

The interaction of two flavonoid species (resorcinolic and fluoroglucinolic) with the 20 essential amino acids was studied by the multiple minima hypersurface (MMH) procedures, through the AM1 and PM3 semiempirical methods. Remarkable thermodynamic data related to the properties of the molecular association of these compounds were obtained, which will be of great utility for future investigations concerning the interaction of flavonoids with proteins. These results are compared with experimental and classical force field results reported in the available literature, and new evidences and criteria are shown. The hydrophilic amino acids demonstrated high affinity in the interaction with flavonoid molecules; the complexes with lysine are especially extremely stable. An affinity order for the interaction of both flavonoid species with the essential amino acids is suggested. Our theoretical results are compared with experimental evidence on flavonoid interactions with proteins of biomedical interest. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Comprehensive evaluation of the antioxidant capacity of Sceptridium ternatum using multiple colorimetric methods and 1,1‐diphenyl‐2‐picrylhydrazyl–high‐performance liquid chromatography analysis

Sceptridium ternatum is a medicinal herb with multiple health benefits. However, its antioxidant activity and active components have not been clarified. In this study, the antioxidant capacity of S. ternatum was comprehensively investigated using multiple colorimetric methods and 1,1‐diphenyl‐2‐picrylhydrazyl–high‐performance liquid chromatography analysis. First, the phenolic content, flavonoid content, and radical scavenging ability of S. ternatum were parallelly determined using colorimetric methods performed in 96‐well microplates. The flavonoid content, rather than the phenolic content, was highly correlated with its antioxidant activity. Sceptridium ternatum was shown to be a rich source of flavonoids, with a highest flavonoid yield of 3.44 ± 0.11 mg/g. Subsequently, 1,1‐diphenyl‐2‐picrylhydrazyl–high‐performance liquid chromatography experiment and quadrupole time‐of‐flight mass spectrometry analyses were carried out for rapid screening of the individual antioxidants. A total of 14 O‐glycosyl flavonoids with quercetin or kaempferol aglycone have been characterized. Particularly, quercetin 3‐O‐rhamnoside‐7‐O‐glucoside exhibited the most potent antioxidant ability. Its half‐maximal effective concentrations for scavenging 1,1‐diphenyl‐2‐picrylhydrazyl and 2,2?‐azino‐bis (3‐ethylbenzthiazoline‐6‐sulfonic acid) radicals were 70.55 ± 2.69 and 106.90 ± 1.76 µg/mL, respectively, which were comparable with those of l ‐ascorbic acid. Our results indicated that the combined colorimetric and chromatographic methods provided a practical strategy for the discovery of bioactive compounds from natural products.     

Synthesis and Biological Evaluation of Flavonoid-Cinnamic Acid Amide Hybrids with Distinct Activity against Neurodegeneration in Vitro and in Vivo

Flavonoids are polyphenolic natural products and have shown significant potential as disease-modifying agents against neurodegenerative disorders like Alzheimer's disease (AD), with activities even in vivo. Hybridization of the natural products taxifolin and silibinin with cinnamic acid led to an overadditive effect of these compounds in several phenotypic screening assays related to neurodegeneration and AD. Therefore, we have exchanged the flavonoid part of the hybrids with different flavonoids, which show higher efficacy than taxifolin or silibinin, to improve the activity of the respective hybrids. Chemical connection between the flavonoid and cinnamic acid was realized by an amide instead of a labile ester bond to improve stability towards hydrolysis. To investigate the influence of a double bond at the C-ring of the flavonoid, the dehydro analogues of the respective hybrids were also synthesized. All compounds obtained show neuroprotection against oxytosis, ferroptosis and ATP-depletion, respectively, in the murine hippocampal cell line HT22. Interestingly, the taxifolin and the quercetin derivatives are the most active compounds, whereby the quercetin derivate shows even more pronounced activity than the taxifolin one in all assays applied. As aimed for, no hydrolysis product was found in cellular uptake experiments after 4 h whereas different metabolites were detected. Furthermore, the quercetin-cinnamic acid amide showed pronounced activity in an in vivo AD mouse model at a remarkably low dose of 0.3 mg/kg.     

A Validated Ultrasound-Assisted Extraction Coupled with SPE-HPLC-DAD for the Determination of Flavonoids in By-Products of Plant Origin: An Application Study for the Valorization of the Walnut Septum Membrane

Walnut byproducts have been shown to exert functional properties, but the literature on their bioactive content is still scarce. Among walnut byproducts, walnut septum is a dry ligneous diaphragm tissue that divides the two halves of the kernel, exhibiting nutritional and medicinal properties. These functional properties are owing to its flavonoid content, and in order to explore the flavonoid fraction, an ultrasound-assisted (UAE) protocol was combined with solid phase extraction (SPE) and coupled to high-performance liquid chromatography with diode array detection (HPLC-DAD) for the determination of flavonoids in Greek walnut septa membranes belonging to Chandler, Vina, and Franquette varieties. The proposed UAE-SPE-HPLC-DAD method was validated and the relative standard deviations (RSD%) of the within-day and between-day assays were lower than 6.2 and 8.5, respectively, showing good precision, and high accuracy ranging from 90.8 (apigenin) to 97.5% (catechin) for within-day assay, and from 88.5 (myricetin) to 96.2% (catechin) for between-day assay. Overall, seven flavonoids were determined (catechin, rutin, myricetin, luteolin, quercetin, apigenin, and kaempferol) suggesting that the walnut septum is a rich source of bioactive constituents. The quantification results were further processed using ANOVA analysis to examine if there are statistically significant differences between the concentration of each flavonoid and the variety of the walnut septum.     

Bioactive compounds, RP-HPLC analysis of phenolics, and antioxidant activity of some Portuguese shrub species extracts

In the ecosystem of Serra Da Estrela, some plant species have the potential to be used as raw material for extraction of bioactive products. The goal of this work was to determine the phenolic, flavonoid, tannin and alkaloid contents of the methanolic extracts of some shrubs (Echinospartum ibericum, Pterospartum tridentatum, Juniperus communis, Ruscus aculeatus, Rubus ulmifolius, Hakea sericea, Cytisus multiflorus, Crataegus monogyna, Erica arborea and Ipomoea acuminata), and then to correlate the phenolic compounds and flavonoids with the antioxidant activity of each extract. The Folin-Ciocalteu's method was used for the determination of total phenols, and tannins were then precipitated with polyvinylpolypyrrolidone (PVPP); a colorimetric method with aluminum chloride was used for the determination of flavonoids, and a Dragendorff's reagent method was used for total alkaloid estimation. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and beta-carotene bleaching tests were used to assess the antioxidant activity of extracts. The identification of phenolic compounds present in extracts was performed using RP-HPLC. A positive linear correlation between antioxidant activity index and total phenolic content of methanolic extracts was observed. The RP-HPLC procedure showed that the most common compounds were ferulic and ellagic acids and quercetin. Most of the studied shrubs have significant antioxidant properties that are probably due to the existence of phenolic compounds in the extracts. It is noteworthy to emphasize that for Echinospartum ibericum, Hakea sericea and Ipomoea acuminata, to the best of our knowledge, no phytochemical studies have been undertaken nor their use in traditional medicine been described.     

High Hydrostatic Pressure to Increase the Biosynthesis and Extraction of Phenolic Compounds in Food: A Review

Phenolic compounds from fruits and vegetables have shown antioxidant, anticancer, anti-inflammatory, among other beneficial properties for human health. All these benefits have motivated multiple studies about preserving, extracting, and even increasing the concentration of these compounds in foods. A diverse group of vegetable products treated with High Hydrostatic Pressure (HHP) at different pressure and time have shown higher phenolic content than their untreated counterparts. The increments have been associated with an improvement in their extraction from cellular tissues and even with the activation of the biosynthetic pathway for their production. The application of HHP from 500 to 600 MPa, has been shown to cause cell wall disruption facilitating the release of phenolic compounds from cell compartments. HPP treatments ranging from 15 to 100 MPa during 10–20 min at room temperature have produced changes in phenolic biosynthesis with increments up to 155%. This review analyzes the use of HHP as a method to increase the phenolic content in vegetable systems. Phenolic content changes are associated with either an immediate stress response, with a consequent improvement in their extraction from cellular tissues, or a late stress response that activates the biosynthetic pathways of phenolics in plants.     

Plant Flavonoids: Chemical Characteristics and Biological Activity

In recent years, more attention has been paid to natural sources of antioxidants. Flavonoids are natural substances synthesized in several parts of plants that exhibit a high antioxidant capacity. They are a large family, presenting several classes based on their basic structure. Flavonoids have the ability to control the accumulation of reactive oxygen species (ROS) via scavenger ROS when they are formed. Therefore, these antioxidant compounds have an important role in plant stress tolerance and a high relevance in human health, mainly due to their anti-inflammatory and antimicrobial properties. In addition, flavonoids have several applications in the food industry as preservatives, pigments, and antioxidants, as well as in other industries such as cosmetics and pharmaceuticals. However, flavonoids application for industrial purposes implies extraction processes with high purity and quality. Several methodologies have been developed aimed at increasing flavonoid extraction yield and being environmentally friendly. This review presents the most abundant natural flavonoids, their structure and chemical characteristics, extraction methods, and biological activity.     

In Vitro Antioxidant and Anticancer Properties of Various E. senegalensis Extracts

Although Erythrina senegalensis is a plant widely used in traditional medicine in sub-Saharan Africa, its biological properties have been poorly investigated to date. We first characterized by conventional reactions the composition of several stem bark extracts and evaluated in acellular and cellular assays their pro- or antioxidant properties supported by their high phenolic and flavonoid content, particularly with the methanolic extract. The pro- or antioxidant effects observed did not correlate with their IC₅₀ concentrations against five cancer cell lines determined by MTT assay. Indeed, the CH₂Cl₂ extract and its ethyl acetate (EtOAc) subfraction appeared more potent although they harbored lower pro- or antioxidant effects. Nevertheless, at equipotent concentration, both extracts induced ER- and mitochondria-derived vacuoles observed by fluorescent microscopy that further led to non-apoptotic cell death. LC coupled to high resolution MS investigations have been performed to identify chemical compounds of the extracts. These investigations highlighted the presence of compounds formerly isolated from E. senegalensis including senegalensein that could be retrieved only in the EtOAc subfraction but also thirteen other compounds, such as 16:3-Glc-stigmasterol and hexadecanoic acid, whose anticancer properties have been previously reported. Nineteen other compounds remain to be identified. In conclusion, E. senegalensis appeared rich in compounds with antioxidant and anticancer properties, supporting its use in traditional practice and its status as a species of interest for further investigations in anticancer drug research.     

Synthesis and antioxidant, antimicrobial evaluation, DFT studies of novel metal complexes derivate from Schiff base

In Iraq, like most developing countries, attempts are being made to synthesize new compounds with several pharmacological properties. (E)-2-(3-(2-imino-1-methylimidazolidin-4-ylidene)-1-methylguanidino)acetic acid (L) has been synthesized and used as a ligand for the formation of Cr(III), Co(II), Ni(II), and Cu(II) complexes. The chemical structures of synthesized compounds were characterized using different spectroscopic methods. All chelates except Ni(II) chelate are found to be octahedral structures, Ni(II) chelate was square planar. The stability for the prepared complexes was studied theoretically using density function theory. The total energy for the complexes was calculated and it was shown that the copper complex is the most stable one. Ligand and complexes were tested against selected types of microbial organisms and showed significant activities. The free-radical scavenging activity of ligand and metal complexes have been determined by their interaction with the stable free-radical DPPH and all the compounds have shown encouraging antioxidant activities.     

Study of the structure and stereochemistry of flavonoid O-rhamnosides with the aid of PMR spectroscopy

The PMR method has been used in the study of the structure and stereochemistry of a number of flavonoid rhamnosides. The systematic study of the PMR spectra of the native compounds and their TMS ethers and complete acetates has permitted the size of the oxide ring, the conformation of the rhamnose residue, and, in combination with the results of polarimetric analysis, the configuration of the glycosidic bond to be determined. Information on the size of the oxide ring is given by — in addition to, the J_{2, 3} proton coupling constant — the signals of the protons at C-5 in the spectra of the full acetates. In the diagnostic region of 3.2–4.0 ppm, only the proton H-5 resonates in the rhamnopyranosides, while for the rhamnofuranosides a different structure of the H-4 signal must be expected. It has been shown that all the compounds studied (more than 20 specimens) are α-L-rhamnopyranosides and have the¹C₄ conformation of the sugar residue. In view of this, the hypothesis has been expressed that the existence of natural flavonoid rhamnosides in the furanoside form is improbable.     

Study of polyphenols in grape berries by reversed-phase high-performance liquid chromatography

Several polyphenols have been tested in grape berries from Spain. The flavonoid content is important because of the pharmacological properties of these compounds, whereas resveratrol has been proved to be an antifungal, antiinflammatory and an anticarcinogenic compound. A reversed-phase HPLC method has been developed and applied to determine resveratrol, quercetine, quercitrine and rutine content in several grape berries samples in a single analysis. Covering the grapes with a preservative paper yields a healthier product, but one which has a lower polyphenol content than unprotected grapes.     

Bioactive constituents of the root bark of Artocarpus rigidus subsp. rigidus

Investigation of the chemical constituents of the root bark of Artocarpus rigidus BLUME subsp. rigidus has led to the isolation of six, structurally diverse phenolic compounds. These included two new compounds with modified skeletons, the flavonoid 7-demethylartonol E (1) and the chromone artorigidusin (2), together with four known phenolic compounds, the xanthone artonol B (3), the flavonoid artonin F (4), the flavonoid cycloartobiloxanthone (5), and the xanthone artoindonesianin C (6). Compounds 1, 4, and 5 exhibited antiplasmodial activity against Plasmodium falciparum. All compounds showed antimycobacterial activity against Mycobacterium tuberculosis, with 4 being the most active compound (MIC 6.25 microg/ml). Compounds 5 and 6 were active against KB cells, whereas 2, 5, and 6 showed varying toxicity to BC cells. Compounds 1-3, 5, and 6 were active in the NCI-H187 cytotoxicity assay, with 3 being the most active compound (IC(50) 1.26 microg/ml).     

Liquid chromatography–tandem mass spectrometry reveals the widespread occurrence of flavonoid glycosides in honey,and their potential as floral origin markers

HPLC-MS–MS analysis of unifloral honey extracts has shown the occurrence of flavonoid glycosides in most of the analyzed samples. These compounds are not present in large amounts, but can reach up to 600 μg/100 g honey in canola and rapeseed honeys. Rhamnosyl-hexosides (tentatively rutinosides and neohesperidosides) and dihexosides (hexosyl(1→2)hexosides and hexosyl(1→6)hexosides) of flavonols such as quercetin, kaempferol, isorhamnetin and 8-methoxykaempferol, are the main flavonoid glycosides found in honey. However, flavonoid triglycosides and monoglycosides are also detected in some floral origins. Eucalyptus and orange blossom nectars were collected and analyzed showing that nectar flavonoid glucosides, as is the case of eucalyptus flavonoids, can be readily hydrolyzed by the bee saliva enzymes, while flavonoid rhamnosyl-glucosides, as is the case of citrus nectar flavonoids, are not hydrolyzed, and because of these reasons the flavonoid glycoside content of citrus honey is higher than that of eucalyptus honey that contains mainly aglycones. The flavonoid glycoside profiles detected in honeys suggest that this could be related to their floral origin and the results show that the HPLC-MSn ion trap analysis of flavonoid glycosides in honey is a promising analytical method to help in the objective determination of the floral origin of unifloral honeys.     

A partial least squares regression study with antioxidant flavonoid compounds

The quantitative structure-activity relationship of a set of 19 flavonoid compounds presenting antioxidant activity was studied by means of PLS (Partial Least Squares) regression. The optimization of the structures and calculation of electronic properties were done by using the semiempirical method AM1. A reliable model (r ²=0.806 and q ²=0.730) was obtained and from this model it was possible to consider some aspects of the structure of the flavonoid compounds studied that are related with their free radical scavenging ability. The quality of the PLS model obtained in this work indicates that it can be used in order to design new flavonoid compounds that present ability to scavenge free radicals.     

Synergistic antinociceptive activity of combined aqueous extracts of Artemisia campestris and Artemisia herba-alba in several acute pain models

In this study, total phenolic and flavonoid contents, acute toxicity and the antinociceptive activity of Artemisia campestris and Artemisia herba-alba, individually and in combination, were investigated using multiple forms of pain in animals. Our results have been shown that plants are relatively safe without clinical signs of toxicity in animals. Thus, extracts were presented high levels in phenolic and flavonoid contents. Artemisia decoctions with 100, 200, 400 mg/kg b-w studied dose, clearly attenuate chemical and thermal noxious stimuli in writhing, formalin and hot-plate tests, and significantly reduced paw oedema in formalin test. Additionally, binary combination forms exhibited a great improvement in intensity and amplitude of antinociceptive activity in comparison with both plants used individually by a relative interference with opioid system. Our findings suggested the central and peripheral analgesic properties and confirmed the folkloric medicinal use of these plants in pain symptom treatment.     

Combined use of pharmacophoric models together with drug metabolism and genotoxicity “in silico” studies in the hit finding process

In this study we propose a virtual screening strategy based on the generation of a pharmacophore hypothesis, followed by an in silico evaluation of some ADME-TOX properties with the aim to apply it to the hit finding process and, specifically, to characterize new chemical entities with potential to control inflammatory processes mediated by T lymphocytes such as multiple sclerosis, systemic lupus erithematosus or rheumatoid arthritis. As a result, three compounds with completely novel scaffolds were selected as final hits for future hit-to-lead optimization due to their anti-inflammatory profile. The biological results showed that the selected compounds increased the intracellular cAMP levels and inhibited cell proliferation in T lymphocytes. Moreover, two of these compounds were able to increase the production of IL-4, an immunoregulatory cytokine involved in the selective deviation of T helper (Th) immune response Th type 2 (Th2), which has been proved to have anti-inflammatory properties in several animal models for autoimmune pathologies as multiple sclerosis or rheumatoid arthritis. Thus our pharmacological strategy has shown to be useful to find molecules with biological activity to control immune responses involved in many inflammatory disorders. Such promising data suggested that this in silico strategy might be useful as hit finding process for future drug development.     

Determination of flavonoids,flavonoid glycosides and biflavonoids inOlea europaea L. Leaves

Summary The flavonoid content of olive leaves was studied by a method based on thin-layer chromatography and recording UV spectra directly on the layer. Three flavonoid glycosides, quercitrin, rutin and luteolin-7-glycoside, one flavonoid aglycone, luteolin, and chlorogenic acid were found in olive leaves. Three compounds with a biflavonoid-type sructure have been characterized. Ten cultivars were investigated in order to indicate qualitative and quantitative differences.     

Chromenone-based GSK-3β inhibitors as potential therapeutic targets for cardiovascular diseases: In silico study,molecular dynamics,and ADMET profiles

Glycogen synthase kinase-3 beta (GSK-3β) regulates glycogen metabolism and many different cellulars, including apoptosis, signaling, and neural. It is a crucial therapeutic receptor in heart disease, type 2 diabetes, and Alzheimer's. In this study, using computational methods, flavonoid compounds were investigated for potential inhibitors against GSK-3β. Virtual screening was utilized to investigate flavonoid compounds obtained from the PubChem database. Structure of human heart mitochondria of GSK-3β receptor constructed by homology modeling. Best binding poses were discovered via in silico molecular docking simulation. We surveyed noncovalent interactions among amino acid residues involved in the active site of the modeled Protein and compounds via molecular docking and molecular dynamics (MD).Moreover, ADMET characteristics of best docking conformers have been investigated. The obtained results revealed that compound 1 containing chromenone moiety with binding energy H-bond ?11.4 kcal/mol inhibited effectively binding pocket of the GSK-3β receptor. Moreover, MD simulation analysis (RMSD and radius of gyration indicated complex of the compound and GSK-3β receptor remained stable throughout 100 ns MD simulation, and also analysis of ADMET profiles revealed that selected compounds had good drug-likeness and pharmacokinetic properties. Hence, it was suggested that compounds with chromenone scaffold could potentially inhibit GSK-3β. Structural modification of the chromenone derivatives may result in the discovery of promising candidates for identifying novel drugs as GSK-3β inhibitors.