By understanding the rampant infections of Mycobacterium tuberculosis (Mtb) and inflammations caused due to the generation of radical species during the Mtb infection, a series of (E)-2-(2-allylidenehydrazinyl)thiazole derivatives, with dual-action properties, was designed. The molecules were designed with a considerable variation in LogP, one of the critical parameters in physicochemical properties, and analyzed for their drug-likeness. For the synthesis, a simple, green, and multicomponent one-pot synthesis method was developed. The in vitro inhibition potentials were evaluated against Mtb H37 Rv by the microplate Alamar Blue assay. The results reveal that compound 6 was potent, with a MIC value of 6.5 µg/ml, and showed better interactions with the KasA protein with binding free energy (ΔG) of -9.4 kcal/mol. Also, the radical scavenging properties were studied to establish the dual-action properties of the molecules. Compound 9 exhibited promising antioxidant and nitric oxide radical scavenging activities, with 81.7% and 81.0%, respectively, at 1,000-μg/ml concentration.
- MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- racionální návrh léčiv * MeSH
- scavengery volných radikálů chemická syntéza chemie farmakologie MeSH
- thiazoly chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
Quercetin is one of the most prominent and widely studied flavonoids. Its oxidation has been previously investigated only indirectly by comparative analyses of structurally analogous compounds, e.g. dihydroquercetin (taxifolin). To provide direct evidence about the mechanism of quercetin oxidation, we employed selective alkylation procedures for the step-by-step blocking of individual redox active sites, i.e. the catechol, resorcinol and enol C-3 hydroxyls, as represented by newly prepared quercetin derivatives 1-3. Based on the structure-activity relationship (SAR), electrochemical, and computational (density functional theory) studies, we can clearly confirm that quercetin is oxidized in the following steps: the catechol moiety is oxidized first, forming the benzofuranone derivative via intramolecular rearrangement mechanism; therefore the quercetin C-3 hydroxy group cannot be involved in further oxidation reactions or other biochemical processes. The benzofuranone is oxidized subsequently, followed by oxidation of the resorcinol motif to complete the electrochemical cascade of reactions. Derivatization of individual quercetin hydroxyls has a significant effect on its redox behavior, and, importantly, on its antiradical and stability properties, as shown in DPPH/ABTS radical scavenging assays and UV-Vis spectrophotometry, respectively. The SAR data reported here are instrumental for future studies on the oxidation of biologically or technologically important flavonoids and other polyphenols or polyhydroxy substituted aromatics. This is the first complete and direct study mapping redox properties of individual moieties in quercetin structure.
Potential metabolites of bioactive compounds are important for their biological activities and as authentic standards for metabolic studies. The phenolic compounds contained in olive oil are an important part of the human diet, and therefore their potential metabolites are of utmost interest. We developed a convenient, scalable, one-pot chemoenzymatic method using the arylsulfotransferase from Desulfitobacterium hafniense for the sulfation of the natural olive oil phenols tyrosol, hydroxytyrosol, and of their monoacetylated derivatives. Respective monosulfated (tentative) metabolites were fully structurally characterized using LC-MS, NMR, and HRMS. In addition, Folin-Ciocalteu reduction, 1,1-diphenyl-2-picrylhydrazyl radical scavenging, and antilipoperoxidant activity in rat liver microsomes damaged by tert-butylhydroperoxide were measured and compared to the parent compounds. As expected, the sulfation diminished the radical scavenging properties of the prepared compounds. These compounds will serve as authentic standards of phase II metabolites.
- MeSH
- acetylace MeSH
- arylsulfotransferasa chemie MeSH
- bakteriální proteiny chemie MeSH
- biokatalýza MeSH
- Desulfitobacterium enzymologie MeSH
- fenethylalkohol analogy a deriváty chemická syntéza chemie MeSH
- fenoly chemie MeSH
- hmotnostní spektrometrie MeSH
- molekulární struktura MeSH
- olivový olej chemie MeSH
- scavengery volných radikálů chemická syntéza chemie MeSH
- sírany chemie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Publikační typ
- časopisecké články MeSH
Silymarin, an extract from milk thistle (Silybum marianum) fruits, is consumed in various food supplements. The metabolism of silymarin flavonolignans in mammals is complex, the exact structure of their metabolites still remains partly unclear and standards are not commercially available. This work is focused on the preparation of sulfated metabolites of silymarin flavonolignans. Sulfated flavonolignans were prepared using aryl sulfotransferase from Desulfitobacterium hafniense and p-nitrophenyl sulfate as a sulfate donor and characterized by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR). Their 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and N,N-dimethyl-p-phenylenediamine (DMPD) radical scavenging; ferric (FRAP) and Folin⁻Ciocalteu reagent (FCR) reducing activity; anti-lipoperoxidant potential; and effect on the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway were examined. Pure silybin A 20-O-sulfate, silybin B 20-O-sulfate, 2,3-dehydrosilybin-20-O-sulfate, 2,3-dehydrosilybin-7,20-di-O-sulfate, silychristin-19-O-sulfate, 2,3-dehydrosilychristin-19-O-sulfate, and silydianin-19-O-sulfate were prepared and fully characterized. Sulfated 2,3-dehydroderivatives were more active in FCR and FRAP assays than the parent compounds, and remaining sulfates were less active chemoprotectants. The sulfated flavonolignans obtained can be now used as authentic standards for in vivo metabolic experiments and for further research on their biological activity.
- MeSH
- antioxidancia chemie MeSH
- flavonolignany chemie MeSH
- hmotnostní spektrometrie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární struktura MeSH
- ostropestřec mariánský chemie MeSH
- ovoce chemie MeSH
- potravní doplňky MeSH
- rostliny chemie ultrastruktura MeSH
- scavengery volných radikálů chemie MeSH
- sírany chemie MeSH
- Publikační typ
- časopisecké články MeSH
Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. In recent years, a plethora of proteins and biochemical pathways has been proposed as possible targets to counteract neurotoxicity. Although the complex scenario is not completely elucidated, close relationships are emerging among some of these actors. In particular, increasing evidence has shown that aggregation of amyloid beta (Aβ), glycogen synthase kinase 3β (GSK-3β) and oxidative stress are strictly interconnected and their concomitant modulation may have a positive and synergic effect in contrasting AD-related impairments. We designed compound 3 which demonstrated the ability to inhibit both GSK-3β (IC50 = 24.36 ± 0.01 μM) and Aβ42 self-aggregation (IC50 = 9.0 ± 1.4 μM), to chelate copper (II) and to act as exceptionally strong radical scavenger (kinh = 6.8 ± 0.5 · 105 M-1s-1) even in phosphate buffer at pH 7.4 (kinh = 3.2 ± 0.5 · 105 M-1s-1). Importantly, compound 3 showed high-predicted blood-brain barrier permeability, did not exert any significant cytotoxic effects in immature cortical neurons up to 50 μM and showed neuroprotective properties at micromolar concentration against toxic insult induced by glutamate.
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- cinnamáty chemická syntéza chemie farmakologie MeSH
- GSK3B antagonisté a inhibitory metabolismus MeSH
- molekulární struktura MeSH
- scavengery volných radikálů chemická syntéza chemie farmakologie MeSH
- stereoizomerie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The effects in vitro of 2,3-dehydrosilybin and several galloyl esters and methyl ethers on the viability, proliferation, and migration of human umbilical vein endothelial cells (HUVECs) were evaluated. The monogalloyl esters were synthesized by a chemoselective esterification method or by Steglich esterification of suitably protected 2,3-dehydrosilybin (1) with protected gallic acid. 2,3-Dehydrosilybin (1) displayed more potent cytotoxic, antiproliferative, and antimigratory activities (IC50 12.0, 5.4, and 12.2 μM, respectively) than silybin. The methylated derivatives were less active, with the least potent being 3,7-di-O-methyl-2,3-dehydrosilybin (6). On the other hand, galloylation at C-7 OH and C-23 OH markedly increased the cytotoxicity and the effects on the proliferation and migration of HUVECs. The most active derivative was 7-O-galloyl-2,3-dehydrosilybin (13; IC50 value of 3.4, 1.6, and 4.7 μM in the cytotoxicity, inhibition of proliferation, and antimigratory assays, respectively). Overall, this preliminary structure-activity relationship study demonstrated the importance of a 2,3-double bond, a C-7 OH group, and a galloyl moiety in enhancing the activity of flavonolignans toward HUVECs.
- MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků MeSH
- kyselina gallová farmakologie MeSH
- lidé MeSH
- methylethery farmakologie MeSH
- molekulární struktura MeSH
- scavengery volných radikálů chemie MeSH
- silymarin chemie farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of model linear copolymers of 2-hydroxyethyl methacrylate (HEMA) and a sterically hindered amine derivative [N-(2,2,6,6-tetramethyl-piperidin-4-yl)methacrylamide (HAS)] were synthesized and characterized. Scavenging activities of the copolymers against reactive oxygen species (peroxyl and hydroxyl radicals) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals were determined. It was found that copolymers with medium HAS content (3.5-4.0 mol %) were better scavengers than copolymers with lower and higher HAS content and also than polyHEMA and polyHAS homopolymers and the HAS monomer. Importantly, these copolymers compared favorably even to established low-molecular weight antioxidant standards (BHA and dexpanthenol). Monomer reactivity ratios were determined, and the microstructure of the copolymers was assessed. Subsequently, cross-linked copolymers in the powder and film forms with optimal HAS content were synthesized. Their scavenging activities against the three types of radicals were determined, revealing that these hydrogels are potent scavengers of reactive oxygen species.
Quercetin 3'-O-sulfate is one of the main metabolites of the natural flavonoid quercetin in humans. This study was designed to prepare quercetin 3'-O-sulfate (1), isoquercitrin 4'-O-sulfate (2) and taxifolin 4'-O-sulfate (3) by the sulfation of quercetin, isoquercitrin (quercetin 3-O-glucoside) and taxifolin (2,3-dihydroquercetin) using the arylsulfate sulfotransferase from Desulfitobacterium hafniense, and to examine the effect of sulfation on selected biological properties of the flavonoids tested. We found that flavonoid sulfates 1-3 were weaker DPPH radical scavengers than the corresponding nonsulfated flavonoids, and that 1-3, unlike quercetin, did not induce the expression of either heme oxygenase-1 in RAW264.7 cells or cytochrome P450 1A1 in HepG2 cells. In both cell types, the cell uptake of compounds 1-3 was much lower than that of quercetin, but comparable to that of the glycoside isoquercitrin. Moreover, HPLC/MS metabolic profiling in HepG2 cells showed that flavonoid sulfates 1-3 were metabolized to a limited extent compared to the nonsulfated compounds. We conclude that sulfation of the tested flavonoids reduces their antiradical activity, and affects their cell uptake and biological activity in vitro.
- MeSH
- buněčné linie MeSH
- buňky Hep G2 MeSH
- cytochrom P-450 CYP1A1 genetika MeSH
- hemoxygenasa-1 genetika MeSH
- lidé MeSH
- myši MeSH
- quercetin analogy a deriváty chemie metabolismus farmakokinetika farmakologie MeSH
- regulace genové exprese účinky léků MeSH
- scavengery volných radikálů chemie metabolismus farmakokinetika farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In the present study, the coupling of adsorption capacity and photocatalytic efficiency of two different industrially produced titania catalysts was investigated and compared. The azo dye Reactive Red 195 was selected as a model compound. The tested catalysts, PK-10 and PK-180, exhibited different adsorption capacities due to their significant difference in their specific surface, but both have proven to be effective photocatalysts for photodegradation of the studied dye. PK-10 exhibited strong adsorption of the studied dye due to its high specific surface area, while the second studied catalyst, PK-180, demonstrated negligible adsorption of Reactive Red 195. The effect of the pH, the concentration of the catalyst and the initial concentration of the dye appear to affect the photocatalytic rate. The effect of the presence of humic acids and inorganic ions was also examined, while the contribution of various reactive species was indirectly evaluated through the addition of various scavengers. To evaluate the extent of mineralisation of the studied dye, total organic carbon (TOC) measurements during the experiment were also conducted. Besides total colour removal, evident reduction of TOC was also achieved using both catalysts.
- MeSH
- adsorpce MeSH
- anionty MeSH
- azosloučeniny izolace a purifikace účinky záření MeSH
- chemické látky znečišťující vodu izolace a purifikace účinky záření MeSH
- čištění vody metody MeSH
- fotolýza MeSH
- huminové látky analýza MeSH
- katalýza MeSH
- koncentrace vodíkových iontů MeSH
- naftalensulfonany izolace a purifikace účinky záření MeSH
- nanočástice chemie MeSH
- scavengery volných radikálů chemie MeSH
- titan chemie MeSH
- ultrafialové záření * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Coumarins represent a large group of 1,2-benzopyrone derivatives which have been identified in many natural sources and synthetized as well. Several studies have shown that their antioxidant capacity is not based only on direct scavenging of reactive oxygen and nitrogen species (RONS) but other mechanisms are also involved. These include: a) the chelation of transient metals iron and copper, which are known to catalyse the Fenton reaction; and b) the inhibition of RONS-producing enzymes (e.g. xanthine oxidase, myeloperoxidase and lipoxygenase), suggesting that mechanism(s) involved on cellular level are complex and synergistic. Moreover, many factors must be taken into account when analysing structure-antioxidant capacity relationships of coumarins due to different in vitro/in vivo methodological approaches. The structural features necessary for the direct RONS scavenging and metal chelation are apparently similar and the ideal structures are 6,7-dihydroxy- or 7,8-dihydroxycoumarins. However, the clinical outcome is unknown, because these coumarins are able to reduce copper and iron, and may thus paradoxically potentiate the Fenton chemistry. The similar structural features appear to be associated with inhibition of lipoxygenase, probably due to interference with iron in its active site. Contrarily, 6,7-dihydroxycoumarin seems to be the most active coumarin in the inhibition of xanthine oxidase while its derivative bearing the 4-methyl group or 7,8-dihydroxycoumarin are less active or inactive. In addition, coumarins may hinder the induction of inducible NO-synthase and cyclooxygenase- 2. Sparse data on inhibition of myeloperoxidase do not enable any clear conclusion, but some coumarins may block it.
- MeSH
- chelátory chemie metabolismus farmakologie MeSH
- cyklooxygenasa 2 metabolismus MeSH
- inhibitory enzymů chemie metabolismus farmakologie MeSH
- kumariny chemie metabolismus farmakologie MeSH
- lidé MeSH
- lipoxygenasa metabolismus MeSH
- měď chemie metabolismus MeSH
- oxidační stres účinky léků MeSH
- peroxidasa antagonisté a inhibitory metabolismus MeSH
- reaktivní formy kyslíku antagonisté a inhibitory metabolismus MeSH
- scavengery volných radikálů chemie metabolismus farmakologie MeSH
- synthasa oxidu dusnatého, typ II antagonisté a inhibitory metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- xanthinoxidasa antagonisté a inhibitory metabolismus MeSH
- železo chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
