Antioxidant activity of the anti-inflammatory compound ebselen: a reversible cyclization pathway via selenenic and seleninic acid intermediates

A revised mechanism that accounts for the glutathione peroxidase (GPx)-like catalytic activity of the organoselenium compound ebselen is described. It is shown that the reaction of ebselen with H(2)O(2) yields seleninic acid as the only oxidized product. The X-ray crystal structure of the seleninic acid shows that the selenium atom is involved in a noncovalent interaction with the carbonyl oxygen atom. In the presence of excess thiol, the Se--N bond in ebselen is readily cleaved by the thiol to produce the corresponding selenenyl sulfide. The selenenyl sulfide thus produced undergoes a disproportionation in the presence of H(2)O(2) to produce the diselenide, which upon reaction with H(2)O(2), produces a mixture of selenenic and seleninic acids. The addition of thiol to the mixture containing selenenic and seleninic acids leads to the formation of the selenenyl sulfide. When the concentration of the thiol is relatively low in the reaction mixture, the selenenic acid undergoes a rapid cyclization to produce ebselen. The seleninic acid, on the other hand, reacts with the diselenide to produce ebselen as the final product. DFT calculations show that the cyclization of selenenic acids to the corresponding selenenyl amides is more favored than that of sulfenic acids to the corresponding sulfenyl amides. This indicates that the regeneration of ebselen under a variety of conditions protects the selenium moiety from irreversible inactivation, which may be responsible for the biological activities of ebselen.     

Synthesis, characterization, and antioxidant activity of some ebselen analogues

Simple synthetic routes for several analogues of the anti-inflammatory organoselenium drug, ebselen, are described. The compounds are characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques and, in some cases, by single-crystal X-ray diffraction studies. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2), tBuOOH, and Cum-OOH as substrates, and thiophenol (PhSH, 4-Me-C(6)H(4)SH) and glutathione (GSH) as cosubstrates. Density functional theory (DFT) calculations have been performed on these systems to understand the effects of various substituents on the (77)Se NMR chemical shifts; these results have been compared with the experimental data. The experimental and theoretical results suggest that the presence of a phenyl substituent on the nitrogen atom is important for the antioxidant activity of ebselen. While ebselen and its analogues are poor catalysts in aromatic thiol assays, these compounds exhibit high GPx activity when GSH is used as the cosubstrate. The poor catalytic activity of ebselen analogues in the presence of aromatic thiols such as PhSH and 4-Me-C(6)H(4)SH can be ascribed to the undesired thiol exchange reaction that takes place at the selenium center due to SeO nonbonding interactions. To understand the effects of different peroxides on the catalytic activities, we have determined the initial rates at various concentrations of GSH and peroxides. These data suggest that the nature of peroxide has little effect on the catalytic efficiencies, although the initial reaction rates observed with hydrogen peroxide were found to be higher than that with tBuOOH and Cum-OOH. In contrast to the effect of peroxides, the nature of thiols appears to have a dramatic effect on the catalytic activity of ebselen and its related derivatives.     

Computational modeling of the kinetics and mechanism of tellurium-based glutathione peroxidase mimic

A new generation of glutathione peroxidase enzyme mimic based on organotellurium was introduced. The catalytic cycles of these mimics, tellura and tellenol, were clarified by density functional theory and solvent-assisted proton exchange procedure as an indirect proton exchange chain. From the kinetic viewpoint, the oxidation of tellura (ΔG^≠ = 23.55 kcal mol⁻¹) was considered as the rate-determining step using a single-step process. Various behaviors of tellenol were examined in the reduction of tellurenylsulfide based on methanethiol nucleophilicity. On the basis of the turnover frequency calculations, during the catalytic cycles of tellura and tellenol, the rate of the catalytic cycle of tellura is faster than that of tellenol. A decrease in the electron density and an increase in the Laplacian from the reactant to the transition states are evidence of the bond rupture, whereas an opposite change is evidence of the bond formation. Finally, different analyses of the electron location function and localized orbital locator within the quantum theory of atoms in molecules were applied and discussed. The covalent nature of the intramolecular interactions suggests that the Te⋯N interaction is stronger than that of Te⋯H. Finally, based on different analyses, tellura can be considered the more reactive GPx mimic than tellenol.     

Formation of diaryl sulfides and sulfoxides: Synthesis,characterization and structure activity correlation studies

Abstract

The synthesis of a series of stable diarylsulfides and sulfoxides is reported. All the newly synthesized compounds were characterized by ¹H, ¹³C NMR and mass spectroscopic techniques. A detailed mechanistic study indicates that the formation of sulfoxides follows the oxidation. In addition to synthesis, characterization and mechanistic studies, the glutathione peroxidase(GPx) mimetic activity of the newly synthesized compounds is described. It is observed that the diaryl sulfides having a heterocyclic ring attached to the nitrogen atom facilitates the oxidation of the sulfur center to form the corresponding sulfoxides. The substituents attached to the nitrogen atom play an important role in the catalytic activity of the substituted diaryl sulfides. The obtained data supports for the higher antioxidant activity of diaryl sulfides than that of the corresponding sulfoxides.     

2-位碲桥联环糊精的制备、表征及其谷胱甘肽过氧化物酶活性的研究

该文以三种母体环糊精(CD),即α-、β-和γ-CD为修饰模板,将功能性基团有机碲引入到环糊精次面的2位羟基上,制备得到了三种具有谷胱甘肽过氧化物酶(GPX)活性的GPX模拟物。采用元素分析、红外光谱、核磁共振等手段对三种环糊精衍生物的结构进行了表征。运用GPX经典双酶体系法测定了三种环糊精衍生物的GPX活性,实验结果表明三者均具有很高的催化活性,其中2-位碲桥联γ-环糊精(2-Te-γ-CD)具有最高的GPX活性,其催化谷胱甘肽(GSH)还原过氧化氢(H2O2),叔丁基过氧化氢(t-BuOOH)和枯烯过氧化氢(CuOOH)的活力分别是传统"小分子硒酶"Ebselen的80.5,333.3和118.3倍。     

Synthesis and Structure–Activity Correlation Studies of Secondary‐ and Tertiary‐Amine‐Based Glutathione Peroxidase Mimics

In this study, a series of secondary‐ and tertiary‐amino‐substituted diaryl diselenides were synthesized and studied for their glutathione peroxidase (GPx) like antioxidant activities with H₂O₂, cumene hydroperoxide, or tBuOOH as substrates and with PhSH or glutathione (GSH) as thiol cosubstrates. This study reveals that replacement of the tert‐amino groups in benzylamine‐based diselenides by sec‐amino moieties drastically enhances the catalytic activities in both the aromatic thiol (PhSH) and GSH assay systems. Particularly, the N‐propyl‐ and N‐isopropylamino‐substituted diselenides are 8–18 times more active than the corresponding N,N‐dipropyl‐ and N,N‐diisopropylamine‐based compounds in all three peroxide systems when GSH is used as the thiol cosubstrate. Although the catalytic mechanism of sec‐amino‐substituted diselenides is similar to that of the tert‐amine‐based compounds, differences in the stability and reactivity of some of the key intermediates account for the differences in the GPx‐like activities. It is observed that the sec‐amino groups are better than the tert‐amino moieties for generating the catalytically active selenols. This is due to the absence of any significant thiol‐exchange reactions in the selenenyl sulfides derived from sec‐amine‐based diselenides. Furthermore, the seleninic acids (RSeO₂H) derived from the sec‐amine‐based compounds are more stable toward further reactions with peroxides than their tert‐amine‐based analogues.     

Chemical composition,antimicrobial and antioxidant activities of the essential oil of Psammogetoncanescens

This study reports the chemical composition, antimicrobial activity and antioxidant properties of Psammogeton canescens essential oil (EO) and its main compounds. The EO was obtained from the aerial parts of P. canescens by hydrodistillation and analysed by using GC/MS. The main constituent was β-bisabolene (25%), followed by α-pinene (20%), apiole (15.34%), γ-terpinene (7.34%), p-cymene (5.35%), β-pinene (5.41%), camphene (5.12%), dill apiole (5%), myrcene (4.54%), colchicine (0.56), sylvestrene (0.56%), β-caryophyllene (0.45%), caryophyllene oxide (0.43%), (Z)-β-farnesene (0.32%), cembrene (0.21%), folic acid (0.21%), germacrene D (0.14) and β-sesquiphellandrene (0.13). β-Bisabolene exhibited strong antioxidant activity (14 ± 0.8 μg/mL). The EO of P. canescens was particularly active against Candida albicans and Escherichia coli, with the lowest minimum inhibitory concentration and minimum bactericidal/fungicidal concentration values. In conclusion, these results support the use of the EO and its main compounds for their antioxidant properties and antimicrobial activity.     

Antidiabetic,cytotoxic and antioxidant activities of oil extracted from Acrocomia aculeata pulp

This study evaluated the hypoglycemic effect of the oil extracted from the Acrocomia aculeata pulp (OPAC) in normoglycemic rats and streptozotocin (STZ), fructose-induced diabetic rat models and its in vitro antioxidant and cytotoxic potential. OPAC (3, 30 or 300 mg/kg, v.o.) significantly decreased (p < 0.05) the high glucose levels induced by a high fructose-diet in rats. Persistent treatment with OPAC for 24 days also reduced the high plasmatic glucose induced by STZ. In normoglycemic animals, OPAC significantly decreased glucose levels. While A. aculeata oil exhibited good in vitro antioxidant activity, no sign of cytotoxicity was observed in LLC-PK1 cells (5–500 μg/mL). OPAC has antidiabetic and antioxidant activities without causing in vitro cytotoxicity.     

Synthesis,antioxidant and antitumor activities of some of new cyclobutane containing triazoles derivatives

Abstract

Thiosemicarbazides (2a–e) were obtained by the interaction of furan-2-carboxylic acid hydrazide (1) with five different isothiocyanate (RNCS) derivatives. By addition of KOH to the reaction medium, ethyl, allyl, phenyl and benzyl, p-tolyl substituted 1,2,4-triazoles (3a–e) were obtained. 3a–e were dissolved in dry acetone containing K₂CO₃ in the presence of 2-chloro-1-(3-methyl-3-mesitylcyclobutyl) ethanone (4) to give 3,4,5-trisubstituted 1,2,4-triazole sulfanyl compounds containing a cyclobutane ring (5a–e). The structures of the final compounds were confirmed by elemental analyses, FT-IR, ¹H-NMR and ¹³C-NMR. The antioxidant and antitumor properties of the synthesized compounds were also investigated. Three of the triazole derivatives with p-tolyl, benzyl and phenyl substituents (5c–e) displayed good antioxidant and antitumor activity in comparison to the standards.     

A new indole alkaloid,antioxidant and antibacterial activities of crude extracts from Saccocalyx satureioides

Abstract

The new acylated indole alkaloid glucoside indole-3-carboxylic acid-(6'-O-caffeoyl)-β-D-glucoside 1 has been isolated from the ethyl acetate (EtOAC) extract of Saccocalyx satureioides Coss. & Dur. (Lamiaceae) together with eight known secondary metabolites 2-9. Two indoles 2 and 3, five methylated flavone aglycones 4-8 and one monoterpene glucoside 9 were reported for the first time in the genus Saccocalyx. The structural elucidation of these compounds was accomplished by spectroscopic methods including 1?D (¹H and ¹³C) and 2?D (COSY, HSQC and HMBC) NMR techniques, and mass spectrometry, and by comparison with literature data. Light petroleum, EtOAc, chloroform and n-butanol (n-BuOH) extracts of S. Satureioides were screened for their antioxidant activity using DPPH radical scavenging and β-carotene bleaching methods. The antibacterial activity of these extracts indicates that n-BuOH and EtOAc extracts possess the strongest activity.     

Synthesis,antioxidant, and anticholinesterase activities of novel N-arylsulfonyl hydrazones bearing sulfonate ester scaffold

In this research, two new series of N-arylsulfonyl hydrazone compounds ( 14 – 25 ) possessing a sulfonate moiety were synthesized and characterized by elemental analysis and various spectroscopic techniques including fourier transform infrared (FT-IR), ¹H-, and ¹³C nuclear magnetic resonance (NMR). These compounds synthesized as target molecules ( 14 – 25 ) were tested for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities and antioxidant potential. The antioxidant capacities of the tested molecules were determined by four different assays. The IC₅₀ values of the screened molecules were determined in the range of 60.14 ± 0.25–84.81 ± 1.09 μM against AChE and in the range of 70.11 ± 0.67–93.60 ± 0.47 μM against BChE. In the AChE assay, 4-hydroxybenzaldehyde-based compound 25 (60.14 ± 0.25 μM) showed the highest activity in comparison to rivastigmine (501 ± 3.08 μM). This compound (71.42 ± 0.19 μM) is also one of the compounds with the highest activity against BChE. In the BChE assay, 2-hydroxybenzaldehyde-based compound 19 (70.11 ± 0.67 μM) indicated the highest activity in comparison to rivastigmine (19.95 ± 0.20 μM). In antioxidant activity studies, the tested molecules showed lower activities than the standard compounds (butylated hydroxytoluene and α-tocopherol). Consequently, some novel compounds can be used as potential inhibitor candidates in future studies.     

Structure-activity correlation between natural glutathione peroxidase (GPx) and mimics: a biomimetic concept for the design and synthesis of more efficient GPx mimics

Among the organoselenium compounds that mimic the action of the natural enzyme glutathione peroxidase (GPx), there are certain basic differences in the activity, substrate specificity and mechanism. These differences arise mainly from the nature of the substituents near the reaction center, and stability and reactivity of the intermediates. As an attempt to draw some general concepts for the development of new mimics, a structure - activity correlation between natural GPx and some existing mimics is described.     

Ultrasound-assisted efficient synthesis of polyfunctional 1,2,4-triazoles as novel antibacterial and antioxidant agents

Novel 4,5-diphenyl-1H-imidazol-1-yl-1H-1,2,4-triazole derivatives were synthesized using a facile and highly efficient, one-pot, four-component procedure in the presence of KHSO₄ as an acidic catalyst under ultrasonic irradiations in short reaction times (10–25 min) and good to excellent yields (70–96%). The synthesized compounds were screened for their antibacterial activities against Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive (Bacillus subtilis, Micrococcus luteus) bacteria, and their antioxidant activity was also evaluated. Some of the products showed potential antibacterial and high antioxidant activities.     

Phenolic content,antioxidant and anti-inflammatory activities of Tunisian Diplotaxis simplex (Brassicaceae)

This study investigates the polyphenol content of Diplotaxis simplex extract and the biological activities of the main organ. The analysed extracts showed that polyphenol contents varied considerably as a function of organs. Furthermore, novel biological activities of this species were assessed. Flower extracts exhibit a potent in vitro antioxidant capacity using oxygen radical absorbance capacity and displayed a strong anti-inflammatory activity, inhibiting nitric oxide release, by 79.3% at 160 μg/mL. Our findings suggested that the Diplotaxis flower is a valuable source of antioxidants and anti-inflammatory agents.     

Synthesis of new annulated pyridazine derivatives and studying their antioxidant and antimicrobial activities

Benzil was reacted with cyanoacetohydrazide under microwave irradiation to give 3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-carbonitrile 1 which used as starting material for the synthesis of new heterocyclic compounds. Chlorination of pyridazinone 1 with POCl₃ afforded the chloro-pyridazine derivative 3, which then condensed with 2-aminothiazole or hydrazine hydrate to produce 3,4-diphenyl-5H-thiazolo[3′,2′:1,2]pyrimido[4,5-c]pyridazin-5-one 5 or 3-hydrazinyl-5,6-diphenylpyridazine-4-carbonitrile 6, respectively. New Schiff bases were obtained by condensation reactions of compound 6 with different aldehydes. On the other hand, compound 6 reacted with different carbon electrophiles naming acetyl acetone, diethyl malonate, and phenyl isothiocyanate producing new pyarazolo-pyridazine derivatives 11, 12, and 14, respectively. Chemical structures of all newly synthesized compounds were confirmed on the basis of spectral data and had been screened for antimicrobial and antioxidant activity.     

Polyphenolic contents and antioxidant activities of aerial parts of Salvia multicaulis from the Iran flora

Abstract

Folk medicine sometimes involves the use of salvia species for therapeutic purposes. Polyphenols with the highest amounts included rosmarinic acid (7.358mg/g), catechin (1.5?mg/g), vanillin (1.00?mg/g), chlorogenic acid (0.53?mg/g), quercetin (0.16?mg/g), and p-coumaric acid (0.015). Furthermore, the results showed that S. multicaulis has a high content of total phenol (4.39?mg/g) and DPPH activity (8.44?mg/g). Salvia multicaulis could be potentially used as a medicinal plant because of its antioxidant activity and polyphenol content.     

Enantioselective approach to indolizidine and quinolizidine scaffolds. Application to the synthesis of peptide mimics

An enantioselective approach to substituted indolizidine and quinolizidine frameworks has been developed. Key steps of the synthesis are the enantioselective, palladium-catalyzed N-allylation of an imide, the nucleophilic allylation of an acyliminium ion and a ring closing metathesis. This general strategy has been applied to the synthesis of indolizidine peptide mimics, starting from a chiral imide derived from l-aspartic acid. It was observed that the preexisting stereogenic center of this substrate has a moderate influence on the stereoselectivity of the electrophilic allylation, which is mainly determined by the sense of chirality of the catalyst.     

Phenolic composition,antioxidant and antinociceptive activities of Syringa vulgaris L. bark and leaf extracts

Metabolite profile, antioxidant and antinociceptive activities of Syringa vulgaris bark and leaf methanolic extracts were investigated. By means of HPLC-DAD-ESI-TOF and HPLC-DAD-ESI-MS/MS, a total of 33 phenolics were identified, including 15 secoiridoids, 6 phenylpropanoids, 3 flavonoids, 3 lignans and 6 low molecular weight phenols. Validated quantitative analysis show that syringin (2.52%) and rutin (1.13%) are the main phenolic compounds in bark and leaf, respectively. Notable radical scavenging and antinociceptive activities of the bark and leaf extracts were confirmed by in vitro DPPH^● and ABTS^●+ assays and by in vivo hot-plate method in mice, respectively. Our results could lay the scientific basic of future clinical perspectives of lilac bark and leaf.     

An efficient one-pot synthesis of coumarin-amino acid derivatives as potential anti-inflammatory and antioxidant agents

Abstract

A series of seven coumarinyl-amino acid ester conjugates have been synthesized and characterized by NMR (¹H and 13C) and mass spectra. Further, the compounds were investigated for their therapeutic applications such as anti-inflammatory and antioxidant activities. Among the synthesized compounds most of the analogs showed good efficiency compared with the standard.     

Chemical composition,antioxidant, antimicrobial and anticancer activities of the essential oil from the rhizomes of Zingiber striolatum Diels

Abstract

The chemical composition and biological activities of the essential oil (EO) from the rhizomes of Zingiber striolatum Diels were reported for the first time. Forty-five compounds were identified, and represented 95.7% of the total composition of the EO. The predominant components of the EO were β-phellandrene (24.0%), sabinene (17.3%), β-pinene (11.4%), geranyl linalool (8.6%), terpinen-4-ol (8.3%), α-pinene (5.6%) and crypton (4.5%). The EO revealed a weak DPPH and ABTS radical-scavenging activity. The EO exhibited significant antimicrobial activity with the inhibition zones (12.86–24.62?mm) and MIC (0.78–3.12?mg/mL) against Enterococcus faecalis, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans. The EO showed significant cytotoxicity against human leukemic (K562), lung cancer (A549) and prostatic carcinoma (PC-3) cell lines with the IC₅₀ values of 29.67, 48.87 and 86.05?μg/mL, respectively. Thus, the EO could be regarded as a bioactive natural product with potential for utilization in the cosmetic and pharmaceutical industry.