Inhibition Of Soybean Lipoxygenase Research Articles

A Comparative Study of in Vitro Lipoxygenase Inhibition and DPPH (1, 1-Diphenyl-2-Picrylhydrazyl) Free Radical Scavenging Activity of Silybum marianum and [Notobasis syriaca (L.) Cass.] Fruits and Linum usitatisimum Seeds

Silybum marianum and Notobasis Syriaca belong to the most widespread thorny plants in the Middle East, the Mediterranean, and large areas of Asia. Both plants are derived from the Asteraceae family, while Flax seed (Linum usitatissmum L.) is belong to the family of Linaceae.
 The aim of this study was to compare the scavenging activity of free radicals, and to evaluate the anti-inflammatory activity of the fruit in vitro compared with flax seed. Methanol and ethanol extracts were prepared and the activity of scavenging free radicals was studied using DPPH, and the anti-inflammatory activity was investigated in-vitro using soybean lipoxygenase, in comparison with quercetin and Lignin as standards.
 The fruit extract from Notobasis Syriaca has the highest capacity to scavenge free radical DPPH (IC50=22.1 μg/ml), and it has higher ability to inhibit soybean lipoxygenase in-vitro (IC50= 2.7 μg/ml) than fruit extract from Silybum marianum (IC50= 9.8 μg/ml). This study showed that Silybum marianum and Notobasis Syriaca have a high ability to scavenge free radicals; and that both plants possess anti-inflammatory properties, while the scavenging potential of free radicals expressed in terms of IC50 (μg/ml) of flax seed showed extraction with a mixture of equal volumes of diethyl ether and ethyl acetate after direct acid hydrolysis exhibited higher antioxidant capacity (IC50=22.257±0.095 μg/ml). The median inhibitory concentration (IC50) was calculated according to the LOX enzyme inhibitory method. The IC50 value of a mixture of equal volumes of diethyl ether and ethyl acetate after direct acid hydrolysis extract of flaxseeds is 73.689±0.585 μg/ml.
 As final conclusion it was found that flax seed extract has the highest anti-inflammatory activity.

Ferulic, Sinapic, 3,4-Dimethoxycinnamic Acid and Indomethacin Derivatives with Antioxidant, Anti-Inflammatory and Hypolipidemic Functionality.

A series of thiomorpholine and cinnamyl alcohol derivatives, conjugated with cinnamic acid-containing moieties, such as ferulic acid, sinapic acid and 3,4-dimethoxycinnamic acid, were synthesized and tested for their antioxidant, anti-inflammatory and hypolipidemic properties. An indomethacin ester with 2,6-di-tert-butyl-4-(hydroxymethyl)phenol was also prepared for reasons of comparison. The majority of the compounds demonstrated considerable antioxidant capacity and radical scavenging activity, reaching up to levels similar to the well-known antioxidant trolox. Some of them had an increased anti-inflammatory effect on the reduction of carrageenan-induced rat paw edema (range 17-72% at 150 μmol/kg), having comparable activity to the NSAIDs (non-steroidal anti-inflammatory drugs) used as reference. They had moderate activity in soybean lipoxygenase inhibition. All the tested compounds exhibited a significant decrease in lipidemic indices in Triton-induced hyperlipidemia in rats, whilst the most active triglycerides and total cholesterol decreased by 72.5% and 76%, respectively, at 150 μmol/kg (i.p.), slightly better than that of simvastatin, a well-known hypocholesterolemic drug, but with negligible triglyceride-lowering effect. Since our designed compounds seem to exhibit multiple pharmacological activities, they may be of use in occasions involving inflammation, oxidative stress, lipidemic deregulation and degenerative conditions.

2,9-Dimethyl-4H-oxazolo[5’,4’:4,5]pyrano[3,2-f]quinolin-4-one

The new 2,9-dimethyl-4H-oxazolo[5’,4’:4,5]pyrano[3,2-f]quinolin-4-one was successfully prepared through the three-component iodine-catalyzed reaction of n-butyl vinyl ether with the new 8-amino-2-methyl-4H-chromeno[3,4-d]oxazol-4-one. The latter was prepared by the reduction of 2-methyl-8-nitro-4H-chromeno[3,4-d]oxazol-4-one with Pd/C in a hydrogen atmosphere. The above nitro compound was synthesized by the condensation of N-(4-hydroxy-6-nitro-2-oxo-2H-chromen-3-yl)acetamide with P2O5 under microwave irradiation. The above acetamide derivative was prepared during the nitration of 2-methyl-4H-chromeno[3,4-d]oxazol-4-one with H2SO4 and KNO3. The structure of the newly synthesized compounds was confirmed by FT-IR, LC-MS, 1H-NMR, and 13C-NMR analyses. Preliminary biological tests show significant anti-lipid peroxidation activity for the title compound and the other synthesized new intermediates, as well as interesting soybean lipoxygenase inhibition for acetamide 2 (IC50 55 μM) and nitro-compound 3 (IC50 27 μM).

Synthesis, structural characterization and study of antioxidant and anti-PrPSc properties of flavonoids and their rhenium(I)–tricarbonyl complexes

This study aims at the synthesis and initial biological evaluation of novel rhenium–tricarbonyl complexes of 3,3′,4′,5,7-pentahydroxyflavone (quercetin), 3,7,4΄-trihydroxyflavone (resokaempferol), 5,7-dihydroxyflavone (chrysin) and 4΄,5,7-trihydroxyflavonone (naringenin) as neuroprotective and anti-PrP agents. Resokaempferol was synthesized from 2,2΄,4-trihydroxychalcone by H2O2/NaOH. The rhenium–tricarbonyl complexes of the type fac-[Re(CO)3(Fl)(sol)] were synthesized by reacting the precursor fac-[Re(CO)3(sol)3]+ with an equimolar amount of the flavonoids (Fl) quercetin, resokaempferol, chrysin and naringenin and the solvent (sol) was methanol or water. The respective Re–flavonoid complexes were purified by semi-preparative HPLC and characterized by spectroscopic methods. Furthermore, the structure of Re–chrysin was elucidated by X-ray crystallography. Initial screening of the neuroprotective properties of these compounds included the in vitro assessment of the antioxidant properties by the DPPH assay as well as the anti-lipid peroxidation of linoleic acid in the presence of AAPH and their ability to inhibit soybean lipoxygenase. From the above studies, it was concluded that the complexes’ properties are mainly correlated with the structural characteristics and the presence of the flavonoids. The flavonoids and their respective Re-complexes were also tested in vitro for their ability to inhibit the formation and aggregation of the amyloid-like abnormal prion protein, PrPSc, by employing the real-time quaking-induced conversion assay with recombinant PrP seeded with cerebrospinal fluid from patients with Creutzfeldt–Jakob disease. All the compounds blocked de novo abnormal PrP formation and aggregation.Graphical abstract

Polyfunctionalized α-Phenyl-tert-butyl(benzyl)nitrones: Multifunctional Antioxidants for Stroke Treatment.

Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on stroke, a more tolerable and efficient therapy for stroke is being sought that focuses on the control and scavenging of highly toxic reactive oxygen species by appropriate small molecules, such as nitrones with antioxidant properties. In this context, herein we report here the synthesis, antioxidant, and neuroprotective properties of twelve novel polyfunctionalized α-phenyl-tert-butyl(benzyl)nitrones. The antioxidant capacity of these nitrones was investigated by various assays, including the inhibition of lipid peroxidation induced by AAPH, hydroxyl radical scavenging assay, ABTS+-decoloration assay, DPPH scavenging assay, and inhibition of soybean lipoxygenase. The inhibitory effect on monoamine oxidases and cholinesterases and inhibition of β-amyloid aggregation were also investigated. As a result, (Z)-N-benzyl-1-(2-(3-(piperidin-1-yl)propoxy)phenyl)methanimine oxide (5) was found to be one of the most potent antioxidants, with high ABTS+ scavenging activity (19%), and potent lipoxygenase inhibitory capacity (IC50 = 10 µM), selectively inhibiting butyrylcholinesterase (IC50 = 3.46 ± 0.27 µM), and exhibited neuroprotective profile against the neurotoxicant okadaic acid in a neuronal damage model. Overall, these results pave the way for the further in-depth analysis of the neuroprotection of nitrone 5 in in vitro and in vivo models of stroke and possibly other neurodegenerative diseases in which oxidative stress is identified as a critical player.

Green Synthesis of Thiazolidine-2,4-dione Derivatives and Their Lipoxygenase Inhibition Activity With QSAR and Molecular Docking Studies.

Thiazolidinediones are five-membered, heterocyclic compounds that possess a number of pharmacological activities such as antihyperglycemic, antitumor, antiarthritic, anti-inflammatory, and antimicrobial. Conventional methods for their synthesis are often environmentally unacceptable due to the utilization of various catalysts and organic solvents. In this study, deep eutectic solvents were used in the synthesis of thiazolidinedione derivatives that acted as both solvents and catalysts. Initially, a screening of 20 choline chloride-based deep eutectic solvents for thiazolidinedione synthesis, via Knoevenagel condensation, was performed in order to find the most suitable solvent. Deep eutectic solvent, choline chloride, N-methylurea, was proven to be the best for further synthesis of 19 thiazolidinedione derivatives. Synthesized thiazolidinediones are obtained in yields from 21.49% to 90.90%. The synthesized compounds were tested for the inhibition of lipid peroxidation as well as for the inhibition of soy lipoxygenase enzyme activity. The antioxidant activity of the compounds was also determined by the ABTS and DPPH methods. Compounds showed lipoxygenase inhibition in the range from 7.7% to 76.3%. Quantitative structure–activity relationship model (R 2 = 0.88; Q 2 loo = 0.77; F = 33.69) for the inhibition of soybean lipoxygenase was obtained with descriptors Mor29m, G2u, and MAXDP. The molecular docking confirms experimentally obtained results, finding the binding affinity and interactions with the active sites of soybean LOX-3.

CD36 down regulation by the macrophage antioxidant 7,8-dihydroneopterin through modulation of PPAR-γ activity

CD36 is the key scavenger receptor driving the formation of cholesterol-loaded foam cells, the principal cellular component of atherosclerotic plaques. CD36 is down regulated by 7,8-dihydroneopterin, a potent superoxide and hypochlorite scavenging antioxidant generated by interferon-γ stimulated macrophages. 7,8-dihydroneopterin downregulates CD36 mRNA and protein levels so inhibiting macrophage foam cell formation in vitro. We examined the mechanism of 7,8-dihydroneopterin downregulation of CD36 by measuring CD36 and PPAR-γ levels by Western blot analysis, in the monocyte-like U937 cells with a range of PPAR-γ stimulants and inhibitors. Lipoxygenase activity was measured by monitoring linoleic acid oxidation at 234 nm for diene formation. Between 100 and 200 μM, 7,8-dihydroneopterin decreased CD36 levels by 50% within 12 h with levels dropping below 25% by 24 h. CD36 levels returned to basal levels after 24 h. Inhibition of protein synthesis by cycloheximide shows 7,8-dihydroneopterin had no effect on CD36 degradation rates. PPAR-γ levels were not altered by the addition of 7,8-dihydroneopterin. MAP Kinase, P38 and NF-κB pathways inhibitors SP600125, PD98059, SB202190 and BAY 11-7082, respectively, did not restore the CD36 levels in the presence of 7,8-dihydroneopterin. The addition of the lipophilic PPAR-γ activators rosiglitazone and azelaoyl-PAF prevented the CD36 downregulation by 7,8-dihydroneopterin. 7,8-dihydroneopterin inhibited soybean lipoxygenase and reduced U937 cell basal levels of cellular lipid oxides as measured by HPLC-TBARS analysis. The data show 7,8-dihydroneopterin down regulates CD36 expression by decreasing the level of lipid oxide stimulation of PPAR-γ promotor activity, potentially through lipoxygenase inhibition.

Discovery of benzothiazole-based thiazolidinones as potential anti-inflammatory agents: anti-inflammatory activity, soybean lipoxygenase inhibition effect and molecular docking studies

ABSTRACT Despite the greatest achievement in the development of anti-inflammatory agents in the last two decades, the current clinical drugs suffer from a variety of complications in community settings and hospital. There is still an urgent need to design novel molecules with better safety profile and with different molecular targets from those in current clinical use. The aim of this research was to discover a series of benzothiazole-based thiazolidinones with lipoxygenase (LOX) inhibitory activity as a mechanism of anti-inflammatory action. Carrageenan-induced mouse foot paw oedema assay was carried out to determine the anti-inflammatory activity, while LOX inhibition was examined through the conversion of sodium linoleate to 13-hydroperoxylinoleic acid. Molecular docking studies were performed using AutoDock 4.2 software. The anti-inflammatory activity of the title compounds was determined in a range of 18.4%-69.57%, where compound #3 was found to be the most potent (69.57%) and also to be more active than the reference drug indomethacin (47%). Moreover, compound #3 showed the highest LOX inhibitory activity with IC50 of 13 μM being less potent to that of the reference NDGA (IC50 = 1.3 μM). Compound #3 has been identified as lead compound for further modification in an attempt to improve anti-inflammatory and LOX inhibitory activities.

A comparative study of in vitro lipoxygenase inhibition and DPPH (1, 1-Diphenyl-2-Picrylhydrazyl) free radical scavenging activity of Silybum marianum and [Notobasis syriaca (L.) Cass.] Fruits

Silybum marianum and Notobasis Syriaca belong to the most widespread thorny plants in the Middle East, the Mediterranean, and large areas of Asia. Both plants are derived from the Asteraceae family. The aim of this study was to compare the phytochemical content of the two plants, the scavenging activity of free radicals, and to evaluate the anti-inflammatory activity of their fruit extracts in vitro. Methanol extracts of the fruits were prepared from both plants. The activity of scavenging free radicals was studied using DPPH, and the anti-inflammatory activity was investigated in-vitro using soybean lipoxygenase, in comparison with quercetin as standard. The qualitative phytochemical screening of the fruits showed that both plants contained flavonoids, and coumarins. Both plants showed negative results with alkaloids, saponins, and anthraquinone. The fruit extract from Notobasis Syriaca has the highest capacity to scavenge free radical DPPH (IC50=22.1 mcg/mL), and it has higher ability to inhibit soybean lipoxygenase in-vitro (IC50= 2.7 mcg/mL) than fruit extract from Silybum marianum (IC50= 9.8 mcg/mL). This study showed that Silybum marianum and Notobasis Syriaca have a high ability to scavenge free radicals; and that both plants possess anti-inflammatory properties.

Pd-Catalyzed N–H or C–H Functionalization/Oxidative Cyclization for the Efficient Synthesis of N-Aryl-Substituted [3,4]-Fused Pyrrolo­coumarins

Abstract1-Aryl-2-methyl- or 3-methylchromeno[4,3-b]pyrrol-4(1H)-ones have been synthesized in excellent yields by the Pd-catalyzed intramolecular aza-Wacker-type cyclization of 3-allyl-4-arylaminocoumarins or C–H insertion/oxidative cyclization of N-allyl-N-aryl-4-aminocoumarins, respectively, in the presence of Cu(OAc)2 in acetic acid under heating. The starting allylcoumarins have been prepared by the allylation of 4-arylaminocoumarins with allyl bromide in CH3CN in the presence of Cs2CO3 at room temperature. Preliminary biological tests indicated interesting antioxidant activity and significant levels of inhibition of soybean lipoxygenase.

Chemical Evaluation, Antioxidant, Antiproliferative, Anti-Inflammatory and Antibacterial Activities of Organic Extract and Semi-Purified Fractions of the Adriatic Sea Fan, Eunicella cavolini.

Due to sedentary lifestyle and harsh environmental conditions, gorgonian coral extracts are recognized as a rich source of novel compounds with various biological activities, of interest to the pharmaceutical and cosmetic industries. The presented study aimed to perform chemical screening of organic extracts and semi-purified fractions obtained from the common Adriatic gorgonian, sea fan, Eunicella cavolini (Koch, 1887) and explore its abilities to exert different biological effects in vitro. Qualitative chemical evaluation revealed the presence of several classes of secondary metabolites extended with mass spectrometry analysis and tentative dereplication by using Global Natural Product Social Molecular Networking online platform (GNPS). Furthermore, fractions F4 and F3 showed the highest phenolic (3.28 ± 0.04 mg GAE/g sample) and carotene (23.11 ± 2.48 mg β-CA/g sample) content, respectively. The fraction F3 inhibited 50% of DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) and ABTS (2,2′-azino-bis (3-ethylbenzthiazolin-6-yl) sulfonic acid) radicals at the concentrations of 767.09 ± 11.57 and 157.16 ± 10.83 µg/mL, respectively. The highest anti-inflammatory potential was exhibited by F2 (IC50 = 198.70 ± 28.77 µg/mL) regarding the inhibition of albumin denaturation and F1 (IC50 = 254.49 ± 49.17 µg/mL) in terms of soybean lipoxygenase inhibition. In addition, the most pronounced antiproliferative effects were observed for all samples (IC50 ranging from 0.82 ± 0.14–231.18 ± 46.13 µg/mL) against several carcinoma cell lines, but also towards non-transformed human fibroblasts pointing to a generally cytotoxic effect. In addition, the antibacterial activity was tested by broth microdilution assay against three human pathogenic bacteria: Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The latter was the most affected by fractions F2 and F3. Finally, further purification, isolation and characterization of pure compounds from the most active fractions are under investigation.

Anti-inflammatory, antibacterial and antioxidant activities of Chenopodium ambrosioides L. (Chenopodiaceae) extracts

Objective: Chenopodium ambrosioides is an aromatic plant widely used in the Togolese traditional medicine. However, little is known about its pharmacological properties. The present study aimed to investigate the anti-inflammatory, antibacterial and antioxidant activities of its extracts. Methodology and results: Thus, an ethnopharmacological survey was undertaken in Kara town in the northern part of Togo to assess the main uses in the traditional medicine and Gas Chromatography coupled with Mass Spectral Analysis (GC-MS) was used to identify several compounds in the extracts. Antioxidant activity was evaluated by FRAP, ABTS, DPPH methods. Anti-inflammatory and antimicrobial activities were assessed by soybean lipoxygenase inhibition and in vitro broth micro dilution techniques, respectively. Propidium iodide cell death was evaluated by flow cytometry and in vivo toxicity was assessed using wistar rats. The ethnopharmacological survey revealed that traditional healers use C. ambrosioides to treat malaria, intestinal worms and inflammation in addition to healing wounds. The hydroethanolic extract had high content of total phenols (324.80±17.30 µgEAG/mg) and flavonoids (63.20±8.70 µgEQ/mg), however the highest antioxidant, antimicrobial and antiinflammatory activities were obtained with the essential oil. GC-MS analysis leads to identification of hydrocarbon monoterpenes such as 2carene, ortho-cymene and α-terpinene as the major components of the essential oil. All the tested extracts induced cell death (14.60 ± 9.23% at 2 µL/mL, 72.64 ± 15.92% at 200µL/mL and 89.50 ± 7.16 at 100 mg/mL for essential oil, hydrosol and hydroethanolic extract, respectively). Conclusion and application of results. The present study demonstrated various pharmacological activities of hydroethanolic extract, essential oil and hydrosol of leaves of Chenopodium ambrosioides. The essential oil had antioxidant, antimicrobial and antiinflammatory activities and could be the most active component of the leaves of Chenopodium ambrosioides. Our findings highlighted perspectives for the discovery of new medicinal molecules derived from plant extrats and confirmed certain practices of traditional healers. Keywords: Chenopodium ambrosioides, extract, pharmacological activities

Hydroxylated 3-(pyridin-2-yl)coumarins as radical scavengers with potent lipoxygenase inhibitor activity

Hydroxylated 3-(pyridin-2-yl)coumarins show radical scavenging activity and are able to inhibit soybean lipoxygenase.

Antioxidant Profile of Home Prepared Taraxacum Officinale Weber Ex Wigg Beverage

Background: Aromatic plants are quite popular for daily use worldwide. However, little is known about the appropriate preparation of beverages in “house conditions” in order to preserve their beneficial characteristics after processing. Taraxacum officinale Weber ex Wigg contains a variety of compounds, with well-documented effects against oxidative stress. This study aims to investigate the optimum preparation conditions of a Taraxacum beverage in the household setting, with respect to its antioxidant characteristics. Methods: Dried, commercial T. officinale was used to prepare beverages boiling for 1, 3 or 5 min. The beverages were extracted using organic solvents of increasing polarity, and the solid residues of each extraction were examined by in vitro analysis on: the evaluation of total phenolic content (Folin Ciocalteau), the evaluation of antioxidant activity (DPPH and ABTS radicals scavenging), the evaluation of the ability of the tested extracts to compete with DMSO for OH radicals, the ability to inhibit lipid peroxidation of linoleic acid and soybean lipoxygenase inhibition assay. Results: All preparations had an overall good antioxidant profile. Regarding the chosen solvents, mid polarity solvents were more likely to give better results in all tests conducted, which can be indicative of the compounds extracted in each fraction. Samples prepared under 3 min boiling presented significant interaction with DPPH and strong lipoxygenase and lipid peroxidation inhibition. Conclusion: As previously observed in the literature, food processing can greatly affect its biochemical characteristics. In the case of Taraxacum, boiling for 3 min resulted in the best overall profile of the beverage with respect to its antioxidant properties. However, due to a variety of components present in each plant, further investigation and stratification, along with in vivo experiments are needed.

Substituted pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines - a promising class of lipoxygenase inhibitors

The modern strategy of potential biologically active molecules search (“drug-design”) is based on several innovation approaches. The method of high thrоughрut biological screening and method of molecular modeling deserves the most attention among such approaches. Lipoxygenase (LOX) is one owf the most perspective biological target for the substituted pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines. So, molecular docking towards LOX and enzyme activating activity was investigated.The aim: Directed search of potential inhibitors of lipoxygenases among the unknown pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines with the use of molecular docking and in vitro high throughput screening.Materials and methods. The research of lipoxygenase activity has been conducted for a number of original pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines. Standard software was used for molecular docking and “drug-like” criteria research. Sodium letinate was used as a substrate to study soybean LOX enzyme activating activity.Results. The results of molecular docking have shown, that substituted pyrrolo[1,2-a][1,2,4]triazolo[1,5-c]quinazolines reveal a strong affinity toward LOX. The main types of interactions with aminoacid residues of mentioned the enzyme were identified. The conducted researches showed, that the substituted pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolines had the highest soybean LOX inhibition activity. Compounds with a fluorine atom and a 2-thienyl moiety in the structure revealed the highest activity inhibiting lipoxygenase by 36.33 % and 39.83 % respectively. The increased lipophilicity of triazine derivatives promotes a higher ability to inhibit soybean LOX, whereas, for triazole derivatives, which have lower molecular weight, an inverse relation is observed.Conclusions. The research of the substituted pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines inhibition ability of soybean LOX as one of the possible mechanisms of their activity is proved and conducted. It is shown, that their lipoxygenase activity depends on lipophilicity and is defined by the availability of donor-acceptor fragments in the molecule, that is capable to form hydrogen and other types of interaction. The specified results are strong arguments for their further study as promising anti-inflammatory agents.

Multi-Target Cinnamic Acids for Oxidative Stress and Inflammation: Design, Synthesis, Biological Evaluation and Modeling Studies.

Inflammation is a complex phenomenon that results as a healing response of organisms to different factors, exerting immune signaling, excessive free radical activity and tissue destruction. Lipoxygenases and their metabolites e.g., LTB4, are associated with allergy, cell differentiation and carcinogenesis. Lipoxygenase 12/15 has been characterized as a mucosal-specific inhibitor of IgA and a contributor to the development of allergic sensitization and airway inflammation. Development of drugs that interfere with the formation or effects of these metabolites would be important for the treatment of various diseases like asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders. In this study we extended our previous research synthesizing a series of multi-target cinnamic acids from the corresponding aldehydes with suitable 4-OH/Br substituted phenyl acetic acid by Knoevenagel condensation. The final products 1i, 3i, 3ii, 4i, 6i, 6ii, and 7i were obtained in high yields (52–98%) Their structures were verified spectrometrically, while their experimentally lipophilicity was determined as RM values. The novel derivatives were evaluated for their antioxidant activity using DPPH, hydroxyl radical, superoxide anion and ABTS+•, anti-lipid peroxidation and soybean lipoxygenase inhibition assays. The compounds presented medium interaction with DPPH (30–48% at 100 µM). In contrast all the synthesized derivatives strongly scavenge OH radicals (72–100% at 100 µM), ABTS+• (24–83% at 100 µM) and presented remarkable inhibition (87–100% at 100 µM) in linoleic acid peroxidation (AAPH). The topological polar surface of the compounds seems to govern the superoxide anion scavenging activity. Molecular docking studies were carried out on cinnamic acid derivative 3i and found to be in accordance with experimental biological results. All acids presented interesting lipoxygenase inhibition (IC50 = 7.4–100 µM) with compound 3i being the most potent LOX inhibitor with IC50 = 7.4 µM combining antioxidant activities. The antioxidant results support the LOX inhibitory activities. The recorded in vitro results highlight compound 3i as a lead compound for the design of new potent lipoxygenase inhibitors for the treatment of asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders.

Mononuclear copper(II) complexes with 2-thiophene carboxylate and N-N donors; DNA interaction, antioxidant/anti-inflammatory and antitumor activity

Redox-active compounds such as copper-phenanthroline are known as artificial/chemical nucleases with a great impact and potential for their applications as metallotherapeutics. In that vein, the mononuclear copper(II) complexes [Cu(L)2(bipy)] (1), [Cu(L)2(bipy)(H2O)] (2) and [Cu(L)2(phen)(H2O)] (3), where L = 2-thiophene carboxylate, bipy = 2,2΄-bipyridine and phen = 1,10-phenanthroline, have been prepared and pharmacochemically studied, while the crystal structure of 1 is also reported. All the tested complexes preferably bind to CT-DNA via minor groove as resulted from UV spectroscopy studies, luminescent titration, EB competition assays and viscosity measurements. Complexes 2 and 3 in aqua behave like a “light switch” for DNA. The intensity enhancement, with the increase of DNA concentration, reached about 3–fold for 2 and 10-fold for 3. In vitro antioxidant activity of compounds 1–3, was evaluated using two different antioxidant assays: a) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical and b) inhibition of lipid peroxidation. Moreover, their inhibitory activity on soybean lipoxygenase (LOX) was evaluated for their anti-inflammatory potency. The tested complexes showed good activity on both lipid peroxidation and soybean LOX inhibition while complex 2 exhibited the best antioxidant/anti-inflammatory activity. A computational analysis over the LOX protein structure 1JNQ was performed, in an effort to support their possible mode of action. The cytotoxicity of the complexes was determined and their efficacy against several human cancer cell lines (ovarian, OAW-42; lung, A549; colon, HT29; breast, MDA-MB-231; kidney, Caki-2; and cervical, Hela) and human non-tumor cell lines (lung, MRC-5; and breast, MTSV1-7) were evaluated. The best cytotoxic activity was appeared for complex 3. In silico, computational methods support antiestrogen activity of the administered complexes on normal breast cells.

Dicoumarol derivatives: Green synthesis and molecular modelling studies of their anti-LOX activity

Dicoumarol derivatives were synthesized in the InCl3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV–Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84–97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC50 = 52.5 µM) and 3i somewhat lower activity (IC50 = 55.5 µM). The bioactive conformations of the best LOX-Ib inhibitors were obtained by means of molecular docking and molecular dynamics. It was shown that, within the bioactive conformations interior to LOX-Ib active site, the most active compounds form the pyramidal structure made of two 4-hydroxycoumarin cores and a central phenyl substituent. This form serves as a spatial barrier which prevents LOX-Ib Fe2+/Fe3+ ion activity to generate the coordinative bond with the C13 hydroxyl group of the α-linoleate. It is worth pointing out that the most active compounds 3b, 3e, 3h and 3i can be candidates for further examination of their in vitro and in vivo anti-inflammatory activity and that molecular modeling study results provide possibility to screen bioactive conformations and elucidate the mechanism of dicoumarols anti-LOX activity.

One-pot Synthesis of 2-Substituted 4H-Chromeno[3,4-d]oxazol-4-ones from 4-Hydroxy-3-nitrocoumarin and Acids in the Presence of Triphenylphosphine and Phosphorus Pentoxide under Microwave Irradiation

2-Substituted 4H-chromeno[3,4-d]oxazol-4-ones are prepared from 4-hydroxy-3-nitrocoumarin and acids by one-pot reaction in the presence of PPh3 and P2O5 under microwave irradiation or by one-pot two-step reactions in the presence of Pd/C and hydrogen and then P2O5 under microwave irradiation. The fused oxazolocoumarins were also synthesized from 3-amido-4-hydroxycoumarins and P2O5 under microwave irradiation. The 3-amido-4-hydroxycoumarins are obtained almost quantitatively from 4-hydroxy-3-nitrocoumarin, acids and PPh3 under microwave irradiation, or in the presence of Pd/C and H2 on heating. Preliminary biological tests indicate significant inhibition of soybean lipoxygenase and antilipid peroxidation for both oxazolocoumarins and o-hydroxyamidocoumarins.

Antioxidant Activity and Chemical Composition of Essential Oils of some Aromatic and Medicinal Plants from Albania

The chemical compositions have been investigated of the volatile oils of nine populations of six species from Albania, namely Artemisia absinthium, Calamintha nepeta, Hypericum perforatum, Sideritis raeseri subsp. raeseri, Origanum vulgare subsp. hirtum from two wild .populations, and Salvia officinalis (sage) from two wild and one cultivated population,. The essential oils were obtained by hydrodistillation and their analyses were performed by GC-MS. The major constituents were: A. absinthium: neryl isovalerate (19.5%), geranyl isobutanoate (16.4%) and carvacrol (8.8%); C. nepeta: pulegone (31.7%), spathulenol (20.0%) and isomenthone (12.7%); H. perforatum: caryophyllene oxide (31.0%), δ-selinene (10.5%) and carvacrol (10.4%); O. vulgare: carvacrol (81.0, 78.6%), y-terpinene (5.5, 7.1%) and p-cymene (4.9, 4.1%) for 0. vulgare originating from Tepelena. and.Vlora, respectively; S. raeseri: carvacrol (36.7%), caryophyllene oxide (17.8%), p-caryphyllene (8.7%), spathulenol (7.7%) and myrtenol (6.4%); S. officinalis: camphor (40.2, 47.8, 45.9%), c-thujone .(19.2, 22.2, 13.7%), eucalyptol (5.4, 2.6, 6.0%), camphene (5.8, 6.1, 3.9, %), borneol (2.1, 2.9, 5.7%) and bornyl acetate (3.3, 1.4, 5.6%) for samples originating from Tepelena, Tirana and Vlora, respectively. The essential oils were also tested for their free radical scavenging activity using the following in vitro assays: i) interaction with the free stable radical of DPPH (1,1-diphenyl-2-picrylhydrazyl), and ii) inhibition of linoleic acid-peroxidation with 2,2'-azobis- 2-methyl-propanimidamide, dihydrochloride (AAPH). Finally, their inhibitory activity toward soybean lipoxygenase was evaluated, using linoleic acid as substrate.The essential oil of 0. vulgare (OV-VL) presented the highest interaction with the stable radical DPPH (76.5%), followed by that of A. absinthium (54.7%). O. vulgare (OV-TP) and A. absinthium showed high anti-lipid peroxidation activity, 97.5% and 96.5%, respectively, higher than that of the reference compound trolox (73.0%). Only the tested sample of O. vulgare (OV-VL) significantly inhibited soybean lipoxygenase (54.2%).