Action of Thioglycosides of 1,2,4-Triazoles and Imidazoles on the Oxidative Stress and Glycosidases in Mice with Molecular Docking

Background: ,2,3-Triazoles and imidazoles are important five-membered heterocyclic scaffolds due to their extensive biological activities. These products have been an area of growing interest to many researchers around the world because of their enormous pharmaceutical scope. Methods: The in vivo and in vitro enzyme inhibition of some thioglycosides encompassing 1,2,4- triazole N1, N2, and N3 and/or imidazole moieties N4, N5, and N6. The effect on the antioxidant enzymes (superoxide dismutase, glutathione S-transferase, glutathione peroxidase and catalase) was investigated as well as their effect on α-glucosidase and β-glucuronidase. Molecular docking studies were carried out to investigate the mode of the binding interaction of the compounds with α- glucosidase and β -glucuronidase. In addition, quantitative structure-activity relationship (QSAR) investigation was applied to find out the correlation between toxicity and physicochemical properties. Results: The decrease of the antioxidant status was revealed by the in vivo effect of the tested compounds. Furthermore, the in vivo and in vitro inhibitory effects of the tested compounds were clearly pronounced on α-glucosidase, but not β-glucuronidase. The IC50 and Ki values revealed that the thioglycoside - based 1,2,4-triazole N3 possesses a high inhibitory action. In addition, the in vitro studies demonstrated that the whole tested 1,2,4-triazole are potent inhibitors with a Ki magnitude of 10-6 and exhibited a competitive type inhibition. On the other hand, the thioglycosides - based imidazole ring showed an antioxidant activity and exerted a slight in vivo stimulation of α-glucosidase and β- glucuronidase. Molecular docking proved that the compounds exhibited binding affinity with the active sites of α -glucosidase and β-glucuronidase (docking score ranged from -2.320 to -4.370 kcal/mol). Furthermore, QSAR study revealed that the HBD and RB were found to have an overall significant correlation with the toxicity. Conclusion: These data suggest that the inhibition of α-glucosidase is accompanied by an oxidative stress action.

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1'-methylspiro[indoline-3,4'-piperidine] Derivatives: Design, Synthesis, Molecular Docking and Anti-tumor Activity Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201117150714 ◽

2020 ◽

Vol 17 ◽

Author(s):

Junjian Li ◽

Lianbao Ye ◽

Yuanyuan Wang ◽

Ying Liu ◽

Xiaobao Jin ◽

...

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Active Sites ◽

Biological Activities ◽

Significant Inhibition ◽

Alkaline Condition ◽

Discovery Studio ◽

Hela Cell Lines ◽

Antiproliferative Activities

Background: Spirocyclic indoline compounds widely exist in numerous natural products with good biological activities and some drug molecules in many aspects. In recent years, it has attracted extensive attention as potent anti-tumor agents in the fields of pharmacology and chemistry. Objective: In this study, we focused on designing and synthesizing a set of novel 1'-H-spiro[indole-3,4'-piperidine] derivatives, which were evaluated by preliminary bioactivity experiment in vitro and molecular docking. Method: The key intermediate 1'-methylspiro[indoline-3,4'-piperidine] (B4) reacted with benzenesulfonyl chloride with different substituents under alkaline condition to obtain its sulfonyl derivatives (B5-B10). We evaluated their antiproliferative activities against A549, BEL-7402 and HeLa cells by MTT assay. We performed the CDOCKER module in Discovery Studio 2.5.5 software for molecular modeling of compound B5, and investigated the binding of compound B5 with the target proteins from PDB database. Results: The results indicated that compounds B4-B10 exhibited good antiproliferative activities against the above three types of cells, in which compound B5 with chloride atom as electron-withdrawing substituent on a phenyl ring showed the highest potency against BEL-7402 cells (IC50=30.03±0.43 μg/mL). By binging of the prominent bioactive compound B5 to CDK, c-Met, EGFR protein crystals, The binding energy of B5 with these three types receptors are -44.3583 kcal/mol, - 38.3292 kcal/mol, -33.3653 kcal/mol respectively. Conclusion: Six 1'-methylspiro[indoline-3,4'-piperidine] derivatives were synthesized and evaluated against BEL-7402, A- 549, HeLa cell lines. Compound B5 showed significant inhibition on BEL-7402 cell lines. Molecular docking revealed that B5 showed good affinity by the good fitting between B5 and these three targets with amino acid residues in active sites which encourage us to conduct further evaluation such as the kinase experiment.

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Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00979-y ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Kecheng Lei ◽

Xiaoxia Gu ◽

Alvaro G. Alvarado ◽

Yuhong Du ◽

Shilin Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Crystal Structures ◽

Active Sites ◽

Redox Homeostasis ◽

Growth Factor Receptor ◽

Quinone Oxidoreductase ◽

Cancer Proliferation ◽

Dual Inhibitor

Abstract Background Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. Methods High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. Results We identified a small molecular inhibitor, “MNPC,” that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. Conclusions Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.

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Baru Pulp (Dipteryx alata Vogel): Fruit from the Brazilian Savanna Protects against Oxidative Stress and Increases the Life Expectancy of Caenorhabditis elegans via SOD-3 and DAF-16

Biomolecules ◽

10.3390/biom10081106 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1106

Author(s):

Natasha Rios Leite ◽

Laura Costa Alves de Araújo ◽

Paola dos Santos da Rocha ◽

Danielle Araujo Agarrayua ◽

Daiana Silva Ávila ◽

...

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Life Expectancy ◽

Biological Activities ◽

Radical Scavenging ◽

Brazilian Savanna ◽

Beneficial Effects ◽

Dipteryx Alata

Fruits are sources of bioactive compounds that are responsible for several biological activities. Therefore, this study aimed to identify the chemical composition of the pulp of the Brazilian Savanna fruit Dipteryx alata; evaluate its toxic effects, influence on the life expectancy of the nematode Caenorhabditis elegans, and its antioxidant activities in vitro and in vivo; and describe the mechanisms involved. The chemical compounds identified include phenols, terpenes, fatty acid derivatives, vitamins, and a carboxylic acid. The in vitro antioxidant activity was demonstrated by radical scavenging methods. in vivo, the D. alata fruit pulp was not toxic and promoted resistance to oxidative stress in nematodes exposed to a chemical oxidizing agent. Furthermore, it promoted an increased life expectancy in wild-type nematodes and increased the expression of superoxide dismutase and the nuclear translocation of DAF-16. These results suggest that the beneficial effects identified are related to these two genes, which are involved in the regulation of metabolic activities, the control of oxidative stress, and the lifespan of C. elegans. These beneficial effects, which may be related to its chemical constituents, demonstrate its potential use as a functional and/or nutraceutical food.

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Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/3640753 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Youngmun Lee ◽

Sunyoung Kim ◽

Yeonsoo Oh ◽

Young-Mi Kim ◽

Young-Won Chin ◽

...

Keyword(s):

Oxidative Stress ◽

Memory Impairment ◽

Neuronal Damage ◽

Biological Activities ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ros Generation ◽

Garcinia Mangostana

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer’s disease.

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Investigation of biological activities of Colocasia gigantea Hook.f. leaves and PASS prediction, in silico molecular docking with ADME/T analysis of its isolated bioactive compounds

10.1101/2020.05.18.101113 ◽

2020 ◽

Author(s):

Safaet Alam ◽

Nazim Uddin Emon ◽

Mohammad A. Rashid ◽

Mohammad Arman ◽

Mohammad Rashedul Haque

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

In Silico ◽

Castor Oil ◽

Biological Activities ◽

Kappa Opioid Receptor ◽

Soluble Extract ◽

Docking Score

AbstractBackgroundColocasia gigantea is locally named as kochu and also better known due to its various healing power. This research is to investigate the antidiarrheal, antimicrobial, and antioxidant possibilities of the methanol soluble extract of Colocasia gigantea.MethodsAntidiarrheal investigation was performed by using in vivo castor oil induced diarrheal method where as in vitro antimicrobial and antioxidant investigation have been implemented by disc diffusion and DPPH scavenging method respectively. Moreover, in silico studies were followed by molecular docking analysis of several secondary metabolites were appraised with Schrödinger-Maestro v 11.1.ResultsThe induction of plant extract (200 and 400 mg/kg, b.w, p.o), the castor oil mediated diarrhea has been minimized 19.05 % (p < 0.05) and 42.86 % (p < 0.001) respectively. The methanolic extract of C. gigantea showed mild sensitivity against almost all the tested strains but it shows high consistency of phenolic content and furthermore yielded 67.68 μg/mL of IC50 value in the DPPH test. The higher and lower binding affinity was shown in beta-amyrin and monoglyceryl stearic acid against the kappa-opioid receptor (PDB ID: 4DJH) with a docking score of -3.28 kcal/mol and -6.64 kcal/mol respectively. In the antimicrobial investigation, Penduletin and Beta-Amyrin showed the highest and lowest binding affinity against the selected receptors with the docking score of -8.27 kcal/mol and -1.66 kcal/mol respectively.ConclusionThe results of our scientific research reflect that the methanol soluble extract of C. gigantea is safe which may provide possibilities of alleviation of diarrhea and as a potential wellspring of antioxidants which can be considered as an alternate source for exploration of new medicinal products.

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Anti-Hyperglycaemic Evaluation of Buddleia indica Leaves Using In Vitro, In Vivo and In Silico Studies and Its Correlation with the Major Phytoconstituents

Plants ◽

10.3390/plants10112351 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2351

Author(s):

Sameh S. Elhady ◽

Fadia S. Youssef ◽

Abdulrahman M. Alahdal ◽

Diena M. Almasri ◽

Mohamed L. Ashour

Keyword(s):

Active Sites ◽

Biological Activities ◽

Serum Insulin ◽

Ethyl Acetate Fraction ◽

In Vivo Studies ◽

Stress Markers ◽

In Silico Studies ◽

Streptozotocin Induced Diabetes

Buddleia indica Lam. is an ornamental evergreen shrub with few reports concerning its phytoconstituents and biological activities. Herein, the antihyperglycaemic activity of B. indica leaves methanol extract (BIT) was evaluated for the first time using in vitro and in vivo studies. Molecular modelling was performed for its major phytoconstituents that were further subjected to ADME/TOPAKT (absorption, distribution, metabolism, excretion and toxicity) prediction. BIT revealed considerable reduction in glucose concentration by 9.93% at 50 μg/mL using 3T3-L1 adipocyte culture. It displayed substantial inhibition versus α-glucosidase and α-amylase with IC50 205.2 and 385.06 μg/mL, respectively. In vivo antihyperglycaemic activity of BIT and the ethyl acetate fraction (BIE) was performed using streptozotocin-induced diabetes in rat model. BIT and BIE effectively ameliorate oxidative stress markers in addition to reducing serum blood glucose by 56.08 and 54.00%, respectively, and are associated with a substantial increase in serum insulin by 4.1 and 12.7%, respectively. This can be attributed to its richness with polyphenolic compounds comprising flavonoids, phenolic acids, phenyl propanoids and iridoids. Molecular docking showed that verbascoside and kaempferol displayed the highest fitting within human α-amylase (HA) and human α-glucosidase (HG) active sites, respectively. They showed reasonable pharmacokinetic, pharmacodynamic and toxicity properties, as revealed by ADME/TOPKAT study.

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Molecular Docking and Preclinical Study of Five-MemberedS,S-Palladaheterocycle as Hepatoprotective Agent

Advanced Pharmaceutical Bulletin ◽

10.15171/apb.2019.079 ◽

2019 ◽

Vol 9 (4) ◽

pp. 674-684 ◽

Cited By ~ 1

Author(s):

Nail Salavatovich Akhmadiev ◽

Albina Midkhatovna Galimova ◽

Vnira Rakhimovna Akhmetova ◽

Veronika Radievna Khairullina ◽

Rozaliia Akramovna Galimova ◽

...

Keyword(s):

Molecular Docking ◽

Survival Data ◽

Active Sites ◽

Cytochromes P450 ◽

Hepatoprotective Activity ◽

Preclinical Study ◽

Therapeutic Effects ◽

Preclinical Trials

Purpose: In order to investigate mechanisms underlying the hepatoprotective action of S,Spalladaheterocycle,inhibition of cytochromes P450 has been modeled by molecular dockingof four palladaheterocycle stereoisomers to the active sites of an enzymatic oxidase system. Toobtain a deeper insight into biochemical aspects providing a basis for the therapeutic effects offive-membered palladacycles (as mixture of stereoisomers), a number of preclinical trials hasbeen conductedMethods: 2D and 3D structures of palladaheterocycle stereoisomers were obtained viaconverting into SDF files by means of software MarvinSketch. Binding of palladaheterocycle atthe active sites of cytochromes P450 2E1 and P450 2C9 has been studied by molecular dockingusing LeadIT 2.3.2. Hepatoprotective activity of palladaheterocycle at 2.5, 25 and 250 mg/kgdoses has been studied based on a model of acute intoxication by CCl4 using in vivo methods.Results: By molecular docking it was identify amino acid fragments responsible for bindingwith palladacyclic isomers. The tested compound is comparable, in terms of its activity tothe hepatoprotective drug SAM according to the in vivo and in vitro experiments such asanimal survival data, the efficiency of correction of the cytolytic syndrome, the liver excretoryfunction, carbohydrate, protein and lipid metabolism, and the correction efficiency of the liverantitoxic function (the latter has been determined based on the results of a hexobarbital controlexperiment).Conclusion: Taking into account results obtained in vivo, in vitro and in silico, it can be concludedthat the five-membered S,S-palladaheterocycle effectively protect the liver against acute damagecaused by CCl4, via activation of catalase and glucuronyltransferase, as well as via inhibition ofthe oxidative stress enzymes.<br />

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Protein Hydrolysates from Anchovy (Engraulis encrasicolus) Waste: In Vitro and In Vivo Biological Activities

Marine Drugs ◽

10.3390/md18020086 ◽

2020 ◽

Vol 18 (2) ◽

pp. 86 ◽

Cited By ~ 4

Author(s):

Alessia Giannetto ◽

Emanuela Esposito ◽

Marika Lanza ◽

Sabrina Oliva ◽

Kristian Riolo ◽

...

Keyword(s):

Oxidative Stress ◽

Biological Activities ◽

Protein Hydrolysates ◽

Bioactive Molecules ◽

Nutritional Properties ◽

Fish Waste ◽

In Vivo Models ◽

Engraulis Encrasicolus

Fish waste utilization to obtain protein hydrolysates has been demonstrated to be a useful strategy to face both environmental and economic impacts while obtaining high-value products with remarkable biological and nutritional properties. In the present study, protein hydrolysates obtained from anchovy Engraulis encrasicolus (APH) by-products were assessed for their potential biological activities in both in vitro and in vivo models. The treatment with APH exerted a significant protection against LPS-induced inflammation in RAW 264.7 cells, decreasing the protein expression of pro-inflammatory mediators (i.e., COX-2) and inhibiting the nuclear translocation of NF-κB through IκB-α. Moreover, APH modulated the expression of iNOS, MnSOD and HO-1, thus decreasing the severity of oxidative stress. The supplementation of APH in the diet of ApoE knockout mice down-regulated the proinflammatory cytokines (i.e., TNF-α, IL-1α, IL-1β, IL-6) in both aorta and heart tissues, and modulated the expression of oxidative stress-related genes (Cu/ZnSod, MnSod, Cat, Gpx and Ho), indicating that APH can exert a beneficial role, having anti-inflammatory and antioxidant activities. The nutritional properties of APH, together with their biological activities herein reported, highlight the possibility of obtaining bioactive molecules from fish waste and encourage their use as potential nutraceuticals in food and pharmaceutical industries in the next future.

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Insight into the Influence of Cultivar Type, Cultivation Year, and Site on the Lignans and Related Phenolic Profiles, and the Health-Promoting Antioxidant Potential of Flax (Linum usitatissimum L.) Seeds

Molecules ◽

10.3390/molecules23102636 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2636 ◽

Cited By ~ 11

Author(s):

Laurine Garros ◽

Samantha Drouet ◽

Cyrielle Corbin ◽

Cédric Decourtil ◽

Thibaud Fidel ◽

...

Keyword(s):

Oxidative Stress ◽

Biological Activities ◽

Yeast Cells ◽

In Vivo Studies ◽

Major Influence ◽

Antioxidant Power ◽

Accumulation Pattern ◽

The Impact

Flaxseeds are a functional food representing, by far, the richest natural grain source of lignans, and accumulate substantial amounts of other health beneficial phenolic compounds (i.e., flavonols, hydroxycinnamic acids). This specific accumulation pattern is related to their numerous beneficial effects on human health. However, to date, little data is available concerning the relative impact of genetic and geographic parameters on the phytochemical yield and composition. Here, the major influence of the cultivar over geographic parameters on the flaxseed phytochemical accumulation yield and composition is evidenced. The importance of genetic parameters on the lignan accumulation was further confirmed by gene expression analysis monitored by RT-qPCR. The corresponding antioxidant activity of these flaxseed extracts was evaluated, both in vitro, using ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and iron chelating assays, as well as in vivo, by monitoring the impact of UV-induced oxidative stress on the lipid membrane peroxidation of yeast cells. Our results, both the in vitro and in vivo studies, confirm that flaxseed extracts are an effective protector against oxidative stress. The results point out that secoisolariciresinol diglucoside, caffeic acid glucoside, and p-coumaric acid glucoside are the main contributors to the antioxidant capacity. Considering the health benefits of these compounds, the present study demonstrates that the flaxseed cultivar type could greatly influence the phytochemical intakes and, therefore, the associated biological activities. We recommend that this crucial parameter be considered in epidemiological studies dealing with flaxseeds.

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Anti-Inflammatory, Antipyretic, and Analgesic Properties of Potamogeton perfoliatus Extract: In Vitro and In Vivo Study

Molecules ◽

10.3390/molecules26164826 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4826

Author(s):

Samar Rezq ◽

Mona F. Mahmoud ◽

Assem M. El-Shazly ◽

Mohamed A. El Raey ◽

Mansour Sobeh

Keyword(s):

Oxidative Stress ◽

Acetic Acid ◽

Biological Activities ◽

Opioid Analgesic ◽

Potential Candidate ◽

Inflammatory Models ◽

Potamogeton Perfoliatus ◽

Anti Inflammatory

Natural antioxidants, especially those of plant origins, have shown a plethora of biological activities with substantial economic value, as they can be extracted from agro-wastes and/or under exploited plant species. The perennial hydrophyte, Potamogeton perfoliatus, has been used traditionally to treat several health disorders; however, little is known about its biological and its medicinal effects. Here, we used an integrated in vitro and in vivo framework to examine the potential effect of P. perfoliatus on oxidative stress, nociception, inflammatory models, and brewer’s yeast-induced pyrexia in mice. Our results suggested a consistent in vitro inhibition of three enzymes, namely 5-lipoxygenase, cyclooxygenases 1 and 2 (COX-1 and COX-2), as well as a potent antioxidant effect. These results were confirmed in vivo where the studied extract attenuated carrageenan-induced paw edema, carrageenan-induced leukocyte migration into the peritoneal cavity by 25, 44 and 64% at 200, 400 and 600 mg/kg, p.o., respectively. Moreover, the extract decreased acetic acid-induced vascular permeability by 45% at 600 mg/kg, p.o., and chemical hyperalgesia in mice by 86% by 400 mg/kg, p.o., in acetic acid-induced writhing assay. The extract (400 mg/kg) showed a longer response latency at the 3 h time point (2.5 fold of the control) similar to the nalbuphine, the standard opioid analgesic. Additionally, pronounced antipyretic effects were observed at 600 mg/kg, comparable to paracetamol. Using LC-MS/MS, we identified 15 secondary metabolites that most likely contributed to the obtained biological activities. Altogether, our findings indicate that P. perfoliatus has anti-inflammatory, antioxidant, analgesic and antipyretic effects, thus supporting its traditional use and promoting its valorization as a potential candidate in treating oxidative stress-associated diseases.

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