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New pyridine- O -glycosides and their acyclic nucleoside analogues were prepared by heterocyclization and glycosylation. The anticancer activity against HCT-116, HepG2 and MCF-7 human cancer cells and BJ-1 cell revealed that the galacto- and xylopyranosyl glycosides possessing 4-bromophenyl have superior cytotoxic activities against HepG2 cell while glycosides 7-9 resulted in superior cytotoxic activities regarding MCF-7 breast cell. In case of HCT-116 colorectal carcinoma cells, two products and the derived glycosides and acyclic analogues showed potent activities. The most potent compounds were investigated for their possible binding affinities to the active site of CDK2 enzyme via in silico molecular docking simulation in addition to computational studies. The results support the antiproliferative effect and elucidate the interactions of 3a and 8 with catalytic sites.

In the present study the authors' main goal is to avoid the corrosive attack of the chloride ions of 3.5% NaCl solution in saline medium on the mild steel (MS), by addition of small amount of a new derivative of the hydrazide called ligand (HL), as a corrosion inhibitor. This study had been achieved by employing different electrochemical measurements such as, open circuit potential (OCP), electrochemical impedance spectroscopy (EIS) and potentio-dynamic polarization (PDP) methods. The results of the electrochemical test (OCP), showed that, the open circuit potential of the mild steel in saline solution, was guided to more positive direction in presence of the ligand (HL), at its ideal concentration (1 × 10 -3  M), compared to the (OCP), of the mild steel in absence of (HL). The results of the electrochemical methods, EIS and PDP presented that, the ligand (HL), was acted as a good corrosion inhibitor for hindering the corrosion process of the mild steel in 3.5% sodium chloride, as it was recorded a good percentage of the inhibition efficiency (77.45%, 53.41%, by EIS and PDP techniques respectively), at its optimum concentration (1 × 10 -3  M). Also, the corrosion rate of the mild steel in the saline medium without (HL), was listed about (0.0017 mm/year), while in existence of (HL), was decreased to a value about (0.00061 mm/year). As well, some of electrical properties of (HL), and its derivative [Pd(II), Cr(III), and Ru(III)], complexes were investigated such as; the activation energy (E a(ac) ), which recorded values in the range of 0.02-0.44 (eV) range and electrical conductivity which listed values at room temperature in the range of 10 -5 -10 -8  S.cm -1 . The results of the AC and DC electrical conductivity measurements for (HL), and its derivative [Pd(II), Cr(III) and Ru(III)] complexes indicate semiconducting nature which suggests that these compounds could be used in electronic devices. Also, the complexes exhibited higher conductivity values than (HL). Photophysical studies showed good florescence properties of HL that indicated that it can be used to determine most of the drugs with no fluorescence properties by quenching and calculating quantum yield. Moreover, the hydrazide ligand (HL), has shown selectivity as an active anticancer candidate drug for both breast and colon cancer in humans. Density function theory demonstrated that, the frontier molecular orbital HOMOs of the complexes have exhibited similar behavior and the charge density has localized in the metallic region of all the studied complexes. Also, the values of the energy gap of the ligand (HL), and its complexes Pd(II), Cr(III) and Ru(III), had been arranged in this order HL > Cr(III) > Ru(III) > Pd(II). All characterization using different spectroscopic techniques were reported to elucidate the proposed structures such as; thermal analysis, elemental analysis of C, H, and N atoms, spectral analysis using IR, UV, 1 H NMR techniques, scanning electron microscopy and energy dispersive X-ray analyses., (© 2024. The Author(s).)

Aminopeptidase N (APN) is regarded as an attractive target for cancer treatment due to its overexpression in various types of malignancies and its close association with cancer angiogenesis, metastasis and invasion. Herein the authors describe the design, synthesis and biological evaluation of some naturally based pyrazoline derivatives. Among these compounds, the diphenylpyrazole carbothioamide 8 showed significant activity and selectivity index (SI = 4.7) on breast (MCF-7) human cancer cell line and was capable of inhibiting APN with pIC 50 value of 4.8, comparable to the reference standard. Further evaluation of derivative 8 against VEGFR2 and MMP9 as biomarkers for angiogenesis and invasion showed that the selected compound had an inhibitory activity on both proteins with pIC 50 values of 6.7 and 6.4, respectively. Additionally, the migration ability of cells following treatment with the diphenylpyrazole derivative decreased to record a percentage wound closure of 57.77 for compound 8 versus 97.03 for the control. The promising derivative arrested cell growth at the G1 phase inducing early and late apoptosis. Finally, docking and ADMET in silico studies were performed., Competing Interests: The authors declared that there are no actual or potential conflicts of interest and have approved the article., (This journal is © The Royal Society of Chemistry.)

The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1-18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and HepG-2 among one non-cancerous BJ-1 human normal cell. Most compounds were precisely potent anticancer candidate drugs. The molecular impact of the most active compounds 9, 10, 11, 13, 15, and 17 was evaluated after MCF-7 treatment. The gene expression of pro- and ant-apoptosis markers P53, Bax, Caspase-3 and Bcl-2 as well as VEGFR-2 and HER2 were determined. Compounds 13 and 15 induced upregulation of pro-apoptosis of P53, Bax, Caspase-3 and downregulation of anti-apoptosis Bcl-2 gene. However, compound 15 showed higher effect compared to 13 and respective control. Moreover, a slight reduction in HER2 gene expression was detected due to compound 15 treatment, while VEGFR-2 gene was upregulated. In agreement, the immunoblotting analysis showed higher accumulation of P53, Bax, Caspase-3 proteins and of decrease the Bcl-2 protein levels. Furthermore, docking studies united with molecular dynamic simulation exposed compounds 13 and 15 fitting in the middle of the active site at the interface linking the ATP binding site and the allosteric hydrophobic binding pocket. Finally, we performed Petra/Osiris/ Molinspiration (POM) analysis for the newly synthesized compounds. The evaluation of primary in silico parameters revealed significant differences among individual polyfunctionalized pyridine compounds, highlighting the most promising candidates. These preliminary results may help in coordinating and initiating other research projects focused on polyfunctionalized pyridine compounds, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A series of thiazoline and thiazolidinone-based 4-hydroxycoumarin derivatives were synthesized using both conventional synthesis procedures and microwave-assisted techniques. The new compounds were evaluated for their cytotoxic effect against three human cancer cell lines; MCF-7, HCT-116 and HepG2 and one normal human cell line (BJ-1). The promising anti-proliferative compounds 2a, 2b, 6a and 6b were assessed for inhibiting EGFR and PI3K/mTOR. Compound 6a showed the highest inhibition activity towards the signaling pathway. The apoptotic effect and cell cycle arrest potential of derivative 6a were examined. Moreover, the molecular docking, physicochemical properties and pharmacokinetic parameters of the promising compound were investigated, as well., Competing Interests: The authors declared that there are no actual or potential conflicts of interest and have approved the article., (This journal is © The Royal Society of Chemistry.)

Isatin-quinoline conjugates 10a - f and 11a - f were assembled by the reaction of N-(bromobutyl) isatin derivatives 3a , b with aminoquinolines 6a - c and their corresponding hydrazinyl 9a - c in good yields. The structures of the resulting conjugates were established by spectroscopic tools and showed data consistent with the proposed structures. In vitro antibacterial activity against different bacterial strains was evaluated. All tested conjugates showed significant biocidal activity with lower MIC than the first line drugs chloramphenicol and ampicillin. Conjugates 10a , 10b and 10f displayed the most potent activity against all clinical isolates. The antibiofilm activity for all tested conjugates was screened against the reference drug vancomycin using the MRSA strain. The results revealed that all conjugates had an inhibitory activity against biofilm formation and conjugate. Conjugate 11a showed 83.60% inhibition at 10 mg/mL. In addition, TEM studies were used to prove the mechanism of antibacterial action of conjugates 10a and 11a against ( MRSA ). Modeling procedures were performed on 10a - f and 11a - f and interestingly the results were nearly consistent with the biological activities. In addition, in silico pharmacokinetic evaluation was performed and revealed that the synthesized compounds 10a - f and 11a - f were considered drug-like molecules with promising bioavailability and high GI absorption. The results confirmed that the title compounds caused the disruption of bacterial cell membranes and could be used as potential leads for the further development and optimization of antibacterial agents.

New 1,3,4-thiadiazole thioglycosides linked to a substituted arylidine system were synthesized via heterocyclization via click 1,3-dipolar cycloaddition. The click strategy was used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycoside-based indolyl systems as novel hybrid molecules by reacting azide derivatives with the corresponding acetylated glycosyl terminal acetylenes. The cytotoxic activities of the compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds, the triazole glycosides linked to p-methoxyarylidine derivatives and the free hydroxyl glycoside had potent activity comparable to the reference drug, doxorubicin, against MCF-7 human cancer cells. Docking simulation studies were performed to check the binding patterns of the synthesized compounds. Enzyme inhibition assay studies were also conducted for the epidermal growth factor receptor (EGFR), and the results explained the activity of a number of derivatives.

The coumarin ring was used as a central scaffold that was substituted with a variety of bioactive functional groups, for designing and synthesizing novel MDM2 inhibitors targeting breast cancer. The synthesized derivatives, 3c, 3d, 3g, 7b, 7c and 8 with IC 50s ranging from 9.4 to 9.9 µM were evaluated for their safety on MCF10a normal breast cell line. The compounds showed selectivity indices of 2.15, 3.85, 2.75, 1.38, 3.72 and 5.20 respectively. 7c was selected for further investigation, the compound was capable of down-regulating MDM2 and the anti-apoptosis proteins Bcl-2 and Bcl-xL, up-regulating the level of p53 and the pro-apoptosis protein BAX, causing cell cycle arrest at G2/M phase and activating Caspase-9 to induce apoptosis. Molecular docking study revealed the capability of derivative 7c to interact with the key amino acids in p53 binding pocket of MDM2 protein. Moreover, the physicochemical properties of compound 7c were studied in silico., (© 2022 John Wiley & Sons Ltd.)

Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2-Acetylbenzofuran derivatives 1a,b and 3-acetylindole 1c were condensed with Wittig reagents 2a-d and Wittig-Horner reagents 3a-e to afford the respective 2-ethylidene derivatives 5a-j and 7a-e. Also, iminomethylene triphenylphosphine (2e) reacted with 1a,b to afford benzofuran-2-ylethylidene aniline derivatives 6a,b. In addition, compounds 1a,b reacted with trialkylphosphites 4a-c to give 1:1 adduct for which the Oxaphospholo[4,3-b]benzofuran-7-yl)diazene derivatives 8a-f, were assigned. The possible reactions mechanisms were discussed and structural reasoning for the new compounds were based upon spectroscopic data. Their antiproliferative activities against two cell lines namely, HepG2 and MCF7 cells were then evaluated. It was found that the benzofuran compounds 5b, 6a, and 8c exhibited the strongest antiproliferative activities against both cell lines compared to doxorubicin. By studying the mechanism of action, compound 6a showed good inhibition of tubulin polymerization which leads to mitotic spindle formation disruption, cell cycle arrest in the G2/M phase, and apoptosis of HepG2 cells. A conducted docking study confirmed the in vitro results indicating that compound 6a fitted properly at the colchicine binding site of tubulin. Based on these findings, compound 6a can be considered as a promising anticancer candidate that can be subjected for further development as a tubulin polymerization inhibitor for treating liver and breast cell carcinoma., (© 2021 Wiley Periodicals LLC.)

Some new pyridinethione and thienopyridine derivatives have been synthesized and evaluated for their antiproliferative activity using the MTT assay. Nicotinamide derivatives 3 have been synthesized and used for the preparation of new condensed thieno [2,3- b ]pyridines by their reactions with active halo compounds. Finally the synthesized thienopyridine underwent ring closure whenever possible through boiling in a solution of sodium ethoxide. The antiproliferative evaluation against (HCT-116, HepG-2, and MCF-7) human cancer cells and one human healthy cell line (BJ-1) revealed that compounds 3b , 4c - 5d , 7b - 12a , 10d , and 13b have interesting antitumor activity specifically as antihepatocellular and anticolon cellular carcinoma agents. Besides, the docking results for most active derivatives were in agreement with the in vitro antitumor results., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Emerging pollutants (EPs) create a worldwide concern owing to their low concentration and severe toxicity to the receptors. The prominent emerging pollutants categories as pharmaceutical and personal care product, plasticizer, surfactants, and persistent organic pollutants. Typically, EPs are widely disseminated in the aquatic ecosystem and capable of perturbing the physiology of water bodies as well as humans. The primary sources of EPs in the environment include anthropogenic release, atmospheric deposition, untreated or substandard treated wastewater, and extreme weather events. Intensive research has been done covering the environmental distribution, ecological disturbance, fate, and removal of EPs in the past decades. However, a systematic review on the distribution of EPs in the engineered and natural aquatic environment and the degradation of different EPs by using anaerobic sludge, aerobic bacteria, and isolated strains are limited. This review article aims to highlight the importance, application, and future perceptions of using different microbes to degrade EPs. Overall, this review article illustrates the superiority of using non-cultivable and cultivable microbes to degrade the EPs as an eco-friendly approach. Practically, the outcomes of this review paper will build up the knowledge base solutions to remove EPs from the wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The presence of 4-nitrophenol (4-NP) in the wastewater industry causes toxicity and inhibition of the anaerobic degrading bacteria. The anaerobes in the multistage anaerobic reactor were loaded by 30.0 mg/gVS Graphene nanoparticles (MAR-G n ) as an electron acceptor to detoxify wastewater industry. The half maximal inhibitory concentration (IC 50 ) was reduced from 455 ± 22.5 to 135 ± 12.7 μg Gallic acid equivalent/mL at 4-NP loading rate of 47.9 g/m 3 d. Furthermore, 4-NP was decreased by a value of 83.7 ± 4.9% in MAR-G n compared to 65.6 ± 4.8% in control MAR. The 4-aminophenol (4-AP) recovery was accounted for 44.8% in the MAR-G n at an average oxidation-reduction potential (ORP) of - 167.3 ± 21.2 mV. The remaining portions of 4-NP and 4-AP in the MAR-G n effluent were efficiently removed by baffled high rate algal pond (BHRAP), resulting in overall removal efficiency of 91.6 ± 6.3 and 92.3 ± 4.6%, respectively. The Methanosaeta (52.9%) and Methanosphaerula (10.9%) were dominant species in MAR-G n for reduction of 4-NP into 4-AP. Moreover, Chlorophyta cells (Chlorella vulgaris, Scenedesmus obliquus, Scenedesmus quadricauda and Ulothrix subtilissima were abundant in the BHRAP for complete degradation of 4-NP and 4-AP., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A novel series of benzothiazole-based derivatives linked to various amino acids and their corresponding ethyl ester analogues were prepared and were initially evaluated for their anticancer activity againstMCF-7 and HepG-2 and were further assessed as VEGFR-2 inhibitors. All the newly synthesized benzothiazole derivatives showed promising cytotoxic activities against the tested cell lines. Derivatives exhibited potent cytotoxic and VEGFR-2 inhibitory activities were then evaluated further as anticancer agents against the resistant MDA-MB-231 and as EGFR inhibitors. The carboxylic acid derivatives 10-12 and their ester analogues 21-23 displayed the highest anticancer activities with IC 50 of 0.73-0.89 µM, against MCF-7 and IC 50 of 2.54-2.80 µM, against HepG-2; compared to doxorubicin (IC 50  = 1.13 and 2.75 µM, respectively); also they showed safety towards the normal cell line, the ethyl ester derivatives 21-23 showed a potent activity against the resistant MDA-MB-231 cell line with IC 50 of 5.45-7.28 µM, relative to doxorubicin (IC 50  = 7.46 µM) surpassing their carboxylic acid analogues 10-12 (IC 50 of 8.88-11.02 µM). Furthermore, the promising derivatives 10-12 and 21-23 displayed promising VEGFR-2 inhibitory activity (IC 50  = 0.15-0.19 µM) comparable to that of sorafenib (IC 50  = 0.12 µM). Against EGFR, the ethyl ester derivatives 21-23 showed superior inhibitory activity relative to the used reference standard, erlotinib, with IC 50 of 0.11-0.16 vs. 0.18 µM, respectively. The QSAR study revealed that the molecular bulkiness and molecular partial charge distribution govern the kinase inhibition potency in this series. Furthermore, the molecular docking study in VEGFR-2 active site showed that the novel synthesized benzothiazole derivatives adopted the common binding pattern of type II PK inhibitors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This work deals with the design and synthesis of a series of new substituted 2-arylbenzothiazole compounds attached to 4-oxothiazolidin-2-ylidene ring 2-12 and chain elongation with different amino acids and their corresponding ester derivatives 13-18. All prepared derivatives were screened for their in vitro cytotoxicity activities against two cancer cell lines (HepG-2 and MCF-7) in comparison with doxorubicin; in addition to their safety towards thenormal cell line. Furthermore, all compounds 2-18 were evaluated as FGFR-1 inhibitors using AZD4547 as a reference. The 4-oxothiazolidin-2-ylidene derivatives 3 and 8 exhibited the highest cytotoxic activity (IC 50 HepG-2  = 2.06, 2.21 µM and IC 50 MCF-7  = 0.73, 0.77 µM, respectively) through their promising FGFR-1 suppression effects (IC 50  = 16.31 and 18.08 nM, respectively) in comparison to AZD4547 (IC 50  = 21.45 nM). Cell cycle and apoptosis analysis indicated that compounds 3 and 8 induce pronounced increase in the cell percentages at pre-G 1 and G 2 /M phase compared to the untreated MCF-7 cancer cells, in addition to their up regulation of caspase-3/7/9. The molecular docking simulation was created to elucidate the binding modes of benzothiazole derivatives 1-18 bearing various scaffolds within the ATP-binding pocket of FGFR-1 enzyme compared with AZD4547., (Copyright © 2021. Published by Elsevier Inc.)

In the current study, new thienopyrimidine conjugates bearing 1,2,3-triazole core and different sugar moieties have been designed and synthesized by Cu(I)-catalysed click dipolar cycloaddition. The cytotoxic activity of the synthesised conjugates 2 , 5 , 7 , and 13 - 18 was studied against HCT-116 and MCF-7 cell lines by the MTT assay. The triazole glycosides 16 and 18 provided significant cytotoxic activities against HCT-116 cell lines comparable to that of doxorubicin and other studied compounds. The cytotoxic behaviour against MCF-7 exhibited that all the investigated compounds were more potent than doxorubicin. Moreover, all screened targets were evaluated against mutant EGFR kinase type L858R and the results revealed that the acetylated 1,2,3-triazole glycosides 13 - 18 exhibited excellent EGFR inhibitory activity in comparison with gefitinib. Furthermore, molecular modelling studies were performed to investigate the binding affinity of the most active compounds to EGFR enzyme.

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile ( 1 ). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine- - C 2 functionalized derivatives. The derived pyrazolpyridine- N -glycosides were synthesized via heterocyclization of the C 2 -thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3',2':4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1 , 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile ( 4 ), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1 H -pyrazolo[3,4-b]pyridin-3-amine ( 8 ), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate ( 11 ), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate ( 14 ) are among the most active inhibitors with IC 50 values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC 50 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC 50 ranges of 31.3-49.0, 19.3-55.5, 22.7-44.8, and 36.8-70.7 μM, respectively compared to doxorubicin (IC 50 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.

The molecular hybridization concept has recently emerged as a powerful approach in drug discovery. A series of novel indole derivatives linked to the pyrazole moiety were designed and developed via a molecular hybridization protocol as antitumor agents. The target compounds ( 5a - j and 7a - e ) were prepared by the reaction of 5-aminopyrazoles ( 1a - e ) with N -substituted isatin ( 4a , b ) and 1 H -indole-3-carbaldehyde ( 6 ), respectively. All products were characterized via several analytical and spectroscopic techniques. Compounds ( 5a - j and 7a - e ) were screened for their cytotoxicity activities in vitro against four human cancer types [human colorectal carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), and human lung carcinoma (A549)] using the MTT assay. The obtained results showed that the newly synthesized compounds displayed good-to-excellent antitumor activity. For example, 5-((1 H -indol-3-yl)methyleneamino)- N -phenyl-3-(phenylamino)-1 H -pyrazole-4-carboxamide ( 7a ) and 5-((1 H -indol-3-yl)methyleneamino)-3-(phenylamino)- N -(4-methylphenyl)-1 H -pyrazole-4-carboxamide ( 7b ) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC 50 values of 6.1 ± 1.9 and 7.9 ± 1.9 μM, respectively, compared to the standard reference drug, doxorubicin (IC 50 = 24.7 ± 3.2 μM). The two powerful anticancer compounds ( 7a and 7b ) were further subjected to cell cycle analysis and apoptosis investigation in HepG2 using flow cytometry. We have also studied the enzymatic assay of these two compounds against some enzymes, namely, caspase-3, Bcl-2, Bax, and CDK-2. Interestingly, the molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the CDK-2 enzyme via different interactions. Overall, the prepared pyrazole-indole hybrids ( 7a and 7b ) can be proposed as strong anticancer candidate drugs against various cancer cell lines., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Lactobacilli probiotics have been suggested to reduce cholesterol with low side effects to host. Bacteriocins and exopolysaccharides (EPSs) production are two meaningful examples of functional applications of lactobacilli in the food industry. Eight Lactobacillus strains were isolated from some Egyptian fermented food and tested for their probiotic properties. Analysis of the monosaccharide composition by thin layer chromatography showed the presence of glucose, galactose and unknown sugar. The main functional groups of EPSs were elucidated by Fourier-Transform Infrared Spectroscopy. Their fermentation cultures displayed powerful antioxidant activities extending from 97.5 to 99%, 40-75% for their EPSs and free cells, respectively, and exhibited in vitro cholesterol downgrading from 48 to 82% and 72 to 91% after 48 and 120 h, respectively. Their EPSs showed good anticancer activities against carcinoma cells with low IC 50 values for HCT-116, PC-3 and HepG-2 cells. To the best of our knowledge, there have been no previous reports on the potential of Lactobacillus EPSs activity against PC-3. The selected strains, L. plantarum KU985433 and L. rhamnosus KU985436 produced two different bacteriocins as detected by gel permeation chromatography with good antimicrobial activities. In vivo study demonstrated that feeding Westar rats with fermented milk exhibited greater cholesterol, LDL and blood triglyceride reduction for both strains. Whereas, HDL was increased by about 43 and 38%, respectively, and the atherogenic indices decreased., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Phytoremediation of polyester resin wastewater containing 1,4-dioxane and heavy metals using Lemna gibba (L.gibba) was enhanced by incorporation of perforated polyethylene carrier materials (PCM) onto the duckweed pond (DWP) system. The DWP module was operated at a hydraulic retention times (HRTs) of 2, 4 and 6 days and as well as 1,4-dioxane loading rate of 16, 25 and 48 g/m 3 .d. The maximum removal efficiency of 54 ± 2.5% was achieved for 1,4-dioxane at an HRT of 6 days and loading rate of 16 g1,4-dioxane/m 3 .d. Similarly, the DWP system provided removal efficiencies of 28.3 ± 2.1, 93.2 ± 7.6, 95.7 ± 8.9 and 93.6 ± 4.9% for Cd 2+ , Cu 2+ , Zn 2+ and Ni 2+ at influent concentration of 0.037 ± 0.01, 1.2 ± 0.9, 27.2 ± 4.7 and 4.6 ± 1.2 mg/L respectively. The structural analysis by Fourier-transform infrared spectroscopy (FTIR) clearly displayed a reduction of 1,4- dioxane in the treated effluent. A strong peak was detected for L. gibba plants at frequency of 3417.71 cm -1 due to N-H stretching, which confirm the proposed mechanism of partially conversion of 1,4-dioxane into amino acids. Glycine, serine, aspartic, threonine and alanine content were increased in L. gibba by values of 35 ± 2.2, 40 ± 3.2, 48 ± 3.7, 31 ± 2.8, and 56 ± 4.1%, respectively. The contribution of DWP unit as a greenhouse gases (GHG) emissions were relatively low (1.65 gCO 2 /Kg BOD removed .d., and 18.3 gCO 2 /Kg biomass .d) due to photosynthesis process, low excess sludge production and consumption of CO 2 for nitrification process (1.4 gCO 2 /kgN removed .d). Based on these results, it is recommended to apply such a technology for treatment of polyester resin wastewater containing 1,4-dioxane and heavy metals at a HRT not exceeding 6 days., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A series of new substituted triazolo[4,5- d ]pyrimidine derivatives linked to thienopyrimidine ring system were prepared as a hybrid heterocyclic systems, as possible nucleobases analogs, starting from the key carboxamide derivative 2 and its azide precursor via heterocyclization reactions and their structures were characterized. Glycosylation of the prepared triazolopyrimidine derivatives was performed and afforded, regioselctively, the corresponding thienopyrimidine-triazolopyrimidine hybrid N 1 -glycosides and their thioglycoside analogues in good yields. The synthesized glycosyl heterocycles were studied for their cytotoxic activity against HepG-2 and MCF-7 human cancer cells and significant results were obtained. Compounds 7a , 8 b , 9 b , 9a and 7 b demonstrated promising activities comparable to the activity of the doxorubicin for (HepG-2) cell line. Furthermore, a number of the afforded triazolopyrimidine glycosides were found potent against cancer cells (MCF-7). Furthermore, docking simulation the promising thienopyrimidine analogues 7-13 was done against EGFR kinase to provide a binding model that could serve in discovery of further anticancer agents.

A series of 3-ethyl(methyl)-2-thioxo-2,3-dihydrobenzo[ g ]quinazolines ( 1 - 17 ) were synthesized, characterized, and evaluated in vitro for their antiangiogenesis VEGFR-2-targeting, antiproliferative, and antiapoptotic activities against breast MCF-7 and liver HepG2 cells. Flow cytometry was used to determine cancer-cell cycle distributions, and apoptosis was detected using annexin-V-FITC (V) and propidium iodide (PI) dyes. Fluorescence microscopy, in combination with Hoechst staining was used to detect DNA fragmentation. Most of the tested benzo[ g ]quinazolines demonstrated promising activity (IC 50 = 8.8 ± 0.5-10.9 ± 0.9 μM) and (IC 50 = 26.0 ± 2.5-40.4 ± 4.1 μM) against MCF-7 and HepG2, respectively. Doxorubicin was used as a reference drug. Compounds 13 - 15 showed the highest activity against both cancer cell lines. Differential effects were detected by cell-cycle analysis, indicating similarities in the actions of 13 and 14 against both MCF7 and HepG2, involving the targeting of G1 and S phases, respectively. Compound 15 showed similar indices against both cells, indicating that its cytotoxicity toward the examined cancer cells could be unselective. Interestingly, 14 and 15 showed the highest apoptosis (30.76% and 25.30%, respectively) against MCF-7. The DNA fragmentation results agreed well with the apoptosis detected by flow cytometry. In terms of antiangiogenesis activity, as derived from VEGFR-2 inhibition, 13 and 15 were comparable to sorafenib and effected 1.5- and 1.4-fold inhibition relative to the standard sorafenib. A docking study was conducted to investigate the interaction between the synthesized benzo[ g ]quinazolines and the ATP-binding site within the catalytic domain of VEGFR-2.

Thirteen 4-hydrazinobenzoic acid derivatives were elaborated and characterized by spectral analyses (NMR and MS). Evaluation of their in vitro cytotoxic activity showed that some of the targets demonstrated potent inhibitory effects against HCT-116 and MCF-7 cancer cells. The IC 50 values ranged between 21.3 ± 4.1 and 28.3 ± 5.1 µM, respectively, whereas those of doxorubicin (reference drug) ranged between 22.6 ± 3.9 and 19.7 ± 3.1 µM, respectively. The active targets 6, 7 and 9 exhibited very weak cytotoxicity on normal cells (RPE-1) and showed higher IC 50 values against HCT-116 and MCF-7 cells in comparison to doxorubicin. Furthermore, compounds 7, 9 and 10 inhibited the proliferation of MCF-7 by the induction of apoptosis. The bioassay results in the regression plots generated in 3D QSAR models were in agreement and correlated with the anticancer results of the target molecules. The 4-hydazinobenzoic acid derivatives can be used as cornerstones for further structural modifications as future anticancer agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A series of novel 7-substituted-5-(1 H -indol-3- yl )tetrazolo[1,5-a]pyrimidine-6-carbonitrile was synthesized via a one-pot, three-multicomponent reaction of appropriate aldehydes, 1 H -tetrazole-5-amine and 3-cyanoacetyl indole in catalytic triethylamine. The cytotoxic activity of the new synthesized tetrazolopyrimidine-6-carbonitrile compounds was investigated against HCT-116, MCF-7, MDA-MB-231, A549 human cancer cell lines and one human healthy normal cell line (RPE-1) using the MTT cytotoxicity assay. Compounds 4h , 4b , 4c , 4i and 4a showed potent anticancer activities against human colon cancer. Additionally, all the compounds showed potent anticancer activities on human lung cancer.

Background: Spirothiazolidines are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity., Objective: To report the first synthesis of Bis Spiro-thiazolidine as a novel heterocyclic ring system., Methods: One-pot three-component reaction including condensation of p-phenyllene diamine; cyclohexanone and thioglycolic acid produced Spiro-thiazolidine 4, which underwent further condensation with cyclohexanone and thioglycolic acid with equimolar ratio to introduce Bis-Spiothiazolidine 5 as the first synthesis. Also, bis spiro-thiazolidine arylidene derivatives 6-13 were synthesized by the reaction of Bis-Spiothiazolidine 5 with different aromatic benzaldehydes., Results: Four compounds 13, 12, 9 and 11 have shown highly significant anticancer activity compared to Doxorubicin® (positive control) against Human liver carcinoma (HepG2) and Human Normal Retina pigmented epithelium (RPE-1) cell lines., Conclusion: The novel bis-spirothiazolidine deriviatives have been synthesized for the first time and showed excellent anticancer activities compare with the corresponding spirothiazolidine derivatives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

New 1,3,4-thiadiazole thioglycosides linked to substituted pyrimidines were synthesized via glycosylation of 1,3,4-thiadiazole thiol compounds. Also, novel 1,2,3-triazole derivatives linked to carbohydrate units were prepared using the standard click chemistry conditions employing the Cu(I)-catalyzed azide-alkyne cycloaddition of substituted-aryl-azides with a selection of alkyne-functionalized sugars. The chemical structures of the new derivatives were verified using various spectroscopic techniques, such as IR, 1 H NMR, 13 C NMR and elemental analyses. The cytotoxic activities of the prepared compounds were investigated in vitro against human liver cancer (HepG-2) and human breast adenocarcinoma (MCF7) cell lines. In addition, the biological evaluation of the new compounds involved the investigation of their effects on a human normal retinal pigmented epithelial cell line (RPE1) using the MTT assay.

New 1,3,4-thiadiazole thioglycosides linked to substituted arylidine systems were synthesized via glycosylation of the prepared 1,3,4-thiadiazole thiol compounds. Click strategy was also used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycosides by reaction of the acetylenic derivatives with different glycosyl azids followed by deacetylation process. The cytotoxic activities of the prepared compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds 2 and 3 , the triazole glycosides linked to p -methoxyarylidine derivatives 14 and 15 in addition to the free hydroxyl glycoside 20 were found potent in activity comparable to the reference drug doxorubicin against MCF-7 human cancer cells. The acetylenic derivative 2 and glycoside 20 were also found highly active against HCT-116 cell lines., Competing Interests: The authors declare no conflicts of interest.

A series of 4-(1 H -1,2,4-triazol-1-yl)benzoic acid hybrids (1-17) was successfully synthesized and their structures were established by NMR and MS analysis. In vitro cytotoxic evaluation indicated that some of the hybrids exhibited potent inhibitory activities against MCF-7 and HCT-116 cancer cell lines, with IC 50 values ranging from 15.6 to 23.9 µM, compared with reference drug doxorubicin (19.7 and 22.6 µM, respectively). Notably, the most potent compounds, 2, 5, 14, and 15, not only exhibited an obvious improvement in IC 50 values, but demonstrated very weak cytotoxic effects toward normal cells (RPE-1) compared with doxorubicin. A further investigation showed that compounds 2 and 14 clearly inhibited the proliferation of MCF-7 cancer cells by inducing apoptosis. In addition, these hybrids showed acceptable correlation with bioassay results in regression plots generated by 2D QSAR models. Our results indicated that 1,2,4-triazole benzoic acid hybrids could be used as a structural optimization platform for the design and development of more selective and potent anticancer molecules., Competing Interests: The authors declare that they have no competing interests., (This journal is © The Royal Society of Chemistry.)

Objective & Methodology: New hybrids of thiopyrimidine-five/six heterocyclic rings were synthesized and in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely HCT116 (human colorectal carcinoma), PC-3 (human prostate adenocarcinoma) and HepG2 (human liver carcinoma) cell lines. The most potency was elicited by the target candidates against the viability of HCT116 cell lines. It was higher than that obtained by the positive control 5-Fluorouracil (IC50 range; 0.11-0.49 μM, IC50, 5-FU; 1.10 μM). Results: Cell cycle analysis and apoptosis activation revealed that compound 20 induced G2/M phase arrest and apoptosis in HCT116 cells. In addition, compound 20 activates the caspases-9 and -3, a process which might mediate the apoptosis of HCT116 cells. Quantitative structure activity relationship study was done and revealed a high predictive power R2 suggesting goodness of the models. Conclusion: Furthermore, there is a good agreement between the observed pIC50 and the predicted pIC50 values, in addition, the low RMSD and standard error values indicate the accuracy of the model. Antimicrobial evaluation revealed that some of these compounds exhibited significant activities against the tested pathogenic bacteria and fungi, wherein compounds 7a, 14, 15a, 21a, produced the most potent and broad spectrum antibacterial and antifungal potency that was equivalent to that revealed by Vibramycin and Ketoconazole (MIC; 125 μg/mL). Moreover, compounds 15a, 21c, investigated dual potent antimicrobial and anticancer activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC 50 values near to that of the reference drug doxorubicin.

Background & Objective: The target tetrazole glycosides were synthesized by construction of ring system by cycloaddition reaction of benzothiazole-linked nitrile derivative and sodium azide followed by N-glycosylation process and deprotection., Methods: The triazole glycosides were prepared by applying click approach involving dipolar cycloaddition of benzothiazole possessing alkyne functionality and different glycosyl azides. The products incorporating acyclic analogs of sugar moieties were synthesized through alkylation using acyclic oxygenated halides., Results: The anticancer activity was studied against human breast adenocarcinoma cells (MCF-7) and human normal Retina pigmented epithelium cells (RPE-1). High activities were revealed by three compounds with IC50 values 11.9-16.5 µM compared to doxorubicin (18.6 µM) in addition to other four derivatives with good inhibition activities., Conclusion: Enzyme docking investigation was performed into cyclin-dependent kinase 2 (CDK2); a potential target for cancer medication. Compounds which have possessed highest activities revealed good fitting inside the binding site of the protein molecular surface and showed minimum binding energy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background & Objective: A new series of thiazoles substituted on the chromene scaffold were prepared by facial approaches starting from (E)-1-(2,3-Dihydrochromen-4-ylidene)thiosemicarbazide derivatives (2a,b). The thiosemicarbazides (2a,b) were reacted with a series of α-halo carbonyl compounds to give the corresponding rhodanine analogues and reacted also with C-acetyl-or Cethoxy- N-hydrazonoyl chlorides to afford the corresponding tri- and tetra-substituted hybrid hydrazinyl thiazole substituted chromenes., Methods: The newly synthesized compounds were screened for their in vitro antimicrobial and antitumor activities by agar diffusion method and MTT assay, respectively., Results: The results of the antimicrobial activity revealed that some of the new compounds exhibited excellent activity against pathogenic microorganism; Candida albicans compared with Ciprofloxacin and nystatin, as the reference drugs. All of the tested compounds exhibited significant cytotoxic activities comparable to that of the reference drug; Doxorubicin® (on HCT116 (colorectal carcinoma human cell line)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background & Objective: New diaryl-substituted pyrimidinedione compounds, their thioxo derivatives as well as their bicyclic thiazole compounds were synthesized and characterized., Methods: The glycosylamino derivatives of the synthesized disubstituted derivatives of the pyrimidine scaffold were also prepared via reaction of the N3-amino derivatives with a number of monosaccharides followed by acetylation., Results: The anticancer activity of the synthesized compounds was studied against human liver cancer (HepG2) and RPE-1cell lines. Compounds 2a, 2b, 3a and 12 showed potent activities with IC50 results comparable to that of doxorubicin., Conclusion: Docking investigations into Cyclin-dependent kinase 2 (CDK-2) enzyme, a potential target for cancer medication, were also reported showing the possible binding interaction into the enzyme active site to support their activity behavior., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A series of N -aryl-7-aryl-pyrazolo[1,5- a ]pyrimidines 18a ⁻ u and N -aryl-pyrazolo[1,5- a ]quinazolines 25a ⁻ c were designed and synthesized via the reaction of 5-aminopyrazoles 11a ⁻ c with enaminones 12a ⁻ g or 19 , respectively. The new compounds were screened for their in vitro antitumor activity toward liver (HepG-2) and breast (MCF-7) human cancer cells using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2 H -tetrazolium bromide MTT assay. From the results, it was found that all compounds showed dose-dependent cytotoxic activities against both HepG-2 and MCF-7 cells. Two compounds 18o and 18a were selected for further investigations. Cell cycle analysis of liver (HepG-2) cells treated with 18o and breast (MCF-7) cells treated with 18a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.

Method: Two new series of 4-styryl-7-oxycoumarin derivatives 3a-i and 4-styryl-7- oxycoumarinyl Mannich bases 6a-r were designed and synthesized. Ten compounds were evaluated for their antioxidant activity in vitro against DPPH and in vivo against lipid Peroxidation, Superoxide Dismutase (SOD), Glutathione-s-Transferase (GST) and Catalase (CAT) activities. Molecular modeling study was performed to predict the mode of binding of the target compounds in the binding site., Results & Conclusion: Although the tested compounds showed moderate to low dose dependent DPPH inhibition activities in vitro, most of them displayed remarkable antioxidant effects in vivo. Compounds 1, 6b, 3c and 6r displayed significant decrease in MDA, SOD and CAT enzyme levels in H2O2 treated rats. Free binding energy was estimated by docking, MM-PBSA and MM-GBSA. Molecular dynamics simulation followed by MM-GBSA calculation was correlated to the antioxidant effect. Compound 1 illustrated the highest MM-GBSA value (-20.38) and the best antioxidant effect., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

New 1-thia-azaspiro[4.5]decane derivatives, their derived thiazolopyrimidine and 1,3,4-thiadiazole compounds were synthesized. The thioglycoside derivatives of the synthesized (1,3,4-thiadiazolyl)thiaazaspiro[4.5]decane and thiazolopyrimidinethione compounds were synthesized by glycosylation reactions using acetylated glycosyl bromides. The anticancer activity of synthesized compounds was studied against the cell culture of HepG-2 (human liver hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma) and HCT116 (human colorectal carcinoma) cell lines and a number of compounds showed moderate to high inhibition activities.

In the present work, a series of 0, 1 and 7 wt% silver nano-particles (Ag NPs) incorporated poly lactic-co-glycolic acid (PLGA) nano-fibers were synthesized by the electrospinning process. The PLGA/Ag nano-fibers sheets were characterized using SEM, TEM and DSC analyses. The three synthesized PLGA/silver nano-fiber composites were screened for anticancer activity against liver cancer cell line using MTT and LDH assays. The anticancer activity of PLGA nano-fibers showed a remarkable improvement due to increasing the concentration of the Ag NPs. In addition to the given result, PLGA nano-fibers did not show any cytotoxic effect. However, PLGA nano-fibers that contain 1 % nano silver showed anticancer activity of 8.8 %, through increasing the concentration of the nano silver to 7 % onto PLGA nano-fibers, the anticancer activity was enhanced to a 67.6 %. Furthermore, the antibacterial activities of these three nano-fibers, against the five bacteria strains namely; E.coli o157:H7 ATCC 51659, Staphylococcus aureus ATCC 13565, Bacillus cereus EMCC 1080, Listeria monocytogenes EMCC 1875 and Salmonella typhimurium ATCC25566 using the disc diffusion method, were evaluated. Sample with an enhanced inhibitory effect was PLGA/Ag NPs (7 %) which inhibited all strains (inhibition zone diameter 10 mm); PLGA/Ag NPs (1 %) sample inhibited only one strain (B. cereus) with zone diameter 8 mm. The PLGA nano-fiber sample has not shown any antimicrobial activity. Based on the anticancer as well as the antimicrobial results in this study, it can be postulated that: PLGA nanofibers containing 7 % nano silver are suitable as anticancer- and antibiotic-drug delivery systems, as they will increase the anticancer as well as the antibiotic drug potency without cytotoxicity effect on the normal cells. These findings also suggest that Ag NPs, of the size (5-10 nm) evaluated in the present study, are appropriate for therapeutic application from a safety standpoint.

2-Acetyl-5,6,7,8-tetrahydronaphthalene (1) was allowed to react with different aromatic aldehydes to produce the cyanopyridones 2a and 2b, which were treated with phosphorous pentasulfide to afford the corresponding thioxopyridine derivatives 3a and 3b, respectively. The reaction of 3a and 3b with ethyl bromoacetate afforded the ester derivatives 4a and 4b, while their condensation with hydrazine hydrate gave the corresponding pyrazolopyridine derivatives 5a and 5b. The reaction of the precursor 2-amino-5,6,7,8-tetrahydronaphthalene (6) with ethoxy methylenemalonic ester led to the formation of aminomethylenemalonate derivative 7. Cyclization of 7 in boiling diphenyl ether gave the derivative - ethyl 6,7,8,9-tetrahydro-4-hydroxybenzo[g]-quinoline-3-carboxylate (8) which was hydrolyzed to produce the corresponding carboxylic acid analogue 9. Further reaction of 3a with 3-chloropropane-1,2-diol and/or iodomethane produced the corresponding nicotinonitrile derivatives 10 and 11. Hydrazinolysis of derivative 11 gave the hydrazinyl derivative 12. Moreover, chlorination of compound 2a with phosphorous oxychloride led to 2-chloro nicotinonitrile derivative 13, which was refluxed with various amines to form the corresponding derivatives 5a, 14 and 15. Treatment of the pyrazolopyridine compound 5a with formic acid and acetic anhydride afforded the corresponding formamide and acetamide analogues 16 and 17, while its reaction with DMF-DMA yielded the corresponding formimidamide derivative 18. The pyridopyrazolo[1,5-a]pyrimidine derivative 19 was obtained by cyclization of 5a with acetyl acetone. The antioxidant activity evaluation of the newly synthesized compounds showed that the pyrazolopyridine derivative 5a exhibited scavenging potency higher than that obtained by ascorbic acid. Tumor inhibitory activity screening revealed that derivatives 8 and 10 showed promising potency against the liver cancer cells (HepG-2) compared to doxorubicin as a reference drug.

Chemical investigations from a foliar extract of Araucaria excelsa (Lamb.) (Araucariaceae) resulted in the identification of seven phenolic metabolites including one flavananol, one flavananol 3-O-glycoside, four C-glycoside flavonoids, and one phenolic acid. Structures were elucidated by spectral determination including: UV, NMR and MS analysis. Moderate antioxidant activity was observed with a 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay in comparison with the reference antioxidant ascorbic acid.

Reaction of benzosuberone 1 with dimethylformamide-dimethylacetal (DMF-DMA) gives 2-dimethylamino-methylenebenozosuberone 2 which in turn reacts with heterocyclic amines to furnish new heterocyclic ring systems 6-9. Moreover, enaminone 2 reacts with hydrazine hydrate and hydroxylamine hydrochloride to afford the corresponding benzo[6,7]cyclohepta[1,2-c]pyrazole (10) and benzo[6,7]cyclohepta[2,1-d]isoxazole (12), respectively. In addition, the reactions of enaminone 2 with active methylene compounds afforded benzo[6,7]cyclohepta[1,2-b]pyridines (13-18). The X-ray crystallographic analysis of compounds 6 and 16, were recorded. We demonstrated the ability of nine new synthesized compounds to inhibit Hepatitis C Virus (HCV) and Subacute Sclerosing Panencephalitis (SSPE) due to structural similarity between ribavirin and some of the newly synthesized compounds were they contain triazoles and its bioisosters. In addition, the ability of ten synthesized compounds to react with the biologically relevant reactive nitrogen species, peroxynitrite was investigated indirectly by measurement of their ability to inhibit ONOO(-)-induced tyrosine nitration. The antioxidant activity of these ten compounds was also studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

In vitro studies were performed to elucidate the human cytochrome P450 enzymes involved in the bioactivation of methyleugenol to its proximate carcinogen 1'-hydroxymethyleugenol. Incubations with Supersomes, expressing individual P450 enzymes to a high level, revealed that P450 1A2, 2A6, 2C9, 2C19, and 2D6 are intrinsically able to 1'-hydroxylate methyleugenol. An additional experiment with Gentest microsomes, expressing the same individual enzymes to roughly average liver levels, indicated that P450 1A2, 2C9, 2C19, and 2D6 contribute to methyleugenol 1'-hydroxylation in the human liver. A study, in which correlations between methyleugenol 1'-hydroxylation in human liver microsomes from 15 individuals and the conversion of enzyme specific substrates by the same microsomes were investigated, showed that P450 1A2 and P450 2C9 are important enzymes in the bioactivation of methyleugenol. This was confirmed in an inhibition study in which pooled human liver microsomes were incubated with methyleugenol in the presence and absence of enzyme specific inhibitors. Kinetic studies revealed that at physiologically relevant concentrations of methyleugenol P450 1A2 is the most important enzyme for bioactivation of methyleugenol in the human liver showing an enzyme efficiency (kcat/Km) that is approximately 30, 50, and > 50 times higher than the enzyme efficiencies of, respectively, P450 2C9, 2C19, and 2D6. Only when relatively higher methyleugenol concentrations are present P450 2C9 and P450 2C19 might contribute as well to the bioactivation of methyleugenol in the human liver. A 5-fold difference in activities was found between the 15 human liver microsomes of the correlation study (range, 0.89-4.30 nmol min(-1) nmol P450(-1)). Therefore, interindividual differences might cause variation in sensitivity toward methyleugenol. Especially lifestyle factors such as smoking (induces P450 1A) and the use of barbiturates (induces P450 2C) can increase the susceptibility for adverse effects of methyleugenol.

In the present study, the cytochrome P450 mediated bioactivation of safrole to its proximate carcinogenic metabolite, 1'-hydroxysafrole, has been investigated for the purpose of identifying the human P450 enzymes involved. The 1'-hydroxylation of safrole was characterized in a variety of in vitro test systems, including Supersomes, expressing individual human P450 enzymes to a high level, and microsomes derived from cell lines expressing individual human P450 enzymes to a lower, average human liver level. Additionally, a correlation study was performed, in which safrole was incubated with a series of 15 human liver microsomes, and the 1'-hydroxylation rates obtained were correlated with the activities of these microsomes toward specific substrates for nine different isoenzymes. To complete the study, a final experiment was performed in which pooled human liver microsomes were incubated with safrole in the presence and absence of coumarin, a selective P450 2A6 substrate. On the basis of the results of these experiments, important roles for P450 2C9*1, P450 2A6, P450 2D6*1, and P450 2E1 were elucidated. The possible consequences of these results for the effects of genetic polymorphisms and life style factors on the bioactivation of safrole are discussed. Polymorphisms in P450 2C9, P450 2A6, and P450 2D6, leading to poor metabolizer phenotypes, may reduce the relative risk on the harmful effects of safrole, whereas life style factors, such as the use of alcohol, an inducer of P450 2E1, and barbiturates, inducers of P450 2C9, and polymorphisms in P450 2D6 and P450 2A6, leading to ultraextensive metabolizer phenotypes, may increase the relative risk.

Oxidation of flavonoids with a catechol structural motif in their B ring leads to formation of flavonoid quinone/quinone methides, which rapidly react with GSH to give reversible glutathionyl flavonoid adducts. Results of the present study demonstrate that as a thiol-scavenging agent for this reaction Cys is preferred over GSH and N-acetylcysteine. The preferential scavenging by Cys over GSH reported in the present study appeared not to provide a basis for detection of thiol-based flavonoid conjugates in biological systems. This is because physiological concentrations of GSH are substantially higher than those of Cys, which was shown to shift the balance of thiol conjugate formation in favor of glutathionyl adduct formation. Furthermore, the cysteinyl quercetin adducts, although not showing the reversible nature of the glutathionyl conjugates, appeared nevertheless to be unstable. Thus, as a biomarker for formation of reactive quercetin quinone/quinone methides in biological systems, detection of the glutathionyl conjugates or the N-acetylcysteinyl conjugates derived from them should still be the method of choice. At GSH levels that dominate the level of other cellular thiol groups, covalent addition of the quinone to other cellular thiol groups may be efficiently prevented. However, various tissues are known to contain higher levels of protein-bound sulfhydryl moieties than of nonprotein sulfhydryl groups, the latter consisting of especially GSH. Thus, the results of the present study indicate that in biological systems covalent addition of quercetin quinone methide to tissue protein sulfhydryl groups can be expected. The transient nature of these adducts, as shown for all three types of thiol quercetin adducts in the present study, will, however, also result in a transient nature of the protein-bound quercetin adducts to be expected. Because stability of the various thiol quercetin adducts appeared a matter of minutes to hours instead of days, this rapid transient nature of possible quercetin quinone methide adducts may also restrict the ultimate toxicity to be expected from the quercetin quinone/quinone methides.

Natural antioxidants like vitamin C, vitamin E, carotenoids, and polyphenols like flavonoids, are at present generally considered to be beneficial components from fruit and vegetables. The anti-oxidative properties of these compounds are often claimed to be responsible for various beneficial health effects of these food ingredients. Together these studies provide the basis for the present rapidly increasing interest for the use of natural antioxidants as functional food ingredients and/or as food supplements. However, at higher doses or under certain conditions antioxidant-type functional food ingredients may exert toxic pro-oxidant activities. The present manuscript gives an overview of especially this pro-oxidative chemistry and toxicity of well-known natural antioxidants including vitamin C, vitamin E, carotenoids and flavonoids.

Formation of quercetin quinone/quinone methide metabolites, reflected by formation of the glutathionyl quercetin adducts as authentic metabolites, was investigated in an in vitro cell model (B16F-10 melanoma cells). Results of the present study clearly indicate the formation of glutathionyl quercetin adducts in a tyrosinase-containing melanoma cell line, expected to be representative also for peroxidase-containing mammalian cells and tissues. The data obtained also support that the adducts are formed intracellular and subsequently excreted into the incubation medium and reveal for the first time evidence for the pro-oxidative metabolism of quercetin in a cellular in vitro model.

In the present study, the formation of glutathionyl adducts from a series of 3',4'-dihydroxy flavonoid o-quinone/p-quinone methides was investigated with special emphasis on the regioselectivity of the glutathione addition as a function of pH. The flavonoid o-quinones were generated using horseradish peroxidase, and upon purification by HPLC, the glutathionyl adducts were identified by LC/MS as well as (1)H and (13)C NMR. The major pH effect observed for the glutathione conjugation of taxifolin and luteolin quinone is on the rate of taxifolin and luteolin conversion and, as a result, on the ratio of mono- to diglutathione adduct formation. With fisetin, 3,3',4'-trihydroxyflavone, and quercetin, decreasing the pH results in a pathway in which glutathionyl adduct formation occurs in the C ring of the flavonoid, being initiated by hydration of the quinone and H(2)O adduct formation also in the C ring of the flavonoid. With increasing pH, for fisetin and 3,3',4'-trihydroxyflavone glutathione adduct formation of the quinone occurs in the B ring at C2' as the preferential site. For quercetin, the adduct formation of its quinone/quinone methide shifts from the C ring at pH 3.5, to the A ring at pH 7.0, to the B ring at pH 9.5, indicating a significant influence of the pH and deprotonation state on the chemical electrophilic behavior of quercetin quinone/quinone methide. Together the results of the present study elucidate the mechanism of the pH-dependent electrophilic behavior of B ring catechol flavonoids, which appears more straightforward than previously foreseen.