Characterization of C-phycocyanin antioxidant, anti-inflammatory, anti-tumour, and anti-HCoV-229E activities and encapsulation for implementation in an innovative functional yogurt.

Functional bioactive ingredients isolated from microalgae as sustainable sources have become a new subject of pharmacology and functional foods. Thus, the work aims to produce crude phycocyanin (C-PC), define it, and investigate its pharmacological effects before warping it in a nanophytosome. Subsequently, the physicochemical properties of nanoparticles were evaluated. Both free and nanophytosomes of C-PC were incorporated into cow milk fermented with the probiotic Lactobacillus rhamnosus KU985435 to make functional yoghurt and the stability of C-PC of both phytosomes was assessed. The amino acid content of C-PC revealed the presence of eight of nine essential amino acids and eight of eleven non-essential amino acids. C-PC has a medium molecular weight (82.992 kDa). Some pharmacological effects like reducing inflammation (98.76 % ± 0.065), fighting free radicals (99.12 % ± 0.027), and being able to inhibit the human coronavirus 229 E with a selective index of 27.9 were observed. The maximum viral inhibitory activity was detected during the adsorption stage. Anti-human liver and colon carcinomas that exceeded Doxorubicin with very low cytotoxicity against normal cell lines were detected. C-PC is an unstable protein that could be degraded in the yoghurt during storage. Therefore, phytosome encapsulation can effectively stabilize C-PC (particle size 44.50 ± 12 nm and zeta-potential -32.4 ± 5 mV) and protect it from the acidic environment of the yoghurt. The produced yoghurt showed the desired physicochemical and functional properties and overall acceptance. The results prove that C-PC from spirulina algae is a renewable source of dyes. The encapsulation process using phytosomes gave it high stability against environmental influences, and therefore, it can be applied in the food and pharmaceutical industries in the future.

EGFR and PI3K/m-TOR inhibitors: design, microwave assisted synthesis and anticancer activity of thiazole-coumarin hybrids.

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.

Synthesis, molecular modeling Insights, and anticancer assessment of novel polyfunctionalized Pyridine congeners.

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.

Design, Synthesis, and Antiproliferative Activity of Novel Neocryptolepine-Rhodanine Hybrids.

A series of novel neocryptolepine-rhodanine hybrids (9a,b, 11a-d, 14, and 16a,b) have been synthesized by combining neocryptolepine core 5 modified at the C-11 position with rhodanine condensed with the appropriate aryl/hetero aryl aldehydes. Based on these findings, the structures of the hybrids were confirmed by spectral analyses. By employing the MTT assay, all hybrids were tested for their in vitro antiproliferative activity against two cancer cell lines, including MDA-MB-231 (human breast) and HepG-2 (hepatocellular carcinoma). Interestingly, the IC50 values of all hybrids except 9b and 11c showed activity comparable to the standard anticancer drug, 5-fluorouracil, against HepG-2 cancer cells. Furthermore, the cytotoxicity of all the synthesized hybrids was investigated on a normal skin human cell line (BJ-1), and the results showed that these compounds had no significant cytotoxicity toward these healthy cells at the highest concentration used in this study. This study also indicated that the active hybrids exert their cytotoxic activity via the induction of apoptosis. A molecular docking study was used to shed light on the molecular mechanism of their anticancer activity. The docking results revealed that the hybrids exert their mode of action through DNA intercalation. Furthermore, in silico assessment for pharmacokinetic properties was performed on the most potent compounds, which revealed candidates with good bioavailability, high tolerability with cell membranes, and positive drug-likeness values.

Synthesis, Biocidal and Antibiofilm Activities of New Isatin-Quinoline Conjugates against Multidrug-Resistant Bacterial Pathogens along with Their In Silico Screening.

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.

Design, Synthesis, Anticancer Activity and Molecular Docking of New 1,2,3-Triazole-Based Glycosides Bearing 1,3,4-Thiadiazolyl, Indolyl and Arylacetamide Scaffolds.

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.

Antiproliferative Activity of Some Newly Synthesized Substituted Nicotinamides Candidates Using Pyridine-2(1H) thione Derivatives as Synthon.

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.

Design, synthesis, and molecular modeling of coumarin derivatives as MDM2 inhibitors targeting breast cancer.

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 IC50s 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.

Novel benzothiazole-based dual VEGFR-2/EGFR inhibitors targeting breast and liver cancers: Synthesis, cytotoxic activity, QSAR and molecular docking studies.

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 IC50 of 0.73-0.89 µM, against MCF-7 and IC50 of 2.54-2.80 µM, against HepG-2; compared to doxorubicin (IC50 = 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 IC50 of 5.45-7.28 µM, relative to doxorubicin (IC50 = 7.46 µM) surpassing their carboxylic acid analogues 10-12 (IC50 of 8.88-11.02 µM). Furthermore, the promising derivatives 10-12 and 21-23 displayed promising VEGFR-2 inhibitory activity (IC50 = 0.15-0.19 µM) comparable to that of sorafenib (IC50 = 0.12 µM). Against EGFR, the ethyl ester derivatives 21-23 showed superior inhibitory activity relative to the used reference standard, erlotinib, with IC50 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.

Identification of 'Voodoo': an emerging substance of abuse in Egypt.

BACKGROUND: 'Voodoo' is a new substance of abuse that recently spread among youth in Egypt. It has numerous potentially dangerous effects on humans. However, to date the composition of the main constituents of this compound is unknown. PURPOSE: We sought to identify the active components of this unknown substance"voodoo". METHODS: Three samples were collected and analysed by high-performance liquid chromatography with photodiode array detector (HPLC-PAD), gas chromatography/mass spectrometry (GC/MS), and ultra-performance liquid chromatography/mass spectrometry (UPLC-MS/MS) using targeted multiple reaction monitoring (MRM). RESULTS: HPLC-PAD analysis showed that samples 1 and 2 had some common major peaks, the same retention time, and similar spectra, whereas sample 3 showed different peaks. GC/MS analysis revealed the presence of various putatively identified bioactive compounds, including quinazolines, morphinan alkaloid, cannabinoids, penitrem A, and the well-known synthetic cannabinoid FUB-AMB (methyl(2S)-2-{[1-[(4-fluorophenyl)methyl]indazole-3-carbonyl]amino}-3 methylbutanoate). UPLC-MS/MS analysis revealed the presence of common compounds such as tetrahydrocannabinol (THC), amphetamine, 3,4-methylenedioxyamphetamine, tramadol, and oxazepam. CONCLUSION: We concluded that Voodoo is a mixture of substances of abuse at varying concentrations.

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors.

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.

Synthesis, anticancer evaluation and molecular docking of new benzothiazole scaffolds targeting FGFR-1.

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 (IC50 HepG-2 = 2.06, 2.21 µM and IC50 MCF-7 = 0.73, 0.77 µM, respectively) through their promising FGFR-1 suppression effects (IC50 = 16.31 and 18.08 nM, respectively) in comparison to AZD4547 (IC50 = 21.45 nM). Cell cycle and apoptosis analysis indicated that compounds 3 and 8 induce pronounced increase in the cell percentages at pre-G1 and G2/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.

The environmental distribution and removal of emerging pollutants, highlighting the importance of using microbes as a potential degrader: A review.

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.

Graphene enhanced detoxification of wastewater rich 4-nitrophenol in multistage anaerobic reactor followed by baffled high-rate algal pond.

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-Gn) as an electron acceptor to detoxify wastewater industry. The half maximal inhibitory concentration (IC50) was reduced from 455 ± 22.5 to 135 ± 12.7 µg Gallic acid equivalent/mL at 4-NP loading rate of 47.9 g/m3d. Furthermore, 4-NP was decreased by a value of 83.7 ± 4.9% in MAR-Gn compared to 65.6 ± 4.8% in control MAR. The 4-aminophenol (4-AP) recovery was accounted for 44.8% in the MAR-Gn 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-Gn 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-Gn 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.

Synthesis, anticancer activity and molecular docking of new triazolo[4,5-d]pyrimidines based thienopyrimidine system and their derived N-glycosides and thioglycosides.

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 N1-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.

Strengthen "the sustainable farm" concept via efficacious conversion of farm wastes into methane.

With escalating global demand for renewable energy, exploitation of farm wastes (i.e., agriculture straw wastes (ASWs), livestock wastewater (LW) and sewage sludge (SS)) has been considered to attain maximum methane yield (MY) via anaerobic digestion (AD). Results pointed that mixture of SS and LW as anaerobes' source with 20 g of ASWs/300 mL of working volume achieved maximum MY and volatile solid (VS) removal efficiency of 0.44 (±0.05) L/gVS and 51.4 (±4.1)%, respectively. This was mainly because of emerging heavy duty bacterial species (i.e., Syntrophorhabdaceae and Synergistaceae) and archaeal community (i.e, Methanosarcina and Methanoculleus) after 70 days of anaerobic incubation. This was acquired along with boosting enzymatic activity, especially xylanase, cellulase and protease up to 71.5(±7.9), 179.3(±14.3) and 207.2(±16.2) U/100 mL, respectively. Furthermore, the digestate contained high concentrations of NH4+ (960.1±(76.8) mg/L), phosphorus (126.3±(10.1) mg/L) and trace metals, making it a good candidate as organic fertilizer.

Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity.

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--C2 functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C2-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)-1H-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 IC50 values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC50 0.394 µM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC50 ranges of 31.3-49.0, 19.3-55.5, 22.7-44.8, and 36.8-70.7 µM, respectively compared to doxorubicin (IC50 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.

Erratum: Elshafie et al. Biological and Spectroscopic Investigations of New Tenoxicam and 1.10-Phenthroline Metal Complexes. Molecules 2020, 25, 1027.

The authors of this paper [...].

Design, Synthesis, Anticancer Evaluation, Enzymatic Assays, and a Molecular Modeling Study of Novel Pyrazole-Indole Hybrids.

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 1H-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-((1H-indol-3-yl)methyleneamino)-N-phenyl-3-(phenylamino)-1H-pyrazole-4-carboxamide (7a) and 5-((1H-indol-3-yl)methyleneamino)-3-(phenylamino)-N-(4-methylphenyl)-1H-pyrazole-4-carboxamide (7b) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC50 values of 6.1 ± 1.9 and 7.9 ± 1.9 µM, respectively, compared to the standard reference drug, doxorubicin (IC50 = 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.

Assessment of exopolysaccharides, bacteriocins and in vitro and in vivo hypocholesterolemic potential of some Egyptian Lactobacillus spp.

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 IC50 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.