Current Bioactive Compounds - Volume 14, Issue 2, 2018
Volume 14, Issue 2, 2018
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Design and Synthesis of Benzimidazole-4-carboxamides as Potent Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors
Authors: Kalam B. Reddy, Gangula M. Rao, Baru V. Kumar, Chinmayee Choudhury and Kombu S. RajanBackground: A significant number of heterocyclic compounds were developed as poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Among them, 2-substituted benzimidazole-4- carboxamide derivatives have gained importance in comparison with other heterocyclic systems.A new library of benzimidazole 4-carboxamides were synthesised and screened for PARP-1 inhibitory activity. Method: A facile and convergent synthesis of 2-[(4-substitutedcarbamoyl)piperidine-1-yl)methyl]-1Hbenzimidazole- 4-carboxamides (9a-m) was achieved from 2-(hydroxymethyl)-1H-benzimidazole-4- carboxamide and piperidine-4-carboxamides (8a-m) using the Mitsunobu reaction. Standard PARP-1 inhibitors, 6(5H)-phenanthridinone and 4-amino-1,8-naphthalimide were procured from Sigma-Aldrich and the data generated from plate reader was exported to the GraphPad Prism (Version 4) statistical analysis software. The IC50 values were determined by plotting the concentration of compounds on xaxis and optical density values on the y-axis. The crystal structure 2rcw.pdb of PARP was used for the docking study. QSAR models were developed by using the heuristic method on CODESSA generated conventional descriptors with the purpose of deriving structural requirements of these inhibitors. The predictive ability of these compounds was verified by taking a set of five PARP inhibitors as a test set. Results: Structures of the compounds (9a-m) were established on the basis of 1H-NMR, 13C-NMR and mass spectral data. Overall, thirteen 2-substituted benzimidazole-4-carboxamide derivatives were synthesised and screened for PARP-1 inhibitory studies. Interactions of compounds library as well as the natural substrate NAD+ with the PARP active site residues were carefully analyzed and it was observed that these inhibitors form a wide range of interactions. Correlation between the docking score and each of their components with the PARP inhibitory activity of the compounds was studied. Conclusion: Among 2-[(4-substitutedcarbamoyl)piperidine-1-yl)methyl]-1H-benzimidazole-4-carboxamides (9a-m), compound 9a with isoquinolinyl group attached to piperidinyl-4-carboxamide group is highly suitable for the PARP-1 inhibitory activity and compounds 9b, 9e, 9g and 9l have also shown good inhibitory activity.
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Pseudonocardiaceae sp. TD-015 from the Thar Desert, India: Antimicrobial Activity and Identification of Antimicrobial Compounds
Background and objective: Isolate TD-015, obtained from the Thar Desert (India), was subjected to investigation for its antimicrobial activity and identification of the contributing compound(s). Method: TD-015 was isolated from the Thar Desert (India), identified by 16S rDNA sequencing and analyzed for the hyper-variable regions. Culture supernatant of TD-015 was tested for antimicrobial activity following organic solvents extraction of the metabolites. The bioactive compounds were extracted from the filtrate culture with ethyl acetate, purified and analyzed using thin layer chromatography and GC-MS procedures. In silico prediction of nearest identified compounds was carried out using the software Prediction of Activity of Spectra for Substances (PASS). Results: TD-015 was identified by 16S rDNA sequencing and analysis of variable region specific for members of Pseudonocardia. Based on 16S rDNA sequence data, isolate TD-015 was identified as belonging to the rare actinomycete genus Pseudonocardia with 91.86% similarity to Yuhushiella deserti. Analysis of the variable region showed that TD-015 was related to members of Pseudonocardiaceae, but formed a distinct clade. Aqueous and ethyl acetate extracts of culture supernatant showed antimicrobial activity against Staphylococcus epidermidis, Micrococcus luteus, Bacillus subtilis, Brevibacterium linens, Pseudomonas fluorescens and a clinical isolate of Escherichia coli (from urine). GC-MS data of the antimicrobial fractions showed nearest identity to two compounds, Dehydroabietic Acid (DHA) and Methyl Dehydroabietate (MD), which were predicted to have antimicrobial activity as per in silico analysis. However, combined analyses of the retention time (RT), similarity index (SI), mass ion spectra (MS) and retention indices (observed and calculated) of these two compounds suggests that they could be potentially novel. Conclusion: We conclude that understudied extreme habitats like Thar Desert continue to be important sources of novel actinomycetes and potential chemodiversity.
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Anti Cancer, Molecular Docking and Structure Activity Relationship Studies of Some Novel Synthetic Spiroindolo[3,2-b]Carbazoles as Predicted HER2 and BrK Kinase Inhibitors
Background: Spirocyclic compounds are important because of their unique structure and diverse biological activities. The indolo-spirocyclic scaffold is regularly found as a core structure of a representative family of bioactive natural products and among pharmaceutics, like alstonisine and spirotyprostatine. In the present work, indolo-spirocyclic compounds 3a-g and 4a,b have been successfully synthesized via electrophilic condensation reactions of indoles with a-cyclic ketones, including cyclopentanone, demidone, cyclohexane-1,3-dione, bicyclo[3.2.0]hept-2-en-6-one and isatin. Revised structure for compound 3c is described. All the synthesized compounds were subjected for the in- vitro cytotoxicity assays against A-549 (human lung carcinoma), MCF-7 (human breast carcinoma) and HCT-116 (human colon carcinoma) cell lines. Methods: Cell viability was investigated using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. This assay depends on the mitochondrial reduction of yellow MTT into purple formazan. All incubations were carried out at 37oC in 5% CO2 incubator in humidified atmosphere (Sheldon, TC2323, and Cornelius, OR, USA). Cells were seeded into 96-well microtiter plastic plates at the concentration (104 cells per well) and allowed to adhere for 24 hours. Medium was aspirated and fresh medium (without serum) was added to the cells with various concentrations of the test compounds (100, 50, 25, 12.5, 6.25, 3.12, 1.56 and 0.78 μg/mL in DMSO) and incubated for 48 hours. Results: The tested components exhibited distinctive pattern of anticancer activity against all tested cancer cell lines. The more potent candidates were 3a, 3b, 3c, 3f, 3h, and 4b, which gave the high percent of growth inhibition (cytotoxicity), ranging from 85.7% to 98.6%. For the human breast adenocarcinoma MCF-7 cell line, compound 3c exhibited the highest activity, compared to other spirocyclic indoles and to the reference drug doxorubicin (IC50=31, 37.6, 38.2 with respect to the used cancer cell lines) with IC50= 3.4 μg/ml. Compound 3c was docked into the crystal structure of the kinase domain of Human HER2 and BrK, which are most commonly associated with human breast adenocarcinoma MCF-7 cell line. SAR and QSAR studies have been described. Conclusion: Ten indolo-spirocyclics 3a-g and 4a,b candidates have been successfully synthesized. All the synthesized compounds were screened for their in-vitro anticancer activities in National Research Centre in Egypt, against A-549, MCF7 and HCT-116 cancer cell lines. As a result, they exhibited distinctive pattern of anticancer activity against all tested cancer cell lines. The most potent candidates were 3a, 3b, 3c, 3f, 3h, and 4b, which gave the highest growth of inhibition percent (cytotoxicity), ranging from 85.7% to 98.6%. For the human breast adenocarcinoma MCF-7, compound 3c exhibited the overall highest activity compared with the other spirocyclic indoles and with the reference drug doxorubicin with IC50: 3.4 μg/ml. Compound 3c was docked into crystal structure of the most common associated protein kinase domains of human MCF-7 cell line, which are kinases HER2 and BrK. SAR and QSAR of compounds under investigation were described.
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Quinoline Fused 2-Azetidinone Derivatives bearing Dihyropyrimidinone: Benign Synthesis and its Pharmacological Assessment
Authors: Ambareen Shaikh and Jyotsna S. MeshramBackground: Literature review for azetidinone and its derivatives suggested its wide applications in almost every stratum. However, despite the evergreen applicative profile, an increase in resistance towards specific class has been on a parallel increase. Thus, in view of the versatility in synthetic method and step into further assessing the pharmacological profile of this class of compounds, it was thought to synthesize the 2-azetidinone heterocycles as new congeners of DHPM by incorporating the quinoline moiety in a single molecular framework. Thus, considering this fact, herein we report a simple, novel and environmentally benign approach using facile, microwave synthesis of 2-azetidinone derivatives of dihydropyrimidinone. Method: Following literature review, we carried out the synthesis of our target compounds following a simple reflux method using microwave irradiation. Results: Varied 2-azetidinone derivatives dihydropyrimidinone incorporating the quinoline motif have been synthesized via a facile and benign synthetic protocol. The products were synthesized in fairly good yields (62-84%) under solvent less and microwave conditions. All the synthesized compounds were characterized by FTIR, 1H NMR and elemental analyses. The compounds were screen for their in vivo anti-inflammatory and analgesic activities on Wistar albino rats using Diclofenac and Indomethacin as standard reference drugs respectively and in vitro anti-bacterial activity against some Gram positive and Gram negative strains of bacteria using Ampicillin and Streptomycin as standard reference. This pharmacological assessment data revealed that compounds showed moderate to good antiinflammatory activity, while some compounds showed the exceptional analgesic effect. Moreover, some compounds also gave excellent results for the anti-bacterial activity evaluation against the selected strains of bacteria. Conclusion: To conclude, a series of varied 2-azetidinone derivatives bearing dihydropyrimidinone skeleton was synthesized in good yields and less reaction time under solvent less and microwave conditions. The fairly good observed yields and improved reaction rates have been attained by utilizing this solvent less condition and the use of microwave radiation. The method thus describes a facile and benign methodology of synthesis thereby providing it a green chemistry approach. The present study thus reveals exceptional anti-inflammatory, analgesic and anti-bacterial potential of the synthesized compounds and thus it opens new doors in the field of Medicinal Drug Chemistry.
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Evaluation of Anti-diarrheal Activity of Probiotic by Castor Oil Induced Diarrhoea in Swiss Albino Mice Model
Authors: Himanshu K. Solanki, Dushyant A. Shah, Chirag A. Patel and Girish K. JaniBackground: Diarrheal disease is a leading cause of mortality and morbidity, especially among children in the developing countries resulting in a major health care problem. So, the present study was designed to investigate antidiarrheal activity and mechanism of action of probiotic using the Swiss mice model of castor oil induced diarrhea. Methods: In the current study, we selected the model of diarrhea induced by castor oil in the Swiss albino mice to examine the effects of preventive treatment containing single as well as multiple oral administrations of probiotic Bacillus coagulans Unique IS2 and Bifidobacterium bifidum at dose 1010 CFU/kg and to examine the mechanisms of action of probiotic by studying its co-administration with antagonist L-arginine. During an observation period, the time of onset of diarrhea, total quantity of faecal output and weight of faeces defecated by the animals were documented. Results: Probiotic Bacillus coagulans Unique IS2 and Bifidobacterium bifidum at dose 1010 cfu/kg, p.o. significantly (p < 0.05-0.001) reduced the faecal output and delayed the onset of diarrhea induced by castor oil when matched with the diarrheal control The effect of probiotic Bacillus coagulans Unique IS2 and Bifidobacterium bifidum was significantly reduced by antagonist L-arginine. Conclusion: The experimental findings suggest a unique mechanism of action for probiotic Bacillus coagulans Unique IS2 and Bifidobacterium bifidum comprising a probable inhibition of nitric oxide production by probiotic. Probiotic Bacillus coagulans Unique IS2 and Bifidobacterium bifidum possess good antidiarrhoeal use as biotherapeutic agent in the treatment of diarrhea.
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Modulation of a Cellular Transport Activity by Capsicum Extracts
Authors: Jie Chen, Vai H. Fong and Amandio VieiraBackground: Microbes are often internalized by host cells as part of the infection process. Compounds that can modulate such uptake may have applications in prevention of infectious diseases. Capsaicinoids, capsinoids, and other Capsicum sp. components are reported to target several pathological processes including microbial infections. Capsicum phytochemicals can alter biophysical properties of animal cell membranes, and such effects may contribute to putative therapeutic effects. Method: Standardized Capsicum (Cayenne pepper) extracts were analyzed for their capacity to modulate membrane transport. Transferrin (Tf), a well-characterized ligand for studies of receptor-mediated endocytosis, was analyzed in a mammalian epithelial cell line. Results: The extracts inhibited transport, IC50 84.2 +/- 4.8 GAE units (p < 0.05 relative to controls). At similar Capsicum polyphenol concentrations, no statistically significant effects (p >> 0.05) were observed for Tf binding or recycling. Conclusion: The results indicate a novel bioactivity of Capsicum, and provide a possible functional mechanism that complements changes in membrane structure and reported anti-infection activities.
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Synthesis and Anticonvulsant Activity of Some Novel Semicarbazone Containing Benzoxazole: Pharmacophore Model Study
Authors: Ravitas Deshmukh, Alok S. Thakur, Arvind K. Jha and Sudhir P. KumarBackground: Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Approximately 60 million people worldwide suffer from epilepsy, making this condition the second leading neurological disorder. Epilepsy also affects about 4% of individuals over their lifetime. The most commonly used anticonvulsant drugs are associated with numerous side effects including ataxia, hepatotoxicity and megaloblastic anemia. This review aims that there is a vast requirement for the development of drugs which is more effective and having safer antiepileptic properties. Method: 5-Chloro-2(3H)-benzoxazolone(i) was synthesized by the reaction of 2-amino-4- chlorophenol and urea in concentrated HCl at 140-180°C. Compound i reacted with 1,4-diamine and reflux it for 1hr in the presence of methanol and glacial acetic acid to get the compound ii. This compound was then treated with sodium cyanate in the presence of glacial acetic acid to get the urea derivative of the compound i.e. compound iii, then the compound iii was reacted with hydrazine hydrate to get the compound iv, then these compound was converted to semicarbazones by condensing it with an aryl/alkyl aldehyde & ketone in the presence of ethanol & glacial acetic acid. Results: In the electroshock method, two compounds (Ve and Vl) were found extensively active as these compounds showed protection at the low dose of 30mg/kg after 0.5h. These compounds also showed the activity after 4.0h, but at the higher dose indicating that the compounds show rapid onset of action as well as the duration of action. Substitutions at the hydrophobic site showed that the compounds give better activity. The substitutions are done at the para position of the hydrophobic aryl ring with the electron withdrawing groups. In the ScPTZ model, compounds showed good anticonvulsant activity, compounds that showed protection at 100mg/kg after 0.5h wereVd, Ve, Vh, Vk and Vl. Among these compounds, Ve and Vlwere found to be active because these compounds showed the activity at the same dose after 4.0h. Conclusion: All the newly synthesized compounds were investigated for the anticonvulsant activity against maximal electroshock-induced seizures (MES) and subcutaneous Pentylenetetrazole (scPTZ) models and their neurotoxicity was also evaluated by the rotarod test. Most of the compounds were found active in the biological screening. The results of the present study confirmed the requirementsof various structural features of four binding site pharmacophore model for anticonvulsant activity.
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Synthesis and Antibacterial Activities of Novel Sulphonamide Containing 1, 3-diarylpyrazolyl Amides
Authors: Laxmikant S. Pavase, Dhananjay V. Mane and Kamalkishor BahetiBackground: Infectious diseases are the leaders among the challenging drug targets because of the multi-drug resist antimicrobial pathogens and continuous rise in the emerging infections from known and unknown sources. Though there is an availability of a large number of antibiotics and chemotherapeutics for medical use, the emerging resistance drives it for the search of new classes of antimicrobial agents. In the present study, a series of novel amides (5a-j) containing 1, 3-diaryl pyrazoles were synthesized, characterized and evaluated for their anti-bacterial properties against gram - positive organisms (B. subtilis) and gram - negative organisms (E. coli). Method: The evaluation of the synthesized compounds (5a-j) for antibacterial activity was carried out by standard literature procedure using agar diffusion method by finding the zone of inhibition of the drug sample against the standard drugs. The organisms employed in vitro testing of the compounds were Escherichia coli (Gram Negative) and Bacillus subtilis (Gram Positive). All the cultures were maintained on Nutrient agar (Microbiology) grade, Hi Media medium by periodic sub culturing. Ciprofloxacin was used as reference compound for antibacterial activity. The compounds were tested at a concentration of a 50 μg/ml and 100 μg/ml and were prepared in Dimethylsulphoxide. Obtained zone of inhibition at tested concentrations was recorded. Minimum inhibitory concentrations (MIC) assay of two superior molecules 5e and 5f was done according to CLSI standard protocol. Ciprofloxacin was used as a standard drug. The minimum inhibitory concentrations (MIC) values were determined. Results: The structures of these novel compounds were confirmed by 1H NMR, ES-MS and elemental analysis. Ciprofloxacin was used as standard reference compound. In the initial inhibitory study at 100 μg/ml, compounds 5e (12 ± 0.816) and 5f (17 ± 0.816) demonstrated comparable zone of inhibition with ciprofloxacin (20.66 ± 0.942) in E. coli strain, while for B. subtilis, at 100μg/ml, compounds 5e (25.66 ± 0.942) and 5f (26.33 ± 0.942) were found to be equipotent as compared to standard ciprofloxacin (27.66 ± 0.471). Hence 5e and 5f were tested for their MIC values (μg/ml) using E. coli and B. subtilis bacterial strains. To summarize, 5e (MIC = 8μg/ml for E. coli and MIC = 4 μg/ml for B. subtilis) and 5f (MIC = 16 μg/ml for E. coli and MIC = 8 μg/ml for B. subtilis) showed better MIC values than the standard Ciprofloxacin (MIC = 20 μg/ml for E. coli and MIC = 12 μg/ml for B. subtilis). Conclusion: We have discovered a series of 1, 3 diaryl pyrazolyl amides, and preliminary bioassay results imply that some of the compounds displayed moderate antibacterial activities against various bacterial species. Two promising compounds 5e and 5f exhibited superior MIC (μg/ml) values in vitro when compared with standard drug. Compounds 5e and 5f were the new findings from this research work and it will be studied further in near future.
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Novel Triazolothiadiazole and Triazolothiadiazine Derivatives Containing Pyridine Moiety: Design, Synthesis, Bactericidal and Fungicidal Activities
Background: One of the important chemical agents in designing of anti-convulsant, antiatherosclerotic and anti-cancer drugs are pyridine derivatives. Alkyl and aryl derivatives of cyanopyridones show antimicrobial, antihypertensive, anti-inflammatory, analgesic, antipyretic properties as well as 1KK-b inhibitor properties. Methods: N-acyclic nucleosides 2-5 were synthesized by the reaction of the sodium salt of (4- chlorophenyl)-2-oxo-6-(thien-2-yl)-1,2-dihydroyridine-3-carbinitrile (1) with the halo derivatives: 2- chloroethanol, chloroacetaldehyde dimethylacetal, 2-chloroethyl methyl ether, and 2-(2- chloroethoxy)ethanol, respectively. On the other hand, the reaction of compound 1 with ethyl bromoacetate gave ethyl {2-((4-(4-Chlorophenyl)-3-cyano-6-(thien-2-yl)pyridin-2-yl)oxy)} acetic acid ester (6). Then, compound 6 reacted with thiocarbohydrazide or ethanolic sodium hydroxide solution producing 4-amino-5-thioxotriazolo derivative 7 or the free acid 8, respectively. Moreover, the reaction of compound 8 with thiosemicarbazide in the presence of phosphorus oxychloride gave the 5- aminothiadiazolyl derivative 9, which in turn gave the 5-oxothiadiazolyl derivative 10 upon nitrozation. Furthermore, compound 7 gave products 11, 13-19 when reacted with 4-chlorobenzaldehyde, isothiocyanate, benzoyl chloride, acetic anhydride, triethylorthoformate, carbon disulfide, , phenacyl bromide, bromoacetic acid, respectively. Finally, all the synthesized compounds were evaluated for their antibacterial Gram (+) and Gram (-) and anti-fungal activities. Results: Three compounds 2, 11 and 17 have high activity against pathogenic bacterial strains and gave inhibition zones ranged between 25 and 38 mm. Moreover, compounds 9, 10, 11, 12 and 18 showed auspicious anti-fungal activity. The MIC of the produced derivatives was calculated and the results indicated that some compounds had bioactivity up to 10 μg/ml. Conclusion: The new synthesized triazolothiadiazole and triazolothiadiazine derivatives containing pyridine moiety showed good bactericidal and fungicidal activities.
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Pharmacognostical Evaluation and HPTLC Fingerprinting Identification of Ficus palmata Forssk. (Bedu) from Western Himalaya
Authors: Devesh Tewari, Archana N. Sah, Sweta Bawari, Himanshu Sharma and Anupam K. MangalBackground: This paper aims at establishing pharmacognostic parameters and anatomical descriptors of Ficus palmata Forssk. (Bedu) for the first time by utilizing more sophisticated modalities like HPTLC fingerprinting and scanning electron microscopy (SEM) in addition to the conventional analytical techniques. Ficus palmata Forssk. is a well known, yet minimally explored plant of western Himalaya despite its tremendous traditional value. Hence, no monograph stating its standardization or rather its pharmacognostic standardization is so far available. Objective: To establish the pharmacognostic standardization parameters of Ficus palmata Forssk. and to perform its anatomical and analytical evaluation by means of scanning electron microscopy and HPTLC fingerprinting, respectively. Method: Pharmacognostical evaluation including microscopy and SEM analysis of the leaves and fruits of Ficus palmata collected from the western Himalayan region of India was done along with preliminary phytochemical screening, fluorescence analysis, and HPTLC fingerprinting studies of fruits of the plant. Results: Presence of carbohydrates, alkaloids, tannins, saponins, lipids and phenols was confirmed in Ficus palmata through phytochemical screening. The physicochemical analysis provided standard ranges for parameters like moisture content, ash values and extractive values. Characteristic anatomical structures such as abundant trichomes, paracytic stomata, lignified fibres, cortex, sclerenchyma, pith with hexagonal cells were observed and stomatal index, vein islet number, and palisade ratio were established. HPTLC fingerprinting revealed the presence of the complex bioactive chemical composition of the extract. Conclusion: The study is an attempt to establish the quality control parameters pertaining to phytochemical, microscopical and anatomical characteristics of F. palmata. The results of the study provide a useful application of the pharmacognostic studies, scanning electron microscopy and HPTLC for quality control of the leaves and fruits of F. palmata.
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Composition and Cytotoxic Activity of the Essential Oils of Mentha mozaffarianii Jamzad at Different Phenological Stages
Authors: Amir R. Jassbi, Younes Mirzaie, Omidreza Firuzi and Mojtaba AsadollahiBackground: The essential oils of Mentha species are used in pharmaceutical, cosmetic and perfume industry and also for flavoring and preservation of several food. Moreover, Mint's essential oils are also searched for their biological activities such as antimicrobial, antioxidant, and cytotoxic properties. Mentha mozaffarianii is an endemic medicinal mint of Iran rich in essential oil, but not yet studied for its cytotxic activity nor the effect of changing seasons on its chemical composition and biological activity. Method: We analyzed the chemical constituents of essential oils (EOs) of M. mozaffarianii at different phenological stages (vegetative, flowering and seed set) by GC-MS and GC-FID. Also, the EOs were evaluated for their cytotoxic potential on three human cancer cell lines namely, breast adenocarcinoma (MCF-7), acute lymphoblastic leukemia (MOLT-4) and acute promyelocytic leukemia cells (HL-60) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Results: Twenty seven, 26 and 25 compounds were detected in the oils at vegetative, flowering and seed set stages, respectively. The predominant components in the oils of the plant were: piperitone oxide (32.9±1.2, 35.3±1.2 and 51.5±0.6%), linalool (14.1±0.3, 17.1±0.6 and 8.7±016%), 1,8-cineole (11.6±1.4, 9.5±0.3 and 8.3±0.26%) and piperitenone oxide (9.8±0.4, 8.1±0.3 and 1.7±0.05%), during the above mentioned developmental stages, respectively. EOs of M. mozaffarianii at the different phenological stages showed the highest cytotoxic activities against MOLT-4 (IC50s: 26.5±6.7, 26.5±2.3 and 22.3±5.4 μg/mL, respectively) followed by HL-60 and MCF-7 cell lines. Conclusion: The results of the present study indicate that the EOs obtained from different phenological stages of the plant showed relatively high cytotoxic activity, which can be attributed to the presence of the oxygenated monoterpenes with highest amounts of piperitone oxide and its derivatives.
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Identification of Lactate Dehydrogenase 5 Inhibitors using Pharmacophore-driven Consensus Docking
Background: Human lactate dehydrogenase 5 (hLDH5) represents a promising anticancer target, particularly for the treatment of hypoxic tumors, where it is often hyperexpressed. In fact, by catalyzing the reduction of pyruvate to lactate, hLDH5 allows the survival of tumor cells under hypoxic conditions by means of glycolysis. Despite the efforts dedicated to the identification and development of hLDH5 inhibitors, only few compounds showing promising activity in cancer cell lines have been reported. Objective: In the present study, we developed a virtual screening (VS) protocol aimed at identifying new small molecule inhibitors of hLDH5. Method: The VS strategy consisted in a pharmacophore-driven consensus docking (CD) approach, combining a structure-based pharmacophore screening and CD protocol employing three different docking methods. Results: The VS protocol was applied to filter the Enamine commercial database and allowed the selection of three candidate ligands to be subjected to hLDH5 inhibition assays. One of the selected compounds showed a promising activity, compared to its low molecular weight, with an IC50 of 180.7 ± 16.5 μM. Conclusion: We identified a new small-molecule inhibitor of hLDH5 that can be considered as a new lead for the development of potent hLDH5 inhibitors. Moreover, these results demonstrate the reliability of the VS protocol developed.
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Identification of Anticandidal Cyclic Trisaccharide from Alhagi pseudalhagi Plant
Authors: Ahmed Z. Abdel Azeiz and Myrna S. ShehataBackground: Alhagi pseudoalhagi (Camel thorn) is a herbaceous perennial plant. Recently, several investigations have been conducted for its medical and pharmaceutical applications. Methods: The aerial part of the plant was air dried and extracted by different solvents with increasing polarity. The residue from each extract was in-vitro tested against C. albicans that has been previously isolated from vaginal candidiasis patients. The ethyl acetate extract showed anti-candidial activity and showed presence of two compounds on the TLC plate eluted with methanol. This extract was further purified by silica gel column eluted with methanol. The obtained two compounds were tested against C. albiacns and the purity of the active compound was confirmed by reversed phase HPLC with methanol as a mobile phase and detected at 240nm. The chemical structure of the active pure compound was elucidated by mass spectrometry, 1D and 2D-NMR and IR analysis. Result: The NMR analyses characterized three sugar molecules cross-linked in a cyclic structure. These three building units are: (4,6-dideoxy,6-methyne, α,D,glucopyranose), (β, D,1-deoxy, 1-methyne, fructofuranose), and (2-deoxy, 3-methyne, 4,6-epoxy, fructofuran). The three units are cross-linked through the methyne group that bind with C6 of 4,6-dideoxy, 6-methyne, α,D-glucopyranose, C1 of 1-deoxy, 1- methyne, fructofuranose and with C3 of 2-deoxy, 4,6-epoxy, 3-methyne, fructofuran moieties. The COSY, HSQC, HMBC and TOCSY analyses confirmed the elucidated structure with a molecular formula C19H26C11 and MW = 430.4. Conclusion: The result from this research identified for the first time the cyclic trisaccharide glycoside from Alhagi pseudoalhagi with antifungal activity against C. albicans.
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Podophyllotoxin: Current Perspectives
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