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Find video protocols related to scientific articles indexed in Pubmed.
Cochlearols A and B, Polycyclic Meroterpenoids from the Fungus Ganoderma cochlear That Have Renoprotective Activities.
Org. Lett.
PUBLISHED: 11-18-2014
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(+)- and (-)-cochlearols A (1) and B (2), two meroterpenoids with novel polycyclic skeletons, were isolated from the fruiting bodies of the fungus Ganoderma cochlear. Their structures and stereochemistry were determined by using spectroscopic, computational and single-crystal X-ray diffraction methods. Cochlearol A is a new normeroterpenoid containing a naturally unusual dioxaspiro[4.5]decane motif. Biological studies showed that (-)-2 is a strong inhibitor of p-Smads, exhibiting renoprotective activities in TGF-?1 induced rat renal proximal tubular cells.
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miR-200a Overexpression in Advanced Ovarian Carcinomas as a Prognostic Indicator.
Asian Pac. J. Cancer Prev.
PUBLISHED: 11-07-2014
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miR-200a expression is frequently altered in numerous cancers. The aim of the present study was to determine the role of microRNA-200a in advanced ovarian carcinomas.
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Synthesis and antifungal activity of 1,2,3-triazole phenylhydrazone derivatives.
Org. Biomol. Chem.
PUBLISHED: 11-07-2014
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A series of 1,2,3-triazole phenylhydrazone derivatives were designed and synthesized as antifungal agents. Their structures were determined based on (1)H-NMR spectroscopy, MS, elemental analysis and X-ray single-crystal diffraction. The antifungal activities were evaluated against four phytopathogenic fungi including Rhizoctonia solani, Sclerotinia sclerotiorum, Fusarium graminearum and Phytophthora capsici, by the mycelium growth inhibition method in vitro. Compound exhibited significant anti-phytopathogenic activity, with the EC50 values of 0.18, 2.28, 1.01, and 1.85 ?g mL(-1), respectively. In vivo testing demonstrated that was effective in the control of rice sheath blight, rape sclerotinia rot and fusarium head blight. A 3D-QSAR model was built for a systematic SAR profile to explore more potent 1,2,3-triazole phenylhydrazone analogs as novel fungicides.
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Systematic review comparing the safety and efficacy of conventional and drug-eluting-bead transarterial chemoembolization for inoperable hepatocellular carcinoma.
Hepatol. Res.
PUBLISHED: 11-02-2014
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Conventional transarterial chemoembolization (cTACE) is widely used for treating patients with inoperable hepatocellular carcinoma (HCC). A variation on the technique based on drug-eluting beads (DEB-TACE) has recently entered the clinic, but trials of its safety and efficacy have given conflicting results. This systematic review aimed to gain a current, comprehensive picture of how DEB-TACE compares with cTACE.
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Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3K?: 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives.
Org. Biomol. Chem.
PUBLISHED: 10-09-2014
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A series of novel 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives were synthesized and evaluated for their biological activities as PI3K inhibitors. In vitro biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound exhibited the most potent and selective activity for PI3K?, with the value of 0.014 ?M, an approximately 30-fold increase in comparison with LY294002. Docking simulation was performed to position compound into the PI3K? active site and the result showed that compound could bind well at the PI3K? active site and it indicated that compound could be a potential inhibitor of PI3K?.
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Design, Synthesis, Antifungal, and Antioxidant Activities of (E)-6-((2-Phenylhydrazono)methyl)quinoxaline Derivatives.
J. Agric. Food Chem.
PUBLISHED: 09-26-2014
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Different substituted phenylhydrazone groups were linked to the quinoxaline scaffold to provide 26 compounds (6a-6z). Their structures were confirmed by (1)H and (13)C NMR, MS, elemental analysis, and X-ray single-crystal diffraction. The antifungal activities of these compounds against Rhizoctonia solani were evaluated in vitro. Compound 6p is the most promising one among all the tested compounds with an EC50 of 0.16 ?g·mL(-1), more potent than the coassayed positive control fungicide carbendazim (EC50: 1.42 ?g·mL(-1)). In addition, these compounds were subjected to antioxidant assay by employing diphenylpicrylhydrazyl (DPPH) and mice microsome lipid peroxidation (LPO) methods. Most of these compounds are potent antioxidants. The strongest compounds are 6e (EC50: 7.60 ?g·mL(-1), DPPH) and 6a (EC50: 0.96 ?g·mL(-1), LPO), comparative to or more potent than the positive control Trolox [EC50: 5.90 ?g·mL(-1) (DPPH) and 18.23 ?g·mL(-1) (LPO)]. The structure and activity relationships were also discussed.
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Iron(II)-catalyzed intermolecular amino-oxygenation of olefins through the N-O bond cleavage of functionalized hydroxylamines.
J. Am. Chem. Soc.
PUBLISHED: 09-16-2014
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An iron-catalyzed diastereoselective intermolecular olefin amino-oxygenation reaction is reported, which proceeds via an iron-nitrenoid generated by the N-O bond cleavage of a functionalized hydroxylamine. In this reaction, a bench-stable hydroxylamine derivative is used as the amination reagent and oxidant. This method tolerates a range of synthetically valuable substrates that have been all incompatible with existing amino-oxygenation methods. It can also provide amino alcohol derivatives with regio- and stereochemical arrays complementary to known amino-oxygenation methods.
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Design, synthesis and molecular modeling of biquinoline-pyridine hybrids as a new class of potential EGFR and HER-2 kinase inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 08-09-2014
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A new series of biquinoline-pyridine hybrids were designed and synthesized by a base-catalyzed cyclocondensation through one-pot multicomponent reaction. All compounds were tested for in vitro anticancer activities against two cancer cell lines A549 (adenocarcinomic human alveolar basal epithelial) and Hep G2 (liver cancer). Enzyme inhibitory activities of all compounds were carried out against EGFR and HER-2 kinase. Of the compounds studied, majority of the compounds showed effective anticancer activity against used cancer cell lines. Compound 9i (IC50=0.09 ?M) against EGFR and (IC50=0.2 ?M) against HER-2 kinase displayed the most potent inhibitory activity as compared to other member of the series. In the molecular modelling study, compound 9i was bound in to the active pocket of EGFR with four hydrogen bonds and two ?-cation interactions having minimum binding energy ?Gb=-54.4 kcal/mol.
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Discovery and molecular modeling of novel 1-indolyl acetate--5-nitroimidazole targeting tubulin polymerization as antiproliferative agents.
Eur J Med Chem
PUBLISHED: 07-30-2014
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A series of 18 novel 1-indolyl acetate-5-nitroimidazole 3a-3r were designed, synthesized, and evaluated for their in vitro biological activities as potential tubulin polymerization inhibitors. Among these compounds, 3p displayed strong antitumor activity with IC50 of 2.00, 1.05, 0.87 ?M against A549, Hela and U251 respectively, and also showed the most potent PLK1 inhibitory activity with IC50 of 2.4 ?M. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized 1-indolyl acetate-5-nitroimidazolefor potential tubulin polymerization inhibitors.
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Synthesis, Molecular Modeling, and Biological Evaluation of Novel 1, 3-Diphenyl-2-propen-1-one Based Pyrazolines as Anti-inflammatory Agents.
Chem Biol Drug Des
PUBLISHED: 07-09-2014
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A novel series of 1,3-diphenyl-2-propen-1-one (chalcone) derivatives was synthesized by a simple, eco-friendly, and efficient Claisen-Schmidt condensation reaction and used as precursors for the synthesis of new pyrazoline derivatives. All the synthesized compounds were screened for anti-inflammatory related activities such as inhibition of phospholipase A2 (PLA2 ), cyclooxygenases (COX-1 and COX-2), IL-6, and TNF-?. The results of the above studies show that the compounds synthesized are effective inhibitors of above pro-inflammatory enzymes and cytokines. Overall, the results of the studies reveal that the pyrazolines with chlorophenyl substitution (1b-6b) seem to be important for inhibition of enzymes and cytokines. Molecular docking experiments were performed to clarify the molecular aspects of the observed COX-inhibitory activities of the investigated compounds.
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Synthesis, molecular docking and biological evaluation of coumarin derivatives containing piperazine skeleton as potential antibacterial agents.
Bioorg. Med. Chem.
PUBLISHED: 07-05-2014
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A series of 4-hydroxycoumarin derivatives were designed and synthesized in order to find some more potent antibacterial drugs. Their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4g represented the most potent antibacterial activity against Bacillus subtilis and S. aureus with MIC of 0.236, 0.355?g/mL, respectively. What's more, it showed the most potent activity against SaFabI with IC50 of 0.57?M. Molecular docking of 4g into S. aureus Enoyl-ACP-reductase active site were performed to determine the probable binding mode, while the QSAR model was built to check the previous work as well as to introduce new directions.
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Design, synthesis and biological evaluation of novel 5-phenyl-1H-pyrazole derivatives as potential BRAF(V600E) inhibitors.
Bioorg. Med. Chem.
PUBLISHED: 06-06-2014
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A series of novel 5-phenyl-1H-pyrazole derivatives (5a-5u) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRAF(V600E) inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC50 value of 0.33?M for BRAF(V600E). Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 2.63 and 3.16?M, respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRAF(V600E) active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives.
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Iron(II)-catalyzed intramolecular olefin aminofluorination.
Org. Lett.
PUBLISHED: 05-14-2014
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An iron(II)-catalyzed diastereoselective olefin aminofluorination is reported (dr up to >20:1). This new transformation applies a functionalized hydroxylamine and Et3N·3HF as the nitrogen and fluorine source, which facilitates the efficient synthesis of ?-fluoro primary amines and amino acids from allylic alcohol derivatives. Preliminary mechanistic studies reveal that an iron-nitrenoid is a possible intermediate and that its reactivity and enantioselectivity can be efficiently modulated by ligands.
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Synthesis of caffeic acid amides bearing 2,3,4,5-tetra-hydrobenzo[b][1,4]dioxocine moieties and their biological evaluation as antitumor agents.
Molecules
PUBLISHED: 05-04-2014
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A series of caffeic acid amides D1-D17 bearing 2,3,4,5-tetrahydrobenzo-[b][1,4]dioxocine units has been synthesized and their biological activities evaluated for potential antiproliferative and EGFR inhibitory activity. Of all the compounds studied, compound D9 showed the most potent inhibitory activity (IC50=0.79 ?M for HepG2 and IC50=0.36 ?M for EGFR). The structures of compounds were confirmed by 1H-NMR, ESI-MS and elemental analysis. Among all, the structure of compound D9 ((E)-N-(4-ethoxyphenyl)-3-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)acrylamide) was also determined by single-crystal X-ray diffraction analysis. Compound D9 was found to be a potential antitumor agent according to biological activity, molecular docking, apoptosis assay and inhibition of HepG2.
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Interspecific competition between Microcystis aeruginosa and Anabaena flos-aquae from Taihu Lake, China.
Z. Naturforsch., C, J. Biosci.
PUBLISHED: 04-30-2014
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Microcystis and Anabaena are the main cyanobacteria that cause cyanobacterial blooms in Taihu Lake, China. The mechanism of population competition between M. aeruginosa and A. flos-aquae was studied by co-cultivation in the laboratory. The growth of M. aeruginosa was inhibited, while the growth of A. flos-aquae was promoted. The degree of inhibition or promotion was related to the ratio of the initial cell densities. Both cell-free filtrates of A. flos-aquae and co-culture inhibited M. aeruginosa growth, while both cell-free filtrates of M. aeruginosa and co-culture promoted A. flos-aquae growth. Analysis of the cell-free filtrate by gas chromatography-mass spectrometry indicated that M. aeruginosa and A. flos-aquae may secrete some extracellular allelochemicals that inhibit (promote) the growth of M. aeruginosa (A. flos-aquae) in co-culture. These compounds included sulfur compounds, naphthalene derivatives, cedrene derivatives, quinones, phenol derivatives, diphenyl derivatives, anthracene derivatives, and phthalate esters. This study can help to understand the characteristics of M. aeruginosa and A. flos-aquae and to provide new concepts for the control of cyanobacterial blooms in Taihu Lake.
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Cryptotanshinone induces inhibition of breast tumor growth by cytotoxic CD4+ T cells through the JAK2/STAT4/ perforin pathway.
Asian Pac. J. Cancer Prev.
PUBLISHED: 04-26-2014
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Cryptotanshinone (CPT), is a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miotiorrhiza bunge. Numerous researchers have found that it could work as a potent antitumor agent to inhibit tumor growth in vitro, buith there has been much less emphasis on its in vivo role against breast tumors. Using a mouse tumor model of MCF7 cells, we showed that CPT strongly inhibited MCF7 cell growth in vivo with polarization of immune reactions toward Th1-type responses, stimulation of naive CD4+ T cell proliferation, and also increased IFN-? and perforin production of CD4+ T cells in response to tumor-activated splenocytes. Furthermore, data revealed that the cytotoxic activity of CD4+ T cells induced by CPT was markedly abrogated by concanamycin A(CMA), a perforin inhibitor, but not IFN-? Ab. On the other hand, after depletion of CD4+ T cells or blocked perforin with CMA in a tumor-bearing model, CPT could not effectively suppress tumor growth, but this phenomenon could be reversed by injecting naive CD4+ T cells. Thus, our results suggested that CPT mainly inhibited breast tumor growth through inducing cytotoxic CD4+ T cells to secrete perforin. We further found that CPT enhanced perforin production of CD4+ T cells by up-regulating JAK2 and STAT4 phosphorylation. These findings suggest a novel potential therapeutic role for CPT in tumor therapy, and demonstrate that CPT performs its antitumor functions through cytotoxic CD4+ T cells.
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Synthesis, biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents.
Bioorg. Med. Chem.
PUBLISHED: 04-13-2014
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A series of 1,3,4-thiadiazol-2-amide derivatives (6a-w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC?? values of 0.03 ?M, 0.06 ?M and 0.05 ?M, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC??=1.73 ?M), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.
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Synthesis and Antifungal Activity of Nicotinamide Derivatives as Succinate Dehydrogenase Inhibitors.
J. Agric. Food Chem.
PUBLISHED: 04-12-2014
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Thirty-eight nicotinamide derivatives were designed and synthesized as potential succinate dehydrogenase inhibitors (SDHI) and precisely characterized by (1)H NMR, ESI-MS, and elemental analysis. The compounds were evaluated against two phytopathogenic fungi, Rhizoctonia solani and Sclerotinia sclerotiorum, by mycelia growth inhibition assay in vitro. Most of the compounds displayed moderate activity, in which, 3a-17 exhibited the most potent antifungal activity against R. solani and S. sclerotiorum with IC50 values of 15.8 and 20.3 ?M, respectively, comparable to those of the commonly used fungicides boscalid and carbendazim. The structure-activity relationship (SAR) of nicotinamide derivatives demonstrated that the meta-position of aniline was a key position contributing to the antifungal activity. Inhibition activities against two fungal SDHs were tested and achieved the same tendency with the data acquired from in vitro antifungal assay. Significantly, 3a-17 was demonstrated to successfully suppress disease development in S. sclerotiorum infected cole in vivo. In the molecular docking simulation, sulfur and chlorine of 3a-17 were bound with PHE291 and PRO150 of the SDH homology model, respectively, which could explain the probable mechanism of action between the inhibitory and target protein.
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Synthesis, molecular docking and biological evaluation of glycyrrhizin analogs as anticancer agents targeting EGFR.
Molecules
PUBLISHED: 04-10-2014
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Glycyrrhizin (GA) analogs in the form of 3-glucuronides and 18-epimers were synthesized and their anticancer activities were evaluated. Alkaline isomerization of monoglucuronides is reported. In vitro and in vivo studies showed that glycyrrhetinic acid monoglucuronides (GAMGs) displayed higher anticancer activities than those of bisglucuronide GA analogs, while anticancer activity of the 18?-epimer was superior to that of the 18?-epimer. 18?-GAMG was firstly nicely bound to epidermal growth factor receptor (EGFR) via six hydrogen bonds and one charge interaction, and the docking calculation proved the correlation between anticancer activities and EGFR inhibitory activities. Highly active 18?-GAMG is thus of interest for the further studies as a potential anticancer agent.
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Design, synthesis, and evaluation of novel fluoroquinolone-flavonoid hybrids as potent antibiotics against drug-resistant microorganisms.
Eur J Med Chem
PUBLISHED: 04-10-2014
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Based on a rationally conceived pharmacophore model to build a multi-target bacterial topoisomerase inhibitor, twenty-one fluoroquinolone-flavonoid hybrids were synthesized. Some obtained hybrids show excellent antibacterial activity against drug-resistant microorganisms with narigenin-ciprofloxacin being the most active, showing 8, 43, 23 and 88 times better activity than ciprofloxacin against Escherichia coli ATCC 35218, Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 25923 and Candida albicans ATCC 90873, respectively. Drug accumulation and DNA supercoiling assays of two active analogues revealed potent inhibition of both the DNA gyrase and efflux pump, confirming the desired dual mode of action. Molecular docking study disclosed that the introduced flavonoid moiety not only provides several additional interactions but also does not disturb the binding mode of the floxacin moiety. Our data also demonstrated that development of antifungals is possible from fluoroquinolones modified at C-7 position.
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Aromatic diacylhydrazine derivatives as a new class of polo-like kinase 1 (PLK1) inhibitors.
Eur J Med Chem
PUBLISHED: 04-08-2014
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A novel class of aromatic diacylhydrazine derivatives was designed as PLK1 inhibitors. All the 19 new synthesized compounds were assayed for antitumor activity against the respective cervical cancer cells. In which, nine compounds with better antitumor activities were further tested for their PLK1 inhibitory activity. Last, we have successfully found that compound 7k showed both the promising antitumor activity with IC50 of 0.17 ?M against the cervical cancer cells, and also processed the most potent PLK1 inhibitory activity with IC50 of 0.03 ?M. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and PKL1 (PDB code: 1umw) protein.
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Access to functionalized bicyclo[4,3,0]nonenes via palladium-catalyzed oxidative cyclization of 2-allylcyclohexyl oximes.
J. Org. Chem.
PUBLISHED: 04-07-2014
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A new palladium-catalyzed oxidative cyclization process leading to the functionalized bicyclo[4,3,0]nonenes is serendipitously discovered during attempts to form aza-heterocycle by the amino-Heck reaction of trans-2-vinylclohexyl phosphinyloxime. Under the influence of Pd(dba)2/Et3N/1:1 N2-O2 (1:1, v/v) (Method A) or Pd(OAc)2/Et3N/O2 (Method B), the reactions afford the substituted cis-1-hydroxyl-8-formyl-bicyclo[4,3,0]non-8(9)-enes or bicycle[4,3,0]non-1(9)-en-8-ones in varying yields with the incorporation of molecular oxygen into the structures. The 5,6-bicyclic scaffold of these products is presumably derived from tandem double intramolecular cyclization followed by the ring-opening of an aza-palladium(II) tricyclic intermediate.
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Design, synthesis and biological evaluation of (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives as a new class of tubulin polymerization inhibitors.
Bioorg. Med. Chem.
PUBLISHED: 04-03-2014
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A series of novel (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives had been synthesized and evaluated their biological activities as potential tubulin polymerization inhibitors. Among these compounds, compound 3q exhibited potent antiproliferative activities against three cancer cell lines in vitro, and antitubulin polymerization activity with IC?? of 0.92 ?M, which was superior to that of colchicine (IC??=1.34 ?M). Docking simulation was performed to insert compound 3q into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. These results suggested that compound 3q may be a promising antitubulin agent for the potential treatment of cancer.
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Design, synthesis and biological evaluation of metronidazole-thiazole derivatives as antibacterial inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 03-31-2014
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A series of metronidazole-thiazole derivatives has been designed, synthesized and evaluated as potential antibacterial inhibitors. All the synthesized compounds were determined by elemental analysis, (1)H NMR and MS. They were also tested for antibacterial activity against Escherichia coli, Bacillus thuringiensis, Bacillus subtilis and Pseudomonas aeruginosa as well as for the inhibition to FabH. The results showed that compound 5e exhibited the most potent inhibitory activity against E. coli FabH with IC50 of 4.9?M. Molecular modeling simulation studies were performed in order to predict the biological activity of proposed compounds. Toxicity assay of compounds 5a, 5b, 5d, 5e, 5g and 5i showed that they were noncytotoxic against human macrophage. The results revealed that these compounds offered remarkable viability.
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Synthesis, crystal structures, and antibacterial evaluation of metal complexes based on functionalized 2-phenylquinoline derivatives.
Acta Chim Slov
PUBLISHED: 03-26-2014
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A series of dinuclear paddle-wheel like transition metal complexes based on 2-phenylquinoline-4-carboxylic derivative L have been synthesized and characterized by IR, elemental analysis, and X-ray diffraction single crystal analysis. The biological activities of L and its complexes were evaluated as assayed antibacterial activities, including Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. The results indicated that these complexes showed better antibacterial activities than the free ligand or metal salts alone. Among them, the Zn(II) and Cd(II) complexes with IC50 of 0.57 µg/mL and 0.51 µg/mL, respectively, showed excellent antibacterial activity against Staphylococcus aureus.
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Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: design, synthesis and evaluation as antibacterial agent.
Bioorg. Med. Chem.
PUBLISHED: 03-12-2014
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3-Arylfuran-2(5H)-one, a novel antibacterial pharmacophore targeting tyrosyl-tRNA synthetase (TyrRS), was hybridized with the clinically used fluoroquinolones to give a series of novel multi-target antimicrobial agents. Thus, twenty seven 3-arylfuran-2(5H)-one-fluoroquinolone hybrids were synthesized and evaluated for their antimicrobial activities. Some of the hybrids exhibited merits from both parents, displaying a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria. The most potent compound (11) in antibacterial assay shows MIC50 of 0.11?g/mL against Multiple drug resistant Escherichia coli, being about 51-fold more potent than ciprofloxacin. The enzyme assays reveal that 11 is a potent multi-target inhibitor with IC50 of 1.15±0.07?M against DNA gyrase and 0.12±0.04?M against TyrRS, respectively. Its excellent inhibitory activities against isolated enzymes and intact cells strongly suggest that 11 deserves to further research as a novel antibiotic.
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Synthesis, biological evaluation, and molecular docking studies of novel 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity.
Bioorg. Med. Chem.
PUBLISHED: 03-09-2014
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A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a-3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC50 value of 3.11 ?M and Hela with IC50 value of 2.54 ?M respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50=0.45 ?M). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.
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Design and synthesis of thiazole derivatives as potent FabH inhibitors with antibacterial activity.
Eur J Med Chem
PUBLISHED: 02-25-2014
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Components of fatty acid biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Compounds of series A (4a-4 g) and series B (5a-5 g) were synthesized by the formation of an amine bond between aromatic acid and 4-phenylthiazol-2-amine or 4-(4-bromophenyl)thiazol-2-amine. These thiazole derivatives have evaluated as potent FabH inhibitors. Nineteen compounds (4b-4h, 4 k, 4 l, 5a-5h, 5k, 5l) are reported for the first time. Most of the synthesized compounds exhibited antibacterial activity in the MTT assay. The MIC value of these compounds ranged from 1.56 ?g/mL to 100 ?g/mL. Moreover, the tested compounds also showed FabH inhibition ability with IC50 value ranging from 5.8 ?M to 48.1 ?M. The IC50 values are near the MIC values. Compound 5f has exhibited the best antibacterial and Escherichia coli FabH inhibitory activity. Docking simulation and the QSAR study was conducted for learning about binding mode and the relationship between structure and activity.
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Single nucleotide polymorphisms of toll-like receptor 7 and toll-like receptor 9 in hepatitis C virus infection patients from central China.
Yonsei Med. J.
PUBLISHED: 02-18-2014
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To analyze the correlation of polymorphisms of toll-like receptor 7 (TLR7) (rs179009) and toll-like receptor 9 (TLR9) (rs187084) in hepatitis C virus (HCV) infections in the Han population.
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Interleukin-7 enhances the in vivo anti-tumor activity of tumor-reactive CD8+ T cells with induction of IFN-gamma in a murine breast cancer model.
Asian Pac. J. Cancer Prev.
PUBLISHED: 02-18-2014
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Interleukin-7 (IL-7) is a potent anti-apoptotic cytokine that enhances immune effector cell functions and is essential for lymphocyte survival. While it known to induce differentiation and proliferation in some haematological malignancies, including certain types of leukaemias and lymphomas, little is known about its role in solid tumours, including breast cancer. In the current study, we investigated whether IL-7 could enhance the in vivo antitumor activity of tumor-reactive CD8+ T cells with induction of IFN-? in a murine breast cancer model. Human IL-7 cDNA was constructed into the eukaryotic expression plasmid pcDNA3.1, and then the recombinational pcDNA3.1-IL-7 was intratumorally injected in the TM40D BALB/C mouse graft model. Serum and intracellular IFN-? levels were measured by ELISA and flow cytometry, respectively. CD8+ T cell-mediated cytotoxicity was analyzed using the MTT method. Our results showed that IL-7 administration significantly inhibited tumor growth from day 15 after direct intratumoral injection of pcDNA3.1-IL-7. The anti-tumor effect correlated with a marked increase in the level of IFN-? and breast cancer cells-specific CTL cytotoxicity. In vitro cytotoxicity assays showed that IL-7-treatment could augment cytolytic activity of CD8+ T cells from tumor bearing mice, while anti-IFN-? blocked the function of CD8+ T cells, suggesting that IFN-? mediated the cytolytic activity of CD8+ T cells. Furthermore, in vivo neutralization of CD8+ T lymphocytes by CD8 antibodies reversed the antitumor benefit of IL-7. Thus, we demonstrated that IL-7 exerts anti-tumor activity mainly through activating CD8+ T cells and stimulating them to secrete IFN-? in a murine breast tumor model. Based on these results, our study points to a potential novel way to treat breast cancer and may have important implications for clinical immunotherapy.
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Schiff's base derivatives bearing nitroimidazole and quinoline nuclei: new class of anticancer agents and potential EGFR tyrosine kinase inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 02-06-2014
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New Schiff's base derivatives 5a-j have been synthesized by reaction between 2-phenoxyquinoline-3-carbaldehydes 3a-j and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide 4 in presence of nickel(II) nitrate as a catalyst in ethanol under reflux in good yield (78-92%). All compounds were tested for anticancer and inhibition of EGFR. Of the compounds studied, majority of the compounds showed effective antiproliferation and inhibition of EGFR and HER-2 activities. Compound 5h showed most effective inhibition (IC50=0.12±0.05 ?M) by binding in to the active pocket of EGFR receptor with minimum binding energy (?Gb=-58.3691 kcal/mol). The binding was stabilized by two hydrogen bonds, two ?-cation and one ?-sigma interactions. Compound 5d showed most effective inhibition (IC50=0.37±0.04 ?M).
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Synthesis, molecular docking and biological evaluation of metronidazole derivatives containing piperazine skeleton as potential antibacterial agents.
Bioorg. Med. Chem.
PUBLISHED: 01-22-2014
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Metronidazole has a broad-spectrum antibacterial activity. Hereby a series of novel metronidazole derivatives were designed and synthesized based on nitroimidazole scaffold in order to find some more potent antibacterial drugs. For these compounds which were reported for the first time, their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4m represented the most potent antibacterial activity against S. aureus ATCC 25923 with MIC of 0.003 ?g/mL and it showed the most potent activity against S. aureus TyrRS with IC50 of 0.0024 ?M. Molecular docking of 4m into S. aureus tyrosyl-tRNA synthetase active site were also performed to determine the probable binding mode.
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Synthesis and biological evaluation of compounds which contain pyrazole, thiazole and naphthalene ring as antitumor agents.
Bioorg. Med. Chem. Lett.
PUBLISHED: 01-09-2014
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A series of compounds which contain pyrazole, thiazole and naphthalene ring (1a-7a, 1b-7b, 1c-7c, 1d-7d) were firstly synthesized and their anti-proliferative activity, EGFR inhibitory activity, cytotoxicity and inhibition to Hela cell migration were evaluated. Compound 2-(3-(3,4-dimethylphenyl)-5-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (7d) displayed the most potent inhibitory activity (IC50=0.86?M for Hela and IC50=0.12?M for EGFR). Structure-activity relationship (SAR) analysis showed that the anti-proliferative activity was affected by A-ring-substituent (-OCH3>-CH3>-H>-Br>-Cl>-F). Docking simulation of compound 7d into EGFR active site showed that naphthalene ring of 7d with LYS721 formed two p-? bonds, which enhanced antitumor activity. Therefore, compound 7d may be developed as a potential antitumor agent.
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Design, synthesis and molecular modeling of pyrazole-quinoline-pyridine hybrids as a new class of antimicrobial and anticancer agents.
Eur J Med Chem
PUBLISHED: 01-07-2014
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A new series of pyrazole-quinoline-pyridine hybrids were designed based on molecular hybridization technique and synthesized by a base-catalyzed cyclocondensation reaction through one-pot multicomponent reaction. All compounds were tested for in vitro antibacterial and anticancer activities. Enzyme inhibitory activities of all compounds were carried out against FabH and EGFR. Of the compounds studied, majority of the compounds showed effective antibacterial as well as anticancer activity against used strains and cancer cell lines respectively. Compound 7k (IC?? = 0.51 ± 0.05 ?M) against EGFR and 7b displayed the most potent inhibitory activity with IC?? of 3.1 ?M against FabH as compared to other member of the series. In the molecular modeling study, compound 7k was bound in to the active pocket of EGFR with three hydrogen bond and one ?-cation interaction with minimum binding energy ?Gb = -54.6913 kcal/mol, as well as compound 7b was bound in to the active site of FabH with hydrogen bond and ?-sigma interactions with minimum binding energy ?Gb = -45.9125 kcal/mol.
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Design and synthesis of 2-styryl of 5-Nitroimidazole derivatives and antimicrobial activities as FabH inhibitors.
Eur J Med Chem
PUBLISHED: 01-07-2014
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A series of 2-Styryl-5-Nitroimidazole derivatives (25-48) have been synthesized and their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus subtilis and Bacillus thuringiensis as potential FabH inhibitors. All the compounds were structurally determined by (1)H NMR, MS, and elemental analysis. E. coli ?-ketoacyl-acyl carrier protein synthase III inhibitory assay and docking simulation indicated that compound 33 with IC?? of 9.0-36.4 ?g/mL and compound 47 with IC?? of 6.3-34.3 ?g/mL against bacterial strains were most potent inhibitors of E. coli FabH. And more, compounds 33 and 47 which possessed a broad-spectrum of antibacterial activities didn't exhibit any toxicity towards macrophage.
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Synthesis, and antibacterial activity of novel 4,5-dihydro-1H-pyrazole derivatives as DNA gyrase inhibitors.
Org. Biomol. Chem.
PUBLISHED: 01-03-2014
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A series of novel 4,5-dihydropyrazole derivatives (4a-4t), containing the dinitrobenzotrifluoride moiety, as DNA gyrase inhibitors were designed and synthesized. Based on the preliminary results, compounds 4d, 4f and 4t with potent inhibitory activity in bacterial growth may be wonderful antibacterial agents; among them, compound 4t displayed the most potent activity with minimum inhibitory concentration (MIC) values of 3.125, 0.39, 0.39 and 0.39 ?g mL(-1) against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli respectively, which was comparable with penicillin and kanamycin B with corresponding MIC values of 3.125, 3.125, 0.39, 0.39 ?g mL(-1) and 1.562, 1.562, 1.562, 1.562 ?g mL(-1), respectively. In particular, compound 4d showed the most potent anti-Gram-positive bacterial activity with a MIC value of 0.39 ?g mL(-1) against the tested Gram-positive bacterial strains and exhibited the most potent B. subtilis DNA gyrase and S. aureus DNA gyrase inhibitory activity with an IC50 of 0.125 ?g mL(-1). Docking simulation was performed to insert compound 4d into the S. aureus DNA gyrase active site to determine the probable binding conformation.
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Percutaneous resolution of lumbar facet joint cysts as an alternative treatment to surgery: a meta-analysis.
PLoS ONE
PUBLISHED: 01-01-2014
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A comprehensive review of the literature in order to analyze data about the success rate of percutaneous resolution of the lumbar facet joint cysts as a conservative management strategy.
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Modification, biological evaluation and 3D QSAR studies of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-yl)phenol derivatives as inhibitors of B-Raf kinase.
PLoS ONE
PUBLISHED: 01-01-2014
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A series of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-yl)phenol derivatives (C1-C24) have been synthesized. The B-Raf inhibitory activity and anti-proliferation activity of these compounds have been tested. Compound C6 displayed the most potent biological activity against B-RafV600E (IC50 = 0.15 µM) and WM266.4 human melanoma cell line (GI50 = 1.75 µM), being comparable with the positive control (Vemurafenib and Erlotinib) and more potent than our previous best compounds. The docking simulation was performed to analyze the probable binding models and poses while the QSAR model was built to check the previous work as well as to introduce new directions. This work aimed at seeking more potent inhibitors as well as discussing some previous findings. As a result, the introduction of ortho-hydroxyl group on 4,5-dihydro-1H-pyrazole skeleton did reinforce the anti-tumor activity while enlarging the group on N-1 of pyrazoline was also helpful.
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Synthesis and Crystal Structures of Ethanol-Coordinated Molybdenum(VI) Oxo Complexes with Tridentate Hydrazone Ligands.
Acta Chim Slov
PUBLISHED: 12-24-2013
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Reaction of [MoO2(acac)2] (where acac = acetylacetonate) with two similar hydrazone ligands in ethanol yielded two ethanol-coordinated mononuclear molybdenum(VI) oxo complexes with general formula [MoO2L(EtOH)], where L = L1 = (N-(3,5-dibromo-2-hydroxybenzylidene)-4-nitrobenzohydrazide (H2L1), and L = L2 = (N-(3,5-dibromo-2-hydroxybenzylidene)-2-fluorobenzohydrazide (H2L2). Crystal and molecular structures of the complexes were determined by single crystal X-ray diffraction method. All of the investigated compounds were further characterized by elemental analysis and FT-IR spectra. Single crystal X-ray structural studies indicate that the hydrazone ligands coordinate to the MoO2 cores through enolate oxygen, phenolate oxygen and azomethine nitrogen. The Mo atoms in both complexes are in octahedral coordination. Thermal stability of the complexes has also been studied.
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Discovery of 4,6-substituted-(diaphenylamino)quinazolines as potent c-Src inhibitors.
Org. Biomol. Chem.
PUBLISHED: 10-31-2013
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A series of 4,6-substituted-(diaphenylamino)quinazolines as c-Src inhibitors have been prepared and their biological activity has also been evaluated. All the compounds displayed potential antiproliferation activities, with IC50 values ranging from 3.42 ?M to 118.81 ?M in five human tumor cell lines. Particularly, compound 15 exhibited higher cytotoxicity against the tested five tumor cell lines compared to the other small molecules. Generally, most of these compounds showed selectivity between the A549 cells and the other four cells, according to their corresponding IC50 values. The results obtained from the in vitro enzyme assay indicated compound 15 has remarkable inhibitory activity against c-Src kinase with an IC50 value of 27.3 nM, which is comparable to the control compounds. Furthermore, molecular docking and QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives.
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Design, synthesis, biological evaluation, and molecular modeling study of 4-alkoxyquinazoline derivatives as potential VEGFR2 kinase inhibitors.
Org. Biomol. Chem.
PUBLISHED: 10-09-2013
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A series of novel 4-alkoxyquinazoline derivatives were prepared and synthesized and their biological activities were evaluated as potential inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). Of these compounds, compound 3j demonstrated the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, the IC50 values of this compound reaching up to 2.72 nM and 0.35 ?M, respectively, compared with Tivozanib (3.40 nM and 0.38 ?M). The obtained results, along with a 3D-QSAR study and molecular docking that was used for investigating the probable binding mode, could provide an important basis for further optimization of compound 3j as a potential tyrosine kinase inhibitor.
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[Liver histopathological features influencing HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B responding to Peg-IFN treatment].
Zhonghua Gan Zang Bing Za Zhi
PUBLISHED: 09-13-2013
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To investigate the therapeutic efficiency of antiviral treatment with pegylated-interferon (Peg-IFN) for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) and to explore whether liver histopathological features or other factors influence the HBeAg seroconversion treatment response.
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Tacolimus postconditioning alleviates apoptotic cell death in rats after spinal cord ischemia-reperfusion injury via up-regulating protein-serine-threonine kinases phosphorylation.
J. Huazhong Univ. Sci. Technol. Med. Sci.
PUBLISHED: 09-11-2013
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The effects of tacrolimus postconditioning on protein-serine-threonine kinases (Akt) phosphorylation and apoptotic cell death in rats after spinal cord ischemia-reperfusion injury were investigated. Ninety male SD rats were randomly divided into sham operation group, ischemia-reperfusion group and tacrolimus postconditioning group. The model of spinal cord ischemia was established by means of catheterization through femoral artery and balloon dilatation. The spinal cord was reperfused 20 min after ischemia via removing saline out of balloon. The corresponding spinal cord segments were excised and determined for Akt activity in spinal cord tissue by using Western blotting at 5, 15, and 60 min after reperfusion respectively. Spinal cord tissue sections were stained immunohistochemically for detection of the phosphorylated Akt expression at 15 min after reperfusion. Flow cytometry was applied to assess apoptosis of neural cells, and dry-wet weights method was employed to measure water content in spinal cord tissue at 24 h after reperfusion. The results showed that the activities of Akt in tarcolimus postconditioning group were significantly higher than those in ischemia-reperfusion group at 5, 15, and 60 min after reperfusion (P<0.05, P<0.01). The Akt activities reached the peak at 15 min after reperfusion in ischemia-reperfusion group and tacrolimus postconditioning group. The percentage of apoptotic cells and water content in spinal cord tissue were significantly reduced (P<0.01) in tacrolimus postconditioning group as compared with those in ischemia-reperfusion group at 24 h after reperfusion. It is concluded that tacrolimus post-conditioning can increase Akt activity in spinal cord tissue of rats, inhibit apoptosis of neural cells as well as tissue edema, and thereby alleviate spinal cord ischemia-reperfusion injury.
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Synthesis, molecular modeling and biological evaluation of N-benzylidene-2-((5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)thio)acetohydrazide derivatives as potential anticancer agents.
Bioorg. Med. Chem.
PUBLISHED: 08-23-2013
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A series of new 1,3,4-oxadiazole derivatives (6a-6x) containing pyridine and acylhydrazone moieties were synthesized and developed as potential telomerase inhibitors. The bioassay tests demonstrated that compounds 6n, 6o, 6q, 6s and 6t exhibited significant broad-spectrum anticancer activity with IC50 range from 0.76 to 9.59?M against the four cancer cell lines (HEPG2, MCF7, SW1116 and BGC823). Moreover, all the title compounds were assayed for telomerase inhibition using the TRAP-PCR-ELISA assay. Compound 6s showed the highest anticancer activity with IC50 of 0.76-1.54?M against the tested cancer cell lines and exhibited the most potent telomerase inhibitory activity with IC50 of 1.18±0.14?M. The docking simulation was carried out to investigate a possible binding mode of compound 6s into the active site of telomerase (pdb. 3DU6) while the QSAR model was built to check the previous work as well as to introduce new directions.
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Synthesis, biological evaluation and molecular docking of novel 5-phenyl-1H-pyrazol derivatives as potential BRAF(V600E) inhibitors.
Org. Biomol. Chem.
PUBLISHED: 08-15-2013
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The RAF-MEK-ERK cascade appears to be intimately involved in the regulation of cell cycle progression and apoptosis. The BRAF(V600E) mutant results in constitutive activation of the ERK pathway, which can lead to cellular growth dysregulation. A series of 5-phenyl-1H-pyrazol derivatives (3a-5e) have been designed and synthesized, and their biological activities were evaluated as potential BRAF(V600E) inhibitors. All the compounds were reported for the first time except 3e, and compound 1-(4-bromo-2-hydroxybenzyl)-3-phenyl-1-(5-phenyl-1H-pyrazol-3-yl)urea (5c) displayed the most potent inhibitory activity (BRAF(V600E) IC50 = 0.19 ?M). Antiproliferative assay results indicated that compound 5c possessed high antiproliferative activity against cell lines WM266.4 and A375 in vitro, with IC50 values of 1.50 and 1.32 ?M, respectively, which were comparable with the positive control vemurafenib. Docking simulations showed that compound 5c binds tightly to the BRAF(V600E) active site and acts as BRAF(V600E) inhibitor. A 3D-QSAR model was also built to provide more pharmacophore understanding towards designing new agents with more potent BRAF(V600E) inhibitory activity.
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Activation of C-H bonds in nitrones leads to iridium hydrides with antitumor activity.
J. Med. Chem.
PUBLISHED: 08-07-2013
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We report the design and synthesis of a series of new cyclometalated iridium hydrides derived from the C-H bond activation of aromatic nitrones and the biological evaluation of these iridium hydrides as antitumor agents. The nitrone ligands are based on the structure of a popular antioxidant, ?-phenyl-N-tert-butylnitrone (PBN). Compared to cisplatin, the iridium hydrides exhibit excellent antitumor activity on HepG2 cells. The metal-coordinated compound with the most potent anticancer activity, 2f, was selected for further analysis because of its ability to induce apoptosis and interact with DNA. During in vitro studies and in vivo efficacy analysis with tumor xenograft models in Institute of Cancer Research (ICR) mice, complex 2f exhibited antitumor activity that was markedly superior to that of cisplatin. Our results suggest, for the first time, that metal hydrides could be a new type of metal-based antitumor agent.
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Design, synthesis and antibacterial activities of 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiol derivatives containing Schiff base formation as FabH inhibitory.
Bioorg. Med. Chem. Lett.
PUBLISHED: 08-04-2013
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A series of novel schiff base derivatives (H(1)-H(20)) containing pyrazine and triazole moiety have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of ?-ketoacyl-acyl carrier protein synthase III (FabH). These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Bacillus amyloliquefaciens and selected compounds among them were tested for their Escherichia coli FabH inhibitory activity. Based on the biological data, compound H(17) showed the most potent antibacterial activity with MIC values of 0.39-1.56?g/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 5.2?M, being better than the positive control Kanamycin B with IC50 of 6.3?M. Furthermore, docking simulation was performed to position compound H(17) into the E. coli FabH active site to determine the probable binding conformation. This study indicated that compound H(17) has demonstrated significant E. coli FabH inhibitory activity as a potential antibacterial agent and provides valuable information for the design of E. coli FabH inhibitors.
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Synthesis, biological evaluation and molecular docking studies of flavone and isoflavone derivatives as a novel class of KSP (kinesin spindle protein) inhibitors.
Eur J Med Chem
PUBLISHED: 08-04-2013
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The kinesin spindle protein (KSP) is involved in the formation of bipolar mitotic spindle during cell division and it becomes a new target to overcome the neurotoxicity of MTs inhibitors. A series of flavone and isoflavone derivatives (1a-7c) have been designed, synthesized and evaluated as potential KSP inhibitors. Among them, 2c displayed the most potent inhibitory activity in vitro, which inhibited the growth of MCF-7 and Hela cell lines with IC50 values of 4.8 and 4.3 ?M, respectively, and also exhibited significant KSP inhibitory activity (IC50 = 0.023 ?M). The new compounds can induce irregular monoastral spindles, the characteristic phenotype for KSP inhibiting agents. Docking simulation was further performed to determine the probable binding model.
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Exploration of structure-based on imidazole core as antibacterial agents.
Curr Top Med Chem
PUBLISHED: 07-26-2013
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Imidazole, a five-membered heterocycle having three carbon atoms, and two double bonds, having efficient antibacterial Escherichia coli, Bacillus subtili, Bacillus proteus, Staphylococcus aureus, Pseudomonas aeruginosa, and Helicobacter pyloriurease etc, shows a broad-spectrum of antibacterial activities. To Search new antibacterial drugs to overcome resistance of microorganisms to antibiotics, to date hundreds of this sort of derivatives have been synthesized and possess potent antibacterial activity. As the structure of imidazole derivatives is various, the target of antibacterial is also diverse including ?-Lactamases, ?-ketoacyl-acyl carrier protein synthase III (FabH), DNA gyrase and topoisomerase, glutamate racemase and urease. In this review, we will discuss the emergence of resistance to antibiotics and attempt to summarize the main developments of imidazole derivatives in the past ten years. We hope that increasing knowledge of the structure-activity relationship (SAR) will be beneficial to the rational design of new generation of small molecule antibacterial drugs.
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Schiffs base derivatives bearing nitroimidazole moiety: new class of antibacterial, anticancer agents and potential EGFR tyrosine kinase inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 07-04-2013
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New Schiffs base derivatives 5a-5h have been synthesized by reaction between 1-(4-bromophenyl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanone 3 and various benzohydrazide 4a-4h in presence of nickel (II) nitrate as a catalyst in ethanol at room temperature in good yield (54-88%). All compounds were tested for antibacterial as well as anticancer and inhibition of EGFR. Of the compounds studied, compounds 5d, 5f and 5g in the case of antiproliferation and inhibition of EGFR as well as compounds 5b, 5c, 5e and 5h in the case of antibacterial activity were found to be most effective compounds in the series. Compound 5f shows effective inhibition (IC50=0.21±0.02 ?M) by binding in to the active pocket of EGFR receptor with minimum binding energy (?Gb=-49.4869 kcal/mol).
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Pyrazole derivatives as antitumor, anti-inflammatory and antibacterial agents.
Mini Rev Med Chem
PUBLISHED: 06-16-2013
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Within the past years, many researches on the synthesis, structure-activity relationships (SAR), antitumor, antiinflammatory and anti-bacterial activities of the pyrazole derivatives have been reported. Several pyrazole derivatives possess important pharmacological activities and they have been proved useful materials in drug research. Pyrazole derivatives play an important role in antitumor agents because of their good inhibitory activity against BRAF(V600E), EGFR, telomerase, ROS Receptor Tyrosine Kinase and Aurora-A kinase. In addition, pyrazole derivatives also show good antiinflammatory and anti-bacterial activities. In this review, the bioactivities of the pyrazole derivatives mentioned above will be summarized in detail. We sincerely hope that increasing knowledge of the SAR and cellular processes underlying the bioactivity of pyrazole derivatives will be beneficial to the rational design of new generation of small molecule drugs.
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Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan.
Bioorg. Med. Chem.
PUBLISHED: 06-11-2013
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A new series of Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan (6a-6ae) were synthesized and characterized by (1)H NMR, ESI-MS and elemental analysis. The structure of 6b was further confirmed by single crystal X-ray diffraction. All these novel compounds were screened for their in vitro antioxidant activity employing 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+)) and ferric reducing antioxidant power (FRAP) scavenging assays. Due to the combination of 1,4-benzodioxan, 1,3,4-oxadiazoles and substituted phenyl ring, most of them exhibited nice antioxidant activities. In all of these three assays mentioned above, compounds 6f and 6e showed significant radical scavenging ability comparable to the commonly used antioxidants, BHT and Trolox. Seven compounds with representative substituents or activities were selected for further assays in chemical simulation biological systems-inhibition of microsomal lipid peroxidation (LPO) and protection against 2,2-azobis (2-amidinopropane hydrochloride) (AAPH) induced DNA strand breakage, in which, 6f and 6e were demonstrated to be of the most potent antioxidant activities.
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Synthesis, biological evaluation and molecular docking studies of pyrazole derivatives coupling with a thiourea moiety as novel CDKs inhibitors.
Eur J Med Chem
PUBLISHED: 04-21-2013
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It was discovered that a number of cyclin dependent kinase inhibitors containing the pyrazole core structure exhibited high inhibitory potency against broad-range CDKs and corresponding anti-proliferative activities. This information guided us to design and synthesize a series of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives (5a-10d), and evaluate their biological activities as CDKs inhibitors. Among all the synthesized compounds, compound 10b inhibited CDK2 with an IC50 value of 25 nM, counteracting tumor cell proliferation of three cancer cell lines (H460, MCF-7, A549) in the micromolar range (from 0.75 ?M to 4.21 ?M), In addition, flow cytometry indicated that compound 10b could induce cycle G0/G1 phase arrest in A549 cells with a dose dependent. Taken together, compound 10b could be selected for further preclinical evaluation.
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3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: synthesis, molecular docking and antibacterial evaluation.
Bioorg. Med. Chem.
PUBLISHED: 04-18-2013
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Thirty-eight 3-aryl-4-acyloxyethoxyfuran-2(5H)-ones were designed, prepared and tested for antibacterial activities. Some of them showed significant antibacterial activity against Gram-positive organism, Gram-negative organism and fungus. Out of these compounds, 4-(2-(3-chlorophenylformyloxy)ethoxy)-3-(4-chlorophenyl)furan-2(5H)-one (d40) showed the widest spectrum of activity with MIC50 of 2.0?g/mL against Staphylococcus aureus, 4.3?g/mL against Escherichia coli, 1.5?g/mL against Pseudomonas aeruginosa and 1.2?g/mL against Candida albicans. Our data disclosed that MIC50 values against whole cell bacteria are positive correlation with MIC50 values against tyrosyl-tRNA synthetase. Meanwhile, molecular docking of d40 into S. aureus tyrosyl-tRNA synthetase active site was also performed, and the inhibitor tightly fitting the active site might be an important reason why it has high antimicrobial activity.
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Design and synthesis of fluoroacylshikonin as an anticancer agent.
Chirality
PUBLISHED: 04-16-2013
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A series of shikonin derivatives, selectively acylated by various fluorinated carboxylic acids at the side chain of shikonin, were synthesized and their anticancer activity evaluated, in which eight compounds are reported for the first time. Among all the compounds tested, compound showed the most potent anticancer activity against B16-F10 (malignant melanoma cells), MG63 (human osteosarcoma cells), and A549 (lung cancer cells) with IC50 0.39 ± 0.01, 0.72 ± 0.04 and 0.58 ± 0.02 µmol/L. Docking simulation of compound was carried out to position into a tubulin active site to determine the probable binding conformation. All the results suggested that compound may be a potential anticancer agent.
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Synthesis and antimicrobical evaluation of a novel class of 1,3,4-thiadiazole: derivatives bearing 1,2,4-triazolo[1,5-a]pyrimidine moiety.
Eur J Med Chem
PUBLISHED: 04-03-2013
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A series of novel 1,3,4-thiadiazole derivatives bearing 1,2,4-triazolo[1,5-a]pyrimidine moiety were synthesized by the method of splicing active substructures. Among these derivatives, compounds 12, 13, 15-22 and 24-31 were firstly reported. All the compounds were assayed for antimicrobial activities against five fungi strains and four bacteria strains. The preliminary results indicated that compounds 25 and 28-31 showed good antifungal activities against Physaclospora piricola and Rhizoctonia solani. Compound 26 exhibited good antifungal activities against Cercospora beticola and R. solani. Most of the compounds showed better antibacterial activities against Gram-negative bacteria strains than Gram-positive bacteria strains. Compounds 25 and 28 showed the best activities against Pseudomonas fluorescence while compounds 30-31 showed good activities against Escherichia coli.
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Synthesis, molecular docking and kinetic properties of ?-hydroxy-?-phenylpropionyl-hydroxamic acids as Helicobacter pylori urease inhibitors.
Eur J Med Chem
PUBLISHED: 03-31-2013
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Inhibition of urease results in Helicobacter pylori growth arrest in the stomach, promoting urease as promising targets for gastrointestinal ulcer therapy. Twenty hybrid derivatives of flavonoid scaffold and hydroxamic acid, ?-hydroxy-?-phenylpropionylhydroxamic acids, were therefore synthesized and evaluated against H. pylori urease. Biological evaluation of these compounds showed improved urease inhibition exhibiting micromolar to mid-nanomolar IC50 values. Most importantly, 3-(3-chlorophenyl)-3-hydroxypropionyl-hydroxamic acid (6g) exhibited high potency with IC50 of 0.083±0.004 ?M and Ki of 0.014±0.003 ?M, indicating that 6g is an excellent candidate to develop novel antiulcer agent. A mixture of competitive and uncompetitive mechanism was putatively proposed to understand the inconsistency between the crystallographic and kinetic studies for the first time, which is supported by our molecular docking studies.
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Design, synthesis and antibacterial activity studies of thiazole derivatives as potent ecKAS III inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 03-26-2013
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Two series of thiazole derivatives containing amide skeleton were synthesized and developed as potent Escherichia coli ?-ketoacyl-(acyl-carrier-protein) synthase III (ecKAS III) inhibitors. All the 24 new synthesized compounds were assayed for antibacterial activity against the respective Gram-negative and Gram-positive bacterial strains, including E. coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. In which, 10 compounds with broad-spectrum antibacterial activities were further tested for their ecKAS III inhibitory activity. Last, we have successfully found that compound 4e showed both the promising broad antibacterial activity with MIC of 1.56-6.25?g/mL against the representative bacterial stains, and also processed the most potent ecKAS III inhibitory activity with IC50 of 5.3?M. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and ecKAS III (PDB code: 1hnj) protein.
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Synthesis, biological evaluation, and molecular docking studies of novel 1,3,4-oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with anticancer activity.
Bioorg. Med. Chem.
PUBLISHED: 03-14-2013
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1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC50 values of 5.68 ?g/ml and 10.21 ?g/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP-PCR-ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC50 values of 1.2±0.3 ?M. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell.
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A functional scaffold in marine alkaloid: an anticancer moiety for human.
Curr. Med. Chem.
PUBLISHED: 02-25-2013
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Marine organisms have been developed as a new source of naturally occurring alkaloids. The bioactive scaffolds of marine alkaloids govern the cross-kingdom actions, possessing "unexpectedly" cytotoxic-related antitumor activities against human cancer cell lines. And the actions of marine alkaloids toward mammalian cells have been well substantiated by the recognition of their analogues as antitumor and enzyme modulatory agents. Different moieties of alkaloids target different cellular pathways. Structure-activity studies and docking analysis of marine alkaloids analogs attached importance to certain privileged moieties, and illustrated the mechanism of alkaloids functionalization in mammals. The fascinating observations prompted us to review five kinds of alkaloid-like moieties including thiazole, pyrroloquinon, oxazole, pyridine and indole, and illuminate suggestively their various roles in common cellular processes of human beings. Meanwhile, an hypothesis was made correlatively to explain the different mechanisms of their anticancer activities in human cell lines.
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Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis.
Eur J Med Chem
PUBLISHED: 02-08-2013
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A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC?? = 23 nM) and 5l (IC?? = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.
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Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents.
Bioorg. Med. Chem.
PUBLISHED: 02-06-2013
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A series of novel 1,3,4-oxadiazole thioether derivatives (compounds 9-44) were designed and synthesized as potential inhibitors of thymidylate synthase (TS) and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 18 bearing a nitro substituent exhibited more potent in vitro anticancer activities with IC50 values of 0.7±0.2, 30.0±1.2, 18.3±1.4 ?M, respectively, which was superior to the positive control. In the further study, it was identified as the most potent inhibitor against two kinds of TS protein (for human TS and Escherichia coli TS, IC50 values: 0.62 and 0.47 ?M, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 ?g/mL against the tested four bacterial strains. Molecular docking and 3D-QSAR study supported that compound 18 can be selected as dual antitumor/antibacterial candidate in the future study.
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Design, synthesis and antimicrobial activities evaluation of Schiff base derived from secnidazole derivatives as potential FabH inhibitors.
Bioorg. Med. Chem.
PUBLISHED: 02-04-2013
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FabH, ?-ketoacyl-acyl carrier protein (ACP) synthase III, is critically important to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and Gram-negative bacteria. A series of novel secnidazole derivatives (1-20) were synthesized and fully characterized by spectroscopic methods and elemental analysis. Among these compounds, 6, 8, 11, 13, 14, 16-20 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. The compounds inhibitory assay and docking simulation indicated that compound 20 (E)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)-N-(3,4,5-trimethylbenzylidene)acetohydrazide with MIC of 3.13-6.25 ?g/mL against the tested bacterial strains was a potent inhibitor of Escherichia coli FabH.
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Synthesis and antitumor activity of 1,3,4-oxadiazole possessing 1,4-benzodioxan moiety as a novel class of potent methionine aminopeptidase type II inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 01-25-2013
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A series of 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (7a-7q) have been designed, synthesized and evaluated for their antitumor activity. Most of the synthesized compounds were proved to have potent antitumor activity and low toxicity. Among them, compound 7a showed the most potent biological activity against Human Umbilical Vein Endothelial cells, which was comparable to the positive control. The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway. Molecular docking was performed to position compound 7a into MetAP2 binding site in order to explore the potential target.
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1,3,4-oxadiazole derivatives as potential biological agents.
Mini Rev Med Chem
PUBLISHED: 01-21-2013
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The synthesis of novel compound libraries along with screening is a rapid and effective approach for the discovery of potential chemical agents, and it becomes an important method in pharmaceutical chemistry research. 1,3,4- oxadiazole derivatives as the typical heterocyclic compounds, exhibit a broad spectrum of biological activities and vital leading compounds for the development of chemical drugs. Herein, we focus on the synthesis and screening of novel 1,3,4-oxadiazoles derivatives with antimicrobial, antitumor or antiviral activities during the past decade. In this review, we discussed the synthetic development of 1,3,4-oxadiazoles derivatives, and also the relevant bioactivity and their prospects as the potential chemical drugs.
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Synthesis, structure-activity relationship analysis and kinetics study of reductive derivatives of flavonoids as Helicobacter pylori urease inhibitors.
Eur J Med Chem
PUBLISHED: 01-11-2013
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In a continuing study for discovering urease inhibitors based on flavonoids, nineteen reductive derivatives of flavonoids were synthesized and evaluated against Helicobacter pylori urease. Analysis of structure-activity relationship disclosed that 4-deoxy analogues are more potent than other reductive products. Out of them, 4,7,8-trihydroxyl-2-isoflavene (13) was found to be the most active with IC50 of 0.85 ?M, being over 20-fold more potent than the commercial available urease inhibitor, acetohydroxamic acid (AHA). Kinetics study revealed that 13 is a competitive inhibitor of H. pylori urease with a Ki value of 0.641 ?M, which is well matched with the results of molecular docking. Biological evaluation and mechanism study of 13 suggest that it is a good candidate for discovering novel anti-gastritis and anti-gastric ulcer agent.
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Potentiating 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives against antibacterial agents: design, synthesis and biology analysis.
Eur J Med Chem
PUBLISHED: 01-08-2013
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A series of novel 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives had been designed, synthesized, isolated and evaluated as potentiators of antibacterial agents. All these synthesized compounds were determined by elemental analysis, (1)H NMR, and MS. Their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus thuringiensis and Bacillus subtilis by MTT method as potential FabH inhibitory. The results showed that compound 30 exhibited the most potent E. coli FabH inhibitory activity with IC50 of 4.6 ?M. Molecular modeling simulation studies were performed in order to predict the biological activities of the proposed compounds. All compounds have been tested for toxicity by MTT assay on human macrophage.
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Optimization of substituted 6-salicyl-4-anilinoquinazoline derivatives as dual EGFR/HER2 tyrosine kinase inhibitors.
PLoS ONE
PUBLISHED: 01-01-2013
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4-Anilinoquinazolines as an important class of protein kinase inhibitor are widely investigated for epidermal growth factor receptor (EGFR) tyrosine kinase or epidermal growth factor receptor 2 (HER2) inhibition. A series of novel 6-salicyl-4-anilinoquinazoline derivatives 9-27 were prepared and evaluated for their EGFR/HER2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on three variant cancer cell lines (A431, MCF-7, and A549). The bioassay results showed most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compound 21 revealed the most potent dual EGFR/HER2 inhibitory activity, with IC50 values of 0.12 µM and 0.096 µM, respectively, comparable to the control compounds Erlotinib and Lapatinib. Furthermore, the kinase selectivity profile of 21 was accessed and demonstrated its good selectivity over the majority of the close kinase targets. Docking simulation was performed to position compound 21 into the EGFR/HER2 active site to determine the probable binding pose. These new findings along with molecular docking observations could provide an important basis for further development of compound 21 as a potent EGFR/HER2 dual kinase inhibitor.
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Synthesis, structure and antibacterial activity of potent DNA gyrase inhibitors: N-benzoyl-3-(4-bromophenyl)-1H-pyrazole-5-carbohydrazide derivatives.
PLoS ONE
PUBLISHED: 01-01-2013
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A total of 19 novel (3a-3s) N-benzoyl-3-(4-bromophenyl)-1H-pyrazole-5-carbohydrazide analogs were designed, synthesized, and evaluated for biological activities as potential DNA gyrase inhibitors. The results showed that compound 3k can strongly inhibit Staphylococcus aureus DNA gyrase and Bacillus subtilis DNA gyrase (with IC50 of 0.15 µg/mL and 0.25 µg/mL, respectively). Structure-activity relationships were also discussed base on the biological and docking simulation results.
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