- Synthesis, crystal structures and insulin-like activity of three new oxidovanadium(V) complexes with aroylhydrazone ligand
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Three new oxidovanadium(V) complexes were designed, synthesized and characterized by C, H, N elemental analysis, single crystal X-ray diffraction,UV/Vis and IR spectra. Complex 1: [VOL1X] (H2L1 = (E)-N′-(2-hydroxybenzylidene)-3-methbenzohydrazide, HX = ethylmaltol = 2-ethyl-3-hydroxy-4-pyrone), Complex 2: [VOL2(CH3O)(CH3OH)], (H2L2 = C16H16N2O4 = (E)-N′-(2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide, CH3OH = methanol), Complex 3: [VOL3X] (H2L3 = (E)-N′-(3-ethoxy-2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide). The insulin-like activity of the three complexes was tested. Both normal and streptozotocin (STZ)-diabetic mice were administered intragastrically for two weeks. It was found that the complexes at doses of 10.0 and 5.0 mg V·kg?1 can significantly decrease the blood glucose level in STZ-diabetic mice, and the blood glucose level in the treated normal mice was not altered. The lesions of kidney and liver caused by diabetes have varying degrees of improvement.
- Zhou, Quan-Cheng,Wang, Tian-Rui,Li, Hui,Chen, Lei,Xin, Jia-Jin,Guo, Shen,Sheng, Gui-Hua,You, Zhong-Lu
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- Hydrazide compounds
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The invention discloses hydrazide compounds. The compounds are characterized by having a structure represented by a formula I shown in the description, wherein Ar1 and Ar2 are each independently selected from the group consisting of aryl, azinyl, piperazinyl, pyrazolyl, imidazolyl, pyrrolyl, phenyl, naphthyl, thiazolyl, thienyl, furyl, aryl, phenyl, piperazinyl, piperidinyl, piperazinyl, and-C13H9represented by a formula 9 shown in the description, only one of the Ar1 and the Ar2 is phenyl, the Ar1 has m substituents R1, Ar2 has n substituents R2, m=0 to 3, and n=0 to 3; and if the formula Ihas a plurality of substituents R1 and R2, the plurality of substituents R1 and R2 are independent with one another, can select the same substituents or different substituents, and the R1 and the R2 are each independently selected from the group consisting of halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, amino, C1-C3 alkyl substituted amino, C1-C3 alkyl disubstituted amino, perfluoro C1-C3alkyl and fluoro substituted C1-C3 alkoxy.
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Paragraph 0088; 0095; 0097; 0098
(2019/10/01)
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- Synthesis, pharmacological evaluation and docking study of a new modulator of microtubule polymerization
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Objectives: The main goal of this paper was to conduct the synthesis to determine cytotoxic activity and to carry out docking studies on new LASSBio-1586 isosteres. LASSBio-1586 is a new combretastatin A4 (CA4) analogue previously identified as a simple antitumor drug candidate, able to inhibit microtubule polymerization with broad in vitro and in vivo cytotoxic activity. Methods: The new isosteres (7b-7h, 8a and 9a) were evaluated against HL-60, OVCAR-8, HCT8 and LUCENA tumor cell lines, using cytotoxic test of MTT. The tubulin polymerization assay was performed using a tubulin polymerization assay kit from cytoskeletonR and by CEREP employing a single concentration of 10 μM. Binding mode at β-tubulin colchicine binding site was stablished by blind molecular docking studies. Results: LASSBio-1920 (7h) was identified as the most potent cytotoxic compound with IC50 values ranging from 0.75 nM to 11.5 nM, although it was inactive against MDR tumor cell line LUCENA (IC50 = 80 μM). This compound presented remarkable cytotoxic selective index in comparison with CA4 and LASSBio-1586. Its ability to modulate microtubule polymerization was confirmed and its mode of interaction with colchicine binding site in β-tubulin was demonstrated. Conclusion: Compound 7h is a new isostere of LASSBio-1586 that displayed potent cytotoxic activity and better cytotoxic selectivity index and has been shown to interact with DAMA-colchicine in its co-crystal with β-tubulin.
- Carneiro, Teiliane R.,do Amaral, Daniel N.,Fokoue, Harold H.,Sant’Anna, Carlos M. R.,Porras, Maria L. G.,Oliveira, Augusto C. A.,Cavalcanti, Bruno C.,Pessoa, Cláudia,Barreiro, Eliezer J.,Lima, Lídia M.
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p. 778 - 786
(2018/09/10)
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- Method for synthesizing aryl formaldehyde compound from aryl formate compound
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The invention discloses a method for synthesizing an aryl formaldehyde compound from an aryl formate compound. The method comprises the following steps: taking the aryl formate compound as a raw material, and reacting under the action of excessive hydrazine hydrate; after the end of the reaction, standing, cooling, filtering and washing, thus respectively obtaining filtrate and filter cake, wherein the filtrate is the hydrazine hydrate, and the filter cake is an aryl formylhydrazine compound; recycling and reusing the filtrate; then dissolving the aryl formylhydrazine compound in a solvent, reacting under the existence of 2-iodoxybenzoic acid and alkali, and carrying out aftertreatment, thus obtaining the aryl formaldehyde compound and a byproduct-2-iodosobenzoic acid; regenerating the 2-iodoxybenzoic acid after oxidizing the 2-iodosobenzoic acid, and repeatedly using the 2-iodoxybenzoic acid. According to the method disclosed by the invention, recycling and cyclic utilization of materials are fully realized, emissions are less, environment friendliness is realized, and the yield is higher.
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Paragraph 0039-0041
(2017/07/06)
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- Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents
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The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin-derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC50?=?2.54?±?0.82?μm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics.
- Wang, Zi-Zhen,Sun, Wen-Xue,Wang, Xue,Zhang, Ya-Han,Qiu, Han-Yue,Qi, Jin-Liang,Pang, Yan-Jun,Lu, Gui-Hua,Wang, Xiao-Ming,Yu, Fu-Gen,Yang, Yong-Hua
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p. 236 - 243
(2017/07/13)
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- Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis
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Herein, we report the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (0.011-0.026 μg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest.
- Karabanovich, Galina,Zemanová, Júlia,Smutny, Tomá?,Székely, Rita,?arkan, Michal,Centárová, Ivana,Vocat, Anthony,Pávková, Ivona,?onka, Patrik,Něme?ek, Jan,Stola?íková, Ji?ina,Vejsová, Marcela,Vávrová, Kate?ina,Klime?ová, Věra,Hrabálek, Alexandr,Pávek, Petr,Cole, Stewart T.,Miku?ová, Katarína,Roh, Jaroslav
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supporting information
p. 2362 - 2380
(2016/04/09)
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- Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand
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Compound 1 is a selective and potent agonist of the G protein-coupled receptor GPR139 (EC50 = 39 nM). In this study, we describe the synthesis, radiolabelling and in vitro evaluation of [3H]-1 for the characterisation of GPR139 and its spatial expression in the brain using autoradiography. Two different synthesis routes for the radiolabelling of 1 based on a reductive debromination strategy were investigated using deuterium (D2, g). The route based on reductive debromination of the bromonaphthyl precursor 5 proved superior over arylbromide 4 and was employed for the radiolabelling experiments. Reductive debromination of precursor 5 was accomplished using 3H2, Pd/C and triethylamine in DMF at ambient temperature to give target molecule [3H]-1 with a specific activity of 19.3 Ci mmol-1 and a radiochemical purity of ≥95%. By application of autoradiography and binding studies, it was not possible to discriminate [3H]-1 binding to wildtype mice brains from GPR139 knockout mice brains and total binding from non-specific binding in CHO-k1 cells stably expressing human GPR139 receptor. Based on these experiments we conclude that [3H]-1 is not a suitable radioligand for the characterisation of GPR139.
- Kuhne, Sebastiaan,N?hr, Anne Cathrine,Marek, Ale?,Elbert, Tomá?,Klein, Anders Bue,Br?uner-Osborne, Hans,Wellendorph, Petrine,Pedersen, Daniel Sejer
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p. 947 - 952
(2016/01/15)
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- Structure activity relationship of brevenal hydrazide derivatives
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Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model.
- Goodman, Allan,McCall, Jennifer R.,Jacocks, Henry M.,Thompson, Alysha,Baden, Daniel,Abraham, William M.,Bourdelais, Andrea
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p. 1839 - 1858
(2014/06/09)
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- Synthesis, characterization and antimicrobial activities of mercaptoxadiazoles, mercaptotriazoles and their derivatives
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Five member heterocycles are famous for their universal activities. Starting with suitably substituted hydrazides 1,3,4-oxadiazole-2-thiones (1-5) and 1,2,4-triazolethionamines (6-11) were synthesized which were later on converted into Mannich products (13-22) and traizolothiadiazines (23-28) respectively. Structures were established by FTIR, hydrogen, carbon NMR, and mass spectrometric analysis. Compounds were evaluated for their antimicrobial studies. Compounds 13, 19 and 23 showed maximum inhibitions in opposition to the bacterial strains while compounds 7, 11, 13 and 27 showed utmost percentage inhibition aligned with the yeast cells.
- Mumtaz, Amara,Saeed, Aamer,Malik, Imran
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p. 852 - 857
(2015/01/30)
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- Synthesis, antibacterial and anticancer evaluation of 5-substituted (1,3,4-oxadiazol-2-yl)quinoline
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2-Chloroquinoline-3-carbaldehyde (2) was synthesized via Vilsmeier-Haack method using acetanilide. Phenoxy/naphthalene-1-yl/naphthalen-2-yloxy methyl-1H-benzimidazol-1-yl)acetohydrazide (7a-c) were synthesized using 2-[2-(phenoxy/naphthalen-1-yl/naphthalen-2-yloxy methyl)-1H-benzimidazol-1-yl]acetohydrazide (6a-c). The title compounds 2-chloro-3-{5-[(2-phenoxy/naphthalene-1-yl/naphthalen-2-yloxy methyl-1-H-benzimidazol-1-yl)methyl]-1,3,4-oxadiazol-2-yl}quinolone (8a-c) were prepared using chloramine-T. In the second series, (2-chloroquinolin-3-yl)methylidene]-substituted benzohydrazide (11a-i) were prepared by the reaction of 2-chloroquinoline-3-carbaldehyde (2) and an acid hydrazide (10a-i). The synthesized compounds were characterized by IR, NMR, Mass spectrometry, elemental analysis and screened for their antibacterial (serial dilution technique and disc diffusion method) and anticancer activity by NCI 60 cell screen at a single high dose (10-5 M) on various panel/cell lines. The synthesized compounds (8a, 8c, 12a, 12b, 12c and 12h) were acting as a magic bullet against gram-positive strains of Bacillus cereus MTCC1305, and the compounds (12a, 12c and 12h) were also found to be extremely active against Klebsiella pneumonia NCTC7447. In the in vitro screen on tested cancer cell line, the compound (12d) showed 95.70 growth percent (GP) and highly active on SNB-75 (CNS cancer) and UO-31 (renal cancer) (GP = 53.35 and 64.35, respectively), and the compound (8a) showed 96.86 GP and highly active on SNB-75 (CNS cancer GP 51.27).
- Salahuddin,Mazumder, Avijit,Shaharyar, Mohammad
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p. 2514 - 2528
(2015/02/19)
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- Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents
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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 μM, 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 μM, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 μg/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.
- Du, Qian-Ru,Li, Dong-Dong,Pi, Ya-Zhou,Li, Jing-Ran,Sun, Jian,Fang, Fei,Zhong, Wei-Qing,Gong, Hai-Bin,Zhu, Hai-Liang
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p. 2286 - 2297
(2013/05/09)
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- Synthesis, molecular modeling and biological evaluation of 2-(benzylthio)-5-aryloxadiazole derivatives as anti-tumor agents
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A series of 2-(benzylthio)-5-aryloxadiazole derivatives have been designed and synthesized, and their biological activities are also evaluated for EGFR inhibitory activity. Fourteen compounds among the twenty compounds are reported for the first time. Their chemical structures are characterized by 1H NMR, MS, and elemental analysis. Anti-proliferative and EGFR inhibition assay results have demonstrated that compound 3e shows the most potent biological activity (IC50 = 1.09 μM for MCF-7 and IC50 = 1.51 μM for EGFR). Docking simulation has been performed to position compound 3e into the EGFR active site to determine the probable binding model, with an estimated binding free energy value of -10.7 kcal/mol. Compound 3e with potent inhibitory activity in tumor growth inhibition may be a promising anti-tumor leading compound for the further research.
- Liu, Kai,Lu, Xiang,Zhang, Hong-Jia,Sun, Juan,Zhu, Hai-Liang
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experimental part
p. 473 - 478
(2012/03/13)
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- Synthesis, biological evaluation and molecular docking studies of novel 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives
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In present study, a series of new 2-(1,3,4-oxadiazol-2-ylthio)-1- phenylethanone derivatives (6a-6x) as potential focal adhesion kinase (FAK) inhibitors were synthesized. The bioassay assays demonstrated that compound 6i showed the most potent activity, which inhibited the growth of MCF-7 and A431 cell lines with IC50 values of 140 ± 10 nM and 10 ± 1 nM, respectively. Compound 6i also exhibited significant FAK inhibitory activity (IC50 = 20 ± 1 nM). Docking simulation was performed to position compound 6i into the active site of FAK to determine the probable binding model.
- Zhang, Li-Rong,Liu, Zhi-Jun,Zhang, Hui,Sun, Jian,Luo, Yin,Zhao, Ting-Ting,Gong, Hai-Bin,Zhu, Hai-Liang
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scheme or table
p. 3615 - 3621
(2012/07/27)
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- 3,5,2′,4′-Tetrahydroxychalcone, a new non-purine xanthine oxidase inhibitor
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Xanthine oxidase is a key enzyme that catalyses hypoxanthine and xanthine to uric acid and the overproduction of uric acid will lead to hyperuricemia which is an important cause of gout. In the present study, three chalcone derivatives were synthesized and evaluated for inhibitory activity against xanthine oxidase in vitro. Of the compounds, only Compound 1, 3,5,2′,4′-tetrahydroxychalcone, exhibited a significant inhibitory activity on xanthine oxidase with an IC50 value of 22.5 μM. Lineweaver-Burk transformation of the inhibition kinetics data demonstrated that it was a competitive inhibitor of xanthine oxidase and Ki value was 17.4 μM. In vivo, intragastric administration of Compound 1 was able to significantly reduce serum uric acid levels and inhibited hepatic xanthine oxidase activities of hyperuricemic mice in a dose-dependent manner. Acute toxicity study in mice showed that Compound 1 was very safe at a dose of up to 5 g/kg. These results suggest that Compound 1 is a novel competitive xanthine oxidase inhibitor and is worthy of further development.
- Niu, Yanfen,Zhu, Huajie,Liu, Jia,Fan, Huafang,Sun, Ling,Lu, Wei,Liu, Xu,Li, Ling
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scheme or table
p. 161 - 166
(2012/01/11)
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- Synthesis, antimicrobial evaluation and QSAR studies of 3-ethoxy-4-hydroxybenzylidene/4-nitrobenzylidene hydrazides
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A series of 3-ethoxy-4-hydroxybenzylidene/4-nitrobenzylidene hydrazides (1-20) was synthesized and tested for in vitro antimicrobial activity. The results of antimicrobial studies indicated that the compounds having dinitro, methoxy, hydroxy and nitro substituents on phenyl ring of the aromatic acids were most active ones. The QSAR investigation indicated the importance of the topological parameter, third order molecular connectivity index ( 3χ) in describing the antimicrobial activity of synthesized hydrazides.
- Kumar, Davinder,Kapoor, Archana,Thangadurai, Ananda,Kumar, Pradeep,Narasimhan, Balasubramanian
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experimental part
p. 1293 - 1296
(2012/01/07)
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- Benzylidene/2-chlorobenzylidene hydrazides: Synthesis, antimicrobial activity, QSAR studies and antiviral evaluation
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A series of benzylidene hydrazides (1-20) was synthesized and tested, in vitro, for antibacterial, antifungal and antiviral activities. The microbial screening results indicated that compounds having chloro and nitro substituents were the most active ones. The antiviral evaluation depicted that compounds 9 and 19 were active against Vesicular stomatitis virus (VSV) in HeLa cell cultures. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial (antibacterial and antifungal) activity over the one-target QSAR models. Further the mt-QSAR model indicated that the topological parameters, second order molecular connectivity index (2χ) and third order Kier's alpha shape index (κα3) are effective in describing the antimicrobial activity of synthesized hydrazides.
- Kumar, Davinder,Judge, Vikramjeet,Narang, Rakesh,Sangwan, Sonia,De Clercq, Erik,Balzarini, Jan,Narasimhan, Balasubramanian
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experimental part
p. 2806 - 2816
(2010/08/20)
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- Identification of a potent new chemotype for the selective inhibition of PDE4
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A series of substituted 3,6-diphenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were prepared and analyzed as inhibitors of phosphodiesterase 4 (PDE4). Synthesis, structure-activity relationships, and the selectivity of a highly potent analogue against related phosphodiesterase isoforms are presented.
- Skoumbourdis, Amanda P.,Huang, Ruili,Southall, Noel,Leister, William,Guo, Vicky,Cho, Ming-Hsuang,Inglese, James,Nirenberg, Marshall,Austin, Christopher P.,Xia, Menghang,Thomas, Craig J.
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p. 1297 - 1303
(2008/09/20)
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- A practical synthesis of trans-resveratrol
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The total synthesis of biologically active substance transresveratrol 1 has been described with moderate overall yield (35.7%). Starting from 3,5-dihydroxybenzoic acid, 3,5-dimethoxybenzonate methyl ester is prepared. The reaction of the ester with hydrazine hydrate followed by oxidation with K3[Fe(CN)6] gives the key intermediate 3,5-dimethoxy-benzaldehyde, which is condensed with diethyl(4-methoxy-benzyl)phosphonate to yield only trans-3,5,4′-trimethylstilbene. The synthesis of trans-resveratrol is completed by the deprotection reaction with BBr3/CH2Cl2.
- Shen, Zhen Lu,Zhuo, Guang Lan,Jiang, Xuan Zhen
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p. 2395 - 2398
(2007/10/03)
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- Long-chain Phenols. Part 16. A Novel Synthesis of Homologous Orsellinic Acids and their Methyl Ethers
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By the novel reaction of 3,5-dimethoxyfluorobenzene with n-alkyl-lithium compounds, followed by carbonation, homologous orsellinic acid dimethyl ethers (6-alkyl-2,4-dimethoxybenzoic acids) have been obtained.The reactions proceeded best with the homologues of methyl-lithium.These reactions are considered to occur by way of 3,5-dimethoxybenzyne. 2,4-Dimethoxyfluorobenzene did not form an aryne but gave 3-fluoro-2,6-dimethoxybenzoic acid instead.Decomposition with water of alkyl-lithium reaction mixtures from 3,5-dimethoxyfluorobenzene yielded 5-n-alkylresorcinol dimethyl ethers.Demethylaton of 6-alkyl-2,4-dimethoxybenzoic acids with boron trichloride proceeded partially and selectively to give the 6-alkyl-2-hydroxy-4-methoxybenzoic acids, and completely with aluminium chloride to give the homologous orsellinic acids.Boron tribromide was less effective, but readily gave the 5-alkyl resorcinols from the corresponding dimethyl ethers.
- Durrani, Aziz A.,Tyman, John H. P.
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p. 1658 - 1666
(2007/10/02)
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