- Synthesis and pharmacological activity of 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles
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An efficient method for the synthesis of novel 9H-imidazo[1,2-a]benzimidazole derivatives containing a biphenyl substituent at position 2 was developed. These compounds, belonging to the privileged substructures, have been tested for a wide range of pharmacological activities in the in vitro test panel. It was shown that the synthesized derivatives demonstrated high antioxidant activity, some of them inhibit type 1B protein tyrosine phosphatase, activate AMP-activated protein kinase, possess antiplatelet properties, and a rare and very interesting kind of activity, the ability to break cross-links of glycated proteins. The most active compounds can be suggested for further optimization.
- Spasov,Zhukovskaya,Brigadirova,Abbas,Anisimova,Sysoeva,Rashchenko,Litvinov,Mayka, O. Yu.,Babkov,Morkovnik
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- Expedient synthesis of novel glycosyl thiazole derivatives
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An efficient protocol for the synthesis of novel glycosyl thiazole derivatives starting from the commercially available D-glucosamine hydrochloride was described by reaction of 1-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea 8 with each of substituted α-bromoacetophenone in ethanol. 1-(1,3,4,6-Tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea was an important intermediate, and its synthetic methods were discussed by comparing two different synthetic routes. Moreover, 2-isothiocyanate-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose was obtained in a new and convenient way. Finally, a series of novel glycosyl incorporated with thiazole moiety was synthesized in good purities and overall yields.
- Cheng, Feng-Chang,Yin, Long,Liu, Wei-Wei,Li, Qu-Xiang,Tang, Li-Juan,Shi, Da-Hua,Cao, Zhi-Ling
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- Substituent effects in the formation of a few acenaphthenone-2-ylidene ketones and their molecular docking studies and in silico ADME profile
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We observed intriguing substituent effects in the reaction between 4-substituted acetophenones and acenaphthenequinone in the presence of KOH in methanol. In all cases, expected Claisen-Schimdt condensation was the first step. However, depending on the nature of 4-substituent on acetophenone, the initially formed condensation product remain unchanged or underwent Domino sequence of reactions to give three different 2:2 adducts arising through three distinct pathways. The interactions of acenaphthenone-2-ylidene ketones with the target proteins were performed by molecular docking studies. The prediction of in silico ADME belongings of the synthesized compounds revealed substantial drug-likeness characters based on Lipinski's rules.
- A, Jesna,Jacob, Jomon P.,Kuriakose, Daly,Thumpakara, Roshini K.
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- Base-Catalyzed Intramolecular Defluorination/O-Arylation Reaction for the Synthesis of 3-Fluoro-1,4-oxathiine 4,4-Dioxide
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A novel process involving base-catalyzed intramolecular defluorination/O-arylation of readily available α-fluoro-β-one-sulfones was realized and provided a series of 3-fluoro-1,4-oxathiine 4,4-dioxide derivatives in good to excellent yields. Unlike traditional defluorination reactions with stoichiometric base as the deacid reagent, this process is triggered by a catalytic amount of base (TMG: tetramethylguanidine) and molecular sieves serve as both an adsorbent to remove HF acid and an activator to assist C-F bond cleavage.
- Kang, Lei,Zhang, Jinlong,Yang, Huameng,Qian, Jinlong,Jiang, Gaoxi
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supporting information
p. 785 - 789
(2021/04/09)
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- Novel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer
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The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is one of the more recently identified mammalian sources of H2S. A recent study identified several novel 3-MST inhibitors with micromolar potency. Among those, (2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one) or HMPSNE was found to be the most potent and selective. We now took the central core of this compound and modified the pyrimidone and the arylketone sides independently. A 63-compound library was synthesized; compounds were tested for H2S generation from recombinant 3-MST in vitro. Active compounds were subsequently tested to elucidate their potency and selectivity. Computer modeling studies have delineated some of the key structural features necessary for binding to the 3-MST's active site. Six novel 3-MST inhibitors were tested in cell-based assays: they exerted inhibitory effects in murine MC38 and CT26 colon cancer cell proliferation; the antiproliferative effect of the compound with the highest potency and best cell-based activity (1b) was also confirmed on the growth of MC38 tumors in mice.
- Bantzi, Marina,Augsburger, Fiona,Loup, Jérémie,Berset, Yan,Vasilakaki, Sofia,Myrianthopoulos, Vassilios,Mikros, Emmanuel,Szabo, Csaba,Bochet, Christian G.
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p. 6221 - 6240
(2021/05/06)
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- Oxidation Potential-Guided Electrochemical Radical-Radical Cross-Coupling Approaches to 3-Sulfonylated Imidazopyridines and Indolizines
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Oxidation potential-guided electrochemical radical-radical cross-coupling reactions between N-heteroarenes and sodium sulfinates have been established. Thus, simple cyclic voltammetry measurement of substrates predicts the likelihood of successful radical-radical coupling reactions, allowing the simple and direct synthetic access to 3-sulfonylated imidazopyridines and indolizines. The developed electrochemical radical-radical cross-coupling reactions to sulfonylated N-heteroarenes boast the green synthetic nature of the reactions that are oxidant- and metal-free.
- Kim, Wansoo,Kim, Hun Young,Oh, Kyungsoo
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p. 15973 - 15991
(2021/07/26)
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- Nucleus-independent chemical shift (NICS) as a criterion for the design of new antifungal benzofuranones
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The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p –1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 μg·mL–1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.
- González-Chávez, Marco Martín,González-Chávez, Rodolfo,Méndez, Francisco,Martínez, Roberto,Ni?o-Moreno, Perla Del Carmen,Ojeda-Fuentes, Luis Enrique,Richaud, Arlette,Zerme?o-Macías, María de los ángeles
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- Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents
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(+)-Usnic acid, a product of secondary metabolism in lichens, has displayed a broad range of biological properties such as antitumor, antimicrobial, antiviral, anti-inflammatory, and insecticidal activities. Interested by these pharmacological activities and to tap into its potential, we herein present the synthesis and biological evaluation of new usnic acid enaminone-conjugated 1,2,3-triazoles 10-44 as antimycobacterial agents. (+)-Usnic acid was condensed with propargyl amine to give usnic acid enaminone 8 with a terminal ethynyl moiety. It was further reacted with various azides A1-A35 under copper catalysis to give triazoles 10-44 in good yields. Among the synthesized compounds, saccharin derivative 36 proved to be the most active analogue, inhibiting Mycobacterium tuberculosis (Mtb) at an MIC value of 2.5 μM. Analogues 16 and 27, with 3,4-difluorophenacyl and 2-acylnaphthalene units, respectively, inhibited Mtb at MIC values of 5.4 and 5.3 μM, respectively. Among the tested Gram-positive and Gram-negative bacteria, the new derivatives were active on Bacillus subtilis, with compounds 18 [3-(trifluoromethyl)phenacyl] and 29 (N-acylmorpholinyl) showing inhibitory concentrations of 41 and 90.7 μM, respectively, while they were inactive on the other tested bacterial strains. Overall, the study presented here is useful for converting natural (+)-usnic acid into antitubercular and antibacterial agents via incorporation of enaminone and 1,2,3-triazole functionalities.
- Bangalore, Pavan K.,Vagolu, Siva K.,Bollikanda, Rakesh K.,Veeragoni, Dileep K.,Choudante, Pallavi C.,Misra, Sunil,Sriram, Dharmarajan,Sridhar, Balasubramanian,Kantevari, Srinivas
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supporting information
p. 26 - 35
(2020/01/03)
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- Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study
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Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.
- Ma, Weifeng,Chen, Peng,Huo, Xiansen,Ma, Yufeng,Li, Yanhong,Diao, Pengcheng,Yang, Fang,Zheng, Shengquan,Hu, Mengjin,You, Wenwei,Zhao, Peiliang
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- Application of poly(vinylphenyltrimethylammonium tribromide) resin as an efficient polymeric brominating agent in the α-bromination and α-bromoacetalization of acetophenones
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The applications of a new supported tribromide reagent based on poly(vinylbenzyltrimethylammonium hydroxide) resin (Amberlite 717) were reported. This supported tribromide resin was used directly in α-bromination and α-bromoacetalization of acetophenones without any other catalyst under mild conditions. The effects of solvents and the amount of the supported tribromide resin on the reactions were investigated. Under the optimal conditions, most of α-bromo and α-bromoacetal of acetophenones were selectively obtained in excellent yields.
- Han, Bingbing,Zheng, Zubiao,Zheng, Dongcheng,Zhang, Lei,Cui, Peng,Shi, Jianjun,Li, Changjiang
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supporting information
p. 2512 - 2520
(2019/07/04)
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- Task-Specific Catalyst Development for Lignin-First Biorefinery toward Hemicellulose Retention or Feedstock Extension
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A catalytic reductive fractionation method for lignocellulosic biomass, termed lignin-first biorefinery, has emerged, which emphasises preferential depolymerization of the protolignin. However, in most studies, the lignin-first biorefinery is only effective for hardwood that has a high syringyl/guaiacol (S/G) ratio of lignin building blocks, and the degradation of hemicellulose also takes place simultaneously to a certain degree. In this study, two task-specific catalysts were developed to realize hemicellulose retention and feedstock extension through the development of an objective performance–structure relationship. It is found that MoxC/carbon nanotube (CNT) is highly selective in the cleavage of bonds between carbohydrates and lignin and ether bonds in lignin during the catalytic reductive fractionation of hardwood, leading to a carbohydrate (both cellulose and hemicellulose) retention degree in the solid product close to the theoretical maximum and a delignification degree as high as 98.1 %. Ru/CMK-3 is demonstrated to be effective in the catalytic reductive fractionation of softwood and grass, resulting from its weak acidity and high mesoporosity.
- Qiu, Shi,Guo, Xuan,Huang, Yong,Fang, Yunming,Tan, Tianwei
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p. 944 - 954
(2019/01/08)
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- Organocatalytic Enantioselective Selenosulfonylation of a C-C Double Bond to Form Two Stereogenic Centers in an Aqueous Medium
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Organocatalytic selenosulfonylation of the C-C double bond of α,β-unsaturated ketones to construct two contiguous stereogenic centers in an aqueous medium was described. A series of α-selenyl and β-sulfonyl ketones with various functional groups were synthesized in good yields and enantioselectivities with saturated NaCl solution as the solvent. In addition, this protocol had been successfully scaled up to a decagram scale via a simple workup procedure.
- Chen, Zhili,Hu, Fangli,Huang, Shengli,Zhao, Zhengxing,Mao, Hui,Qin, Wenling
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p. 8100 - 8111
(2019/06/17)
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- Design, synthesis and biological evaluation of flexible and rigid analogs of 4H-1,2,4-triazoles bearing 3,4,5-trimethoxyphenyl moiety as new antiproliferative agents
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Several flexible and rigid analogs of 4H-1,2,4-triazoles (compounds 8a-g and 9a-g) bearing trimethoxyphenyl pharmacophoric unit, were designed and synthesized as potential anticancer agents. The in vitro cytotoxic assay indicated that both flexible and rigid analogs (8 and 9, respectively) can potentially inhibit the growth of cancerous cells (A549, MCF7, and SKOV3), with IC50 values less than 5.0 μM. Furthermore, compounds 10a-l as regional isomers of compounds 9 exhibited remarkable cytotoxic activity with IC50 values ranging from 0.30 to 5.0 μM. The rigid analogs 9a, 10h and 10k were significantly more potent than etoposide against MCF7, SKOV3 and A549 cells, respectively. These compounds showed high selectivity towards cancer cells over normal cells, as they had no significant cytotoxicity against L929 cells. In addition, the representative compounds 9a and 10h could inhibit the tubulin polymerization at micro-molar levels. By determining changes in the colchicine-tubulin fluorescence, it was suggested that compound 10h could bind to the tubulin at the colchicine pocket. The molecular docking study further confirmed the inhibitory activity of promising compounds 9a, 10h and 10k on tubulin polymerization through binding to the colchicine-binding site.
- Ansari, Mahsa,Shokrzadeh, Mohammad,Karima, Saeed,Rajaei, Shima,Hashemi, Seyedeh Mahdieh,Mirzaei, Hassan,Fallah, Marjan,Emami, Saeed
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- Identification of Anti-Mycobacterial Biofilm Agents Based on the 2-Aminoimidazole Scaffold
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Tuberculosis (TB) remains a significant global health problem for which new therapeutic options are sorely needed. The ability of the causative agent, Mycobacterium tuberculosis, to reside within host macrophages and form biofilm-like communities contributes to the persistent and drug-tolerant nature of the disease. Compounds that can prevent or reverse the biofilm-like phenotype have the potential to serve alongside TB antibiotics to overcome this tolerance, and decrease treatment duration. Using Mycobacterium smegmatis as a surrogate organism, we report the identification of two new 2-aminoimidazole compounds that inhibit and disperse mycobacterial biofilms, work synergistically with isoniazid and rifampicin to eradicate preformed M. smegmatis biofilms in vitro, are nontoxic toward Galleria mellonella, and exhibit stability in mouse plasma.
- Nguyen, T. Vu,Minrovic, Bradley M.,Melander, Roberta J.,Melander, Christian
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p. 927 - 937
(2019/03/26)
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- 2-Amino-4-arylthiazoles through One-Pot Transformation of Alkylarenes with NBS and Thioureas
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Treatment of alkylarenes with N-bromosuccinimide in a mixture of ethyl acetate and water at 60 °C, a mixture of acetonitrile and water at 80 °C, or a mixture of diethyl carbonate and water under irradiation with a tungsten lamp, followed by a reaction with thioureas or arenethioamides provided the corresponding 2-amino- 4-arylthiazoles or 2,4-diarylthiazoles in good to moderate yields, respectively, in one pot. The present reaction is an efficient one-pot transformation method of alkylarenes into 2-amino-4-arylthiazoles and 2,4-diarylthiazoles directly under mild and transition-metal-free conditions.
- Shibasaki, Kaho,Togo, Hideo
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p. 2520 - 2527
(2019/04/04)
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- One-Pot Sequential Bromination and Fluorination to Access 3-Fluoroimidazo[1,2-a]pyridines from Arylketones
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3-Fluoro-2-arylimidazo[1,2-a]pyridines were selectively synthesised in one-pot from acetophenones and 2-aminopyridines under mild conditions. The sequence of reactions involved bromination, condensation, and late-stage fluorination. Two halogenating reagents play key roles in the process. We found that tetrabutylammonium tribromide and SelectfluorTM gave excellent yields of the desired products in the one-pot sequential reaction.
- Udavant, Rohini N.,Yadav, Ashok R.,Shinde, Sandip S.
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p. 3432 - 3436
(2018/07/25)
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- Tropylium Ion Catalyzes Hydration Reactions of Alkynes
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The hydration of alkynes is one of the most atom-economic and versatile synthetic protocols to access carbonyl compounds. This fundamental reaction, however, often requires transition-metal catalysts or harsh reaction conditions to promote the addition of water to the carbon–carbon triple bond. In this work, it is demonstrated that the non-benzenoid aromatic tropylium ion can be used as an organic Lewis acid promoter for the hydration of alkynes under simple reaction conditions with excellent outcomes.
- Oss, Giulia,Ho, Junming,Nguyen, Thanh Vinh
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supporting information
p. 3974 - 3981
(2018/08/17)
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- One-Pot Preparation of Aromatic Amides, 4-Arylthiazoles, and 4-Arylimidazoles from Arenes
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Simple treatment of arenes with α-bromoacetyl chloride and AlCl3, followed by the reaction with molecular iodine and aq. NH3, thioamides, or amidines gave the corresponding primary aromatic amides, 4-arylthiazoles, or 4-arylimidazoles in good yields, respectively. Aryl α-bromomethyl ketones are the key intermediates in those reactions. Primary aromatic amides were formed from arenes through the reaction of aryl α-bromomethyl ketones with molecular iodine and aq. NH3, and 4-arylthiazoles and 4-arylimidazoles were formed from arenes through the reactions of aryl α-bromomethyl ketones with thioamides and amidines, respectively, in one pot under transition-metal-free conditions.
- Yamamoto, Takahiro,Togo, Hideo
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p. 4187 - 4196
(2018/08/21)
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- α-Ketothioamide Derivatives: A Promising Tool to Interrogate Phosphoglycerate Dehydrogenase (PHGDH)
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Given the putative role of PHGDH in cancer, development of inhibitors is required to explore its function. In this context, we established and validated a straightforward enzymatic assay suitable for high-throughput screening and we identified inhibitors with similar chemical scaffolds. Through a convergent pharmacophore approach, we synthesized α-ketothioamides that exhibit interesting in vitro PHGDH inhibition and encouraging cellular results. These novel probes may be used to understand the emerging biology of this metabolic target.
- Ravez, Séverine,Corbet, Cyril,Spillier, Quentin,Dutu, Alice,Robin, Anita D.,Mullarky, Edouard,Cantley, Lewis C.,Feron, Olivier,Frédérick, Rapha?l
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supporting information
p. 1591 - 1597
(2017/03/08)
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- Novel biphenyl ester derivatives as tyrosinase inhibitors: Synthesis, crystallographic, spectral analysis and molecular docking studies
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Biphenyl-based compounds are clinically important for the treatments of hypertension and inflammatory, while many more are under development for pharmaceutical uses. In the present study, a series of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl benzoates, 2(a-q), and 2-([1,1'- biphenyl]-4-yl)-2-oxoethyl pyridinecarboxylate, 2(r-s) were synthesized by reacting 1-([1,1'- biphenyl]-4-yl)-2-bromoethan-1-one with various carboxylic acids using potassium carbonate in dimethylformamide at ambient temperature. Single-crystal X-ray diffraction studies revealed a more closely packed crystal structure can be produced by introduction of biphenyl moiety. Five of the compounds among the reported series exhibited significant antityrosinase activities, in which 2p, 2r and 2s displayed good inhibitions which are comparable to standard inhibitor kojic acid at concentrations of 100 and 250 μg/mL. The inhibitory effects of these active compounds were further confirmed by computational molecular docking studies and the results revealed the primary binding site is active-site entrance instead of inner copper binding site which acted as the secondary binding site.
- Kwong, Huey Chong,Kumar, C. S. Chidan,Mah, Siau Hui,Chia, Tze Shyang,Quah, Ching Kheng,Loh, Zi Han,Chandraju, Siddegowda,Lim, Gin Keat
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- Visible Light as a Sole Requirement for Intramolecular C(sp3)-H Imination
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A novel, simple, and practical visible-light-mediated intramolecular α-C(sp3)-H imination of tertiary aliphatic amines containing β-O-aryl oximes leading to N-heterocycles has been developed. The reaction was performed well at rt with tolerance of some functional groups. Importantly, the selective C-H functionalization did not require added catalyst, oxidant, additive, acid, and base; visible light was the sole requirement.
- Li, Jingjing,Zhang, Pengxiang,Jiang, Min,Yang, Haijun,Zhao, Yufen,Fu, Hua
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supporting information
p. 1994 - 1997
(2017/04/28)
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- AuIII-Catalyzed Formation of α-Halomethyl Ketones from Terminal Alkynes
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A AuIII-catalyzed synthesis of α-halomethyl ketones from terminal alkynes was developed. This approach features excellent functional group compatibility and good yields for both aromatic and aliphatic terminal alkynes. The resulting α-halomethyl ketones were used to prepare heterocyclic indolizine structures. The plausible mechanism of the one-pot reaction is proposed.
- Xing, Yalan,Zhang, Ming,Ciccarelli, Sarah,Lee, John,Catano, Bryant
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supporting information
p. 781 - 785
(2017/02/15)
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- Synthesis, activity, and docking study of phenylthiazole acids as potential agonists of PPARγ
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Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-mediated transcription factor playing key roles in glucose and lipid homeostasis, and PPARγ ligands possess therapeutic potential in these as well as other areas. In this study, a series of phenylthiazole acids have been synthesized and evaluated for agonistic activity by a convenient fluorescence polarization-based PPARγ ligand screening assay. Compound 4t, as a potential PPARγ agonist with half maximal effective concentration (EC50) 0.75±0.20 μM, exhibited in vitro potency comparable with a 0.83±0.14 μM of the positive control rosiglitazone. Molecular docking and molecular dynamics simulations indicated that phenylthiazole acid 4t interacted with the amino acid residues of the active site of the PPARγ complex in a stable manner, consistent with the result of the in vitro ligand assay.
- Ma, Liang,Wang, Taijin,Shi, Min,Ye, Haoyu
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p. 1807 - 1815
(2016/06/09)
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- Palladium-Catalyzed Chemo- and Enantioselective C?O Bond Cleavage of α-Acyloxy Ketones by Hydrogenolysis
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A chemoselective C?O bond cleavage of the ester alkyl side-chain of α-acyloxy ketones was realized for the first time by a highly efficient palladium-catalyzed hydrogenolysis (S/C=6000, the highest catalytic efficiency by far). Furthermore, a kinetic resolution of α-acyloxy ketones was first developed by enantioselective hydrogenolysis with good yields and up to 99 % ee.
- Chen, Jianzhong,Zhang, Zhenfeng,Liu, Delong,Zhang, Wanbin
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supporting information
p. 8444 - 8447
(2016/07/19)
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- A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines
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A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines has been successfully realized with 2.5 mol% of B(C6F5)3 as a catalyst to furnish a variety of 3,4-dihydro-2H-1,4-benzoxazines in 93-99% yields. Up to 42% ee was also achieved for the asymmetric hydrogenation with the use of a chiral diene and HB(C6F5)2.
- Wei, Simin,Feng, Xiangqing,Du, Haifeng
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supporting information
p. 8026 - 8029
(2016/09/09)
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- Method for preparing 3,4-dihydrobenzo[b][1,4]oxazine derivatives
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The invention provides a method for preparing 3,4-dihydrobenzo[b][1,4]oxazine derivatives. The method comprises the following step: carrying out reduction reaction on [b][1,4]oxazines in the presence of hydrogen gas by using B(C6F5)3 as a catalyst to obtain the mixture containing the 3,4-dihydrobenzo[b][1,4]oxazines disclosed as Formula I. Benzo[b][1,4]oxazines in different structures are used as a substrate to synthesize the benzo[b][1,4]oxazines at high yield by using the B(C6F5)3 as the catalyst. The method has the advantages of cheap and accessible raw materials, high reaction activity, no participation of transition metals and wide substrate application range, and has huge industrialization potential.
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Paragraph 0071
(2016/10/10)
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- Synthesis and biological evaluation of novel C1-glycosyl thiazole derivatives as acetylcholinesterase inhibitors
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A new series of C1-glycosyl thiazole derivatives was synthesised by the reaction of 1-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea with 2-bromoacetophenone derivatives. Subsequent removal of the acetyl groups were conducted using NaOMe-MeOH. The structures of all new products were confirmed by IR, 1H NMR and HRMS (ESI). The acetylcholinesterase inhibitory activities of these new compounds were tested. Among them, N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(4-nitrophenyl)-1,3-thiazole-2-amine showed the best activity with an inhibition rate of 43.21%.
- Yin, Long,Cheng, Feng-Chang,Li, Qu-Xiang,Liu, Wei-Wei,Liu, Xiu-Jian,Cao, Zhi-Ling,Shi, Da-Hua
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p. 545 - 548
(2016/10/05)
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- In(OTf)3/acid co-catalyzed hydration of 1-haloalkynes to α-halomethyl ketones
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A novel and efficient In(OTf)3and HOAc cooperatively catalyzed hydration of 1-haloalkynes is described. This method provides ready access to α-chloromethyl ketones, α-bromomethyl ketones and α-iodomethyl ketones in moderate to high yields from simple, inexpensive starting materials. A broad substrate scope is achieved, and the reaction is compatible with various functional groups, including alkoxy, trifluoromethyl, halide, hydroxyl, cyclohexyl, and heterocyclic groups.
- Zeng, Ming,Huang, Rui-Xue,Li, Wen-Yi,Liu, Xiao-Wen,He, Fu-Ling,Zhang, Yi-Yuan,Xiao, Fang
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p. 3818 - 3822
(2016/07/06)
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- First Catalyzed Hydration of Haloalkynes by a Recyclable Catalytic System
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The hydration of haloalkynes to give α-halomethyl ketones was achieved based on a combination of a Cu(OAc)2 catalyst and a TFA (trifluoroacetic acid) promoter. This is the first synthesis of chloro/bromo/iodo methyl ketones through a hydration reaction catalyzed by a recyclable catalytic system. The catalytic system has a wide substrate scope and excellent chemoselectivity, and the procedure can also be scaled up.
- Zou, Huaxu,He, Weibao,Dong, Qizhi,Wang, Ruijia,Yi, Niannian,Jiang, Jun,Pen, Dongming,He, Weimin
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p. 116 - 121
(2016/01/26)
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- Highly Efficient Synthesis of α-Halomethylketones via Ce(SO4)2/Acid Co-Catalyzed Hydration of Alkynes
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A general atom-economical approach for the synthesis of α-halomethyl ketones is demonstrated through Ce(SO4)2/acid co-catalyzed hydration of a wide range of haloalkynes. The reactions are conducted under convenient conditions and provide products with excellent regioselectivity in good to excellent yields, with broad substrate scope. This protocol is an alternative to conventional α-halogenation of ketones.
- Zou, Huaxu,Jiang, Jun,Yi, Niannian,Fu, Wenqiang,Deng, Wei,Xiang, Jiannan
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supporting information
p. 1251 - 1254
(2016/12/27)
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- Metal-free hydration of aromatic haloalkynes to α-halomethyl ketones
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A highly regioselective and efficient metal-free hydration of aromatic haloalkynes to α-halomethyl ketones using cheap tetrafluoroboric acid as catalyst is described. The protocol is conducted under convenient conditions and affords products in good to excellent yields, with broad substrate scope, including a variety of aromatic alkynyl chlorides, alkynyl bromides, and alkynyl iodides.
- Ye, Min,Wen, Yuelu,Li, Huifang,Fu, Yejuan,Wang, Qinghao
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supporting information
p. 4983 - 4986
(2016/10/21)
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- 1,3-Dibromo-5,5-dimethylhydantoin (DBH) mediated one-pot syntheses of α-bromo/amino ketones from alkenes in water
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α-Bromo ketones are versatile intermediates of high practical utility. Traditional approaches to these compounds are restricted to a relatively hazardous/complex reagent combination, a long reaction time, the use of non-environmentally friendly solvents, or a limited substrate scope. Herein, we describe the development of a new methodology for the preparation of α-bromo ketones from alkenes using 1,3-dibromo-5,5-dimethylhydantoin (DBH) as a bromine source and an oxidant simultaneously. This easy to carry out two-step one-pot protocol proceeds in water and provides high yield of a great variety of α-bromo ketones. Addition of an amine to the intermediate α-bromo ketone further enables the preparation of α-amino ketones in a one-pot sequence.
- Xu, Senhan,Wu, Ping,Zhang, Wei
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p. 11389 - 11395
(2016/12/18)
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- Facile Suzuki-Miyaura coupling of activated aryl halides using new CpNiBr(NHC) complexes
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Nine new Ni(II)-NHC complexes, [CpNiBr(NHC)], were synthesised from nickelocene and the corresponding symmetric or asymmetric alkyl/-benzyl/phenylethyl imidazolium bromide ligands in relatively high yield. Access to each of the synthesised symmetric or asymmetric alkyl/benzyl/phenylethyl imidazolium bromide salts was obtained through deprotonation of imidazole, followed by treatment with an alkyl- or aryl halide, which is subsequently followed with reaction of a secondary alkyl-, benzyl-, or phenylethyl halide. The series of [CpNiBr(NHC)] exhibited catalytic activity in the Suzuki-Miyaura coupling of activated aryl halides with phenylboronic acid to give the respective biphenyl and biphenyl-containing products. In general, the more electron-donating NHC-bearing Ni complexes showed higher activity with aryl halides bearing electron-withdrawing functionalities including carboxaldehyde moieties. All complexes were characterised by 1H and 13C NMR spectroscopy, FT-IR spectroscopy, CHN and MS analyses, along with six selected single crystal X-ray structures that are reported here.
- Malan, Frederick P.,Singleton, Eric,Van Rooyen, Petrus H.,Landman, Marilé
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- Development of new highly potent imidazo[1,2-b[pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1
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Using a structure-based design approach, we have developed a new series of imidazo[1,2-b]pyridazines, targeting the calcium-dependent protein kinase-1 (CDPK1) from Toxoplasma gondii. Twenty derivatives were thus synthesized. Structure-activity relationships and docking studies confirmed the binding mode of these inhibitors within the ATP binding pocket of TgCDPK1. Two lead compounds (16a and 16f) were then identified, which were able to block TgCDPK1 enzymatic activity at low nanomolar concentrations, with a good selectivity profile against a panel of mammalian kinases. The potential of these inhibitors was confirmed in vitro on T. gondii growth, with EC50 values of 100 nM and 70 nM, respectively. These best candidates also displayed low toxicity to mammalian cells and were selected for further in vivo investigations on murine model of acute toxoplasmosis.
- Moine, Espérance,Dimier-Poisson, Isabelle,Enguehard-Gueiffier, Cécile,Logé, Cédric,Pénichon, Mélanie,Moiré, Nathalie,Delehouzé, Claire,Foll-Josselin, Beátrice,Ruchaud, Sandrine,Bach, Stéphane,Gueiffier, Alain,Debierre-Grockiego, Fran?oise,Denevault-Sabourin, Caroline
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- Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
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Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl) ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4- phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death. Stop the cycle! The attachment of an aryl ring to the iminic carbon produced thiazolidinones that are conformationally more restricted than first-generation thiazolidinones. This enhanced the potency of antiparasitic thiazolidinones, as observed under treatment with compound 4 h where parasite development and invasion in host cells were substantially reduced. Copyright
- Moreira, Diogo Rodrigo Magalhaes,Lima Leite, Ana Cristina,Cardoso, Marcos Verissimo Oliveira,Srivastava, Rajendra Mohan,Hernandes, Marcelo Zaldini,Rabello, Marcelo Montenegro,Da Cruz, Luana Faria,Ferreira, Rafaela Salgado,De Simone, Carlos Alberto,Meira, Cassio Santana,Guimaraes, Elisalva Teixeira,Da Silva, Aline Caroline,Dos Santos, Thiago Andre Ramos,Pereira, Valeria Rego Alves,Pereira Soares, Milena Botelho
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supporting information
p. 177 - 188
(2014/01/17)
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- Design and synthesis of 3-trifluoromethyl-3h-pyrazoles and further investigations of their transformation to 1h-pyrazoles
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An efficient intramolecular cycloaddition strategy for the synthesis of trifluoromethyl-substituted 3H-pyrazoles was developed. Subsequently, their wide applications were demonstrated: they (1) react with dioxane by a radical process and (2) undergo [1,5] sigmatropic rearrangements. These applications are useful as the products were obtained in high yields and with excellent regioselectivity.
- Sha, Qiang,Liu, Haixuan,Wei, Yunyang
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supporting information
p. 7707 - 7715
(2015/04/22)
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- AgF/TFA-promoted highly efficient synthesis of α-haloketones from haloalkynes
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A AgF/TFA-promoted highly efficient synthesis of a wide range of α-haloketones from haloalkynes is described. The reactions are conducted under convenient conditions and provide products in moderate to excellent yields, with broad substrate scope, including a variety of aromatic chloroalkynes and bromoalkynes.
- Chen, Zheng-Wang,Ye, Dong-Nai,Ye, Min,Zhou, Zhong-Gao,Li, Shen-Huan,Liu, Liang-Xian
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supporting information
p. 1373 - 1375
(2014/03/21)
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- Synthesis and evaluation of non-dimeric HCV NS5A inhibitors
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Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).
- Amblard, Franck,Zhang, Hongwang,Zhou, Longhu,Shi, Junxing,Bobeck, Drew R.,Nettles, James H.,Chavre, Satish,McBrayer, Tamara R.,Tharnish, Philip,Whitaker, Tony,Coats, Steven J.,Schinazi, Raymond F.
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p. 2031 - 2034
(2013/05/09)
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- Target-oriented synthesis: Miscellaneous synthetic routes to access 1,4-enediones through the coupling of 1,3-dicarbonyl compounds with multiform substrates
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Target-oriented synthetic protocol was presented for the synthesis of 1,4-enediones. The approach can efficiently construct 1,4-enediones through different reaction pathways from multiform substrates α-halo aromatic ketones, 2-hydroxy-aromatic ketones and methyl carbinols. In this reaction, CuI was found to be the most efficient catalyst. Multiform substrates were also found to perform well to afford the products in a one-pot fashion.
- Zhu, Yan-Ping,Cai, Qun,Gao, Qing-He,Jia, Feng-Cheng,Liu, Mei-Cai,Gao, Meng,Wu, An-Xin
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supporting information
p. 6392 - 6398
(2013/07/25)
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- Palladium-catalyzed asymmetric hydrogenation of α-acyloxy-1- arylethanones
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First hand: The first example of a palladium-catalyzed asymmetric hydrogenation of α-acyloxy ketones (1) was accomplished to give the hydrogenated products 2 with by far the highest catalytic efficiency in up to quantitative conversions and excellent enantioselectivities. The hydrogenated products could serve as important intermediates for the preparation of many drug candidates. TFE=2,2,2-trifluoroethanol. Copyright
- Chen, Jianzhong,Liu, Delong,Butt, Nicholas,Li, Chao,Fan, Dongyang,Liu, Yangang,Zhang, Wanbin
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supporting information
p. 11632 - 11636
(2013/11/06)
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- Design, synthesis and docking-based 3D-QSAR study of novel 2-substituted 2-aminopropane-1,3-diols as potent and selective agonists of sphingosine-1-phosphate 1 (S1P1) receptor
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Spingosine-1-phosphate receptor 1 (S1P1) has been actively pursued as an important therapeutic target in immune regulation. A series of 2-substituted 2-aminopropane-1,3-diols were designed and synthesized as selective S1P1 agonists. Most of the compounds with a biphenyl ether scaffold showed moderate to excellent S1P1/S1P3 selectivity. Compound 40c is identified as a potent S1P1 agonist with 350-fold S1P1/S1P3 selectivity. 39c, the alcohol form of 40c exerted good lymphopenia activity in vivo but with weak influence on heart rate. To investigate the SARs of 2-substituted 2-aminopropane-1,3-diols in more details, COMFA (q2 = 0.547, r2 = 0.986) and COMSIA (q 2 = 0.544, r2 = 0.943) models were established based on molecular docking alignment, which were validated with high reliability in predicting activities of agonists. The 3D-QSAR models will be helpful in the design of novel, potent and selective S1P1 agonists. The Royal Society of Chemistry.
- Tian, Yulin,Jin, Jing,Wang, Xiaojian,Han, Weijuan,Li, Gang,Zhou, Wanqi,Xiao, Qiong,Qi, Jianguo,Chen, Xiaoguang,Yin, Dali
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supporting information
p. 1267 - 1274
(2013/09/12)
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- Small molecule suppression of carbapenem resistance in ndm-1 producing klebsiella pneumoniae
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The already considerable global public health threat of multidrug-resistant Gram-negative bacteria has become even more of a concern following the emergence of New Delhi metallo-β-lactamase (NDM-1) producing strains of Klebsiella pneumoniae and other Gram-negative bacteria. As an alternative approach to the traditional development of new bactericidal entities, we have identified a 2-aminoimidazole-derived small molecule that acts as an antibiotic adjuvant and is able to suppress resistance of a NDM-1 producing strain of K. pneumoniae to imipenem and meropenem, in addition to suppressing resistance of other β-lactam nonsusceptible K. pneumoniae strains. The small molecule is able to lower carbapenem minimum inhibitory concentrations by up to 16-fold, while exhibiting little bactericidal activity itself.
- Worthington, Roberta J.,Bunders, Cynthia A.,Reed, Catherine S.,Melander, Christian
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supporting information; experimental part
p. 357 - 361
(2012/07/01)
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- Triplet phenacylimidazoliums-catalyzed photocycloaddition of 1,4-dihydropyridines: An experimental and theoretical study
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The photocycloadditions of 1,4-dihydropyridines (DHPs) were achieved by using phenacylimidazoliums (PIms) as photosensitizers. Irradiation of DHPs 3a-g in the presence of PIms 1a-e and 2 performed an efficient formation of 3,9-diazatetraasteranes in shorter times under a lower power lamp. The mechanism of photocycloaddition catalyzed by PIm was studied by laser flash photolysis and theoretical DFT computation. These time-resolved results showed that the triplet excited states of PIms were generated with high efficiency and detected by their characteristic ultraviolet absorptions, which were quenched by DHP at almost diffusion controlled rate. Theoretical studies suggest that PIm is involved in the photocycloaddition process through the 3(DHP? PIm)* triplet complexes and assists the stabilization of intermediates. All subsequent steps are predicted to be favorable and exothermic, leading to the cage dimers.
- Zhu, Xiaohe,Li, Weipeng,Yan, Hong,Zhong, Rugang
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experimental part
p. 13 - 20
(2012/08/13)
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- Facile one-pot procedure for the synthesis of 2-aminothiazole derivatives
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A facile, efficient synthesis of 2-aminothiazole derivatives by the reaction of easily available aromatic methyl ketones with thiourea/N-substituted thioureas in the presence of copper(II) bromide was developed. The reaction underwent a one-pot ?-bromination/cyclization process.
- Yin, Guodong,Ma, Junrui,Shi, Houqiang,Tao, Qing
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experimental part
p. 1941 - 1948
(2012/09/07)
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- Synthesis of oxathiane and morpholine from acyclic precursors: A modified Mitsunobu reaction
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Synthesis of a set of isomeric 2,4,6-triarylmorpholines and 2,6-diaryloxathianes from the corresponding 1,5-diols has been described. The method provides an efficient route to six-membered heterocycles from acyclic diols and is found to be better than Mitsunobu procedure in yield and waste management. In a related study, the ring contraction of pyranone to two isomeric cyclopentenone derivatives through Nazarov reaction has been noticed.
- Paul, Nidhin,Kaladevi, Selvam,Beneto, Arockiam Jesin,Muthusubramanian, Shanmugam,Bhuvanesh, Nattamai
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scheme or table
p. 6892 - 6901
(2012/09/11)
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- N-Halosuccinimide/SiCl4 as general, mild and efficient systems for the α-monohalogenation of carbonyl compounds and for benzylic halogenation
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Combinations of N-halosuccinimide and tetrachlorosilane in acetonitrile were found to be efficient systems for the selective α-monohalogenation of carbonyl compounds as well as for benzylic halogenation under mild conditions.
- Salama, Tarek A.,Novák, Zoltán
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experimental part
p. 4026 - 4029
(2011/08/09)
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- Direct synthesis of α-bromoketones from alkylarenes by aerobic visible light photooxidation
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The direct synthesis of α-bromoketones from alkylarenes by aerobic photooxidation with hydrobromic acid is reported. The key success for this direct oxidative reaction is due to control of bromination with acetic acid and ethanol, which are generated in situ by solvolysis of ethyl acetate in the course of the reaction.
- Tada, Norihiro,Ban, Kazunori,Hirashima, Shin-Ichi,Miura, Tsuyoshi,Itoh, Akichika
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supporting information; experimental part
p. 4701 - 4704
(2010/11/17)
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- Synthesis, structure, and biological activity of novel 1H-1,2,4-triazol-1- yl-thiazole derivatives
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2-Amino-4-aryl-5-(1H-1,2,4-triazol-1-yl)thiazole derivatives were synthesized from the reaction of α-bromo substituted acetophenone and thiourea. The structures were confirmed by elemental analysis, 1H NMR and single crystal X-ray diffraction analysis. Biological evaluation showed that some of them possess antifungal and plant growth regulatory activities. Copyright Taylor & Francis Group, LLC.
- Ling, Shao,Xin, Zhou,Qing, Zhang,Jian-Bing, Liu,Zhong, Jin,Jian-Xin, Fang
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p. 199 - 207
(2007/10/03)
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- Butyl 2-(4-[1.1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate, a potent sodium channel blocker for the treatment of neuropathic pain
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A series of 4-arylimidazole carbamates was synthesized and their binding affinities to the site-2 sodium (Na+) channel were determined. SAR studies led to the identification of compound 10, a potent Na+ channel blocker which was efficacious in pain models in vivo.
- Liberatore, Anne-Marie,Schulz, Jocelyne,Favre-Guilmard, Christine,Pommier, Jacques,Lannoy, Jacques,Pawlowski, Emilia,Barthelemy, Marie-Anne,Huchet, Marion,Auguet, Michel,Chabrier, Pierre-Etienne,Bigg, Dennis
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p. 1746 - 1749
(2008/02/07)
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- Design and synthesis of novel hydantoin-containing melanin-concentrating hormone receptor antagonists
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We report here new chemical series acting as antagonists of melanin-concentrating hormone receptor 1 (MCHR-1). Synthesis and structure-activity relationships are described leading to the identification of compounds with optimized in vitro pharmacological and in vitro ADME profiles. In vivo activity has been demonstrated in animal models of food intake and depression.
- Balavoine, Fabrice,Malabre, Patrice,Alleaume, Thierry,Rey, Astrid,Cherfils, Valerie,Jeanneton, Olivier,Seigneurin-Venin, Sophie,Revah, Frederic
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p. 3754 - 3759
(2008/02/10)
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