- Design, Synthesis, and Study of the Insecticidal Activity of Novel Steroidal 1,3,4-Oxadiazoles
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A series of novel steroidal derivatives with a substituted 1,3,4-oxadiazole structure was designed and synthesized, and the target compounds were evaluated for their insecticidal activity against five aphid species. Most of the tested compounds exhibited potent insecticidal activity against Eriosoma lanigerum (Hausmann), Myzus persicae, and Aphis citricola. Compounds 20g and 24g displayed the highest activity against E. lanigerum, showing LC50 values of 27.6 and 30.4 μg/mL, respectively. Ultrastructural changes in the midgut cells of E. lanigerum were detected by transmission electron microscopy, indicating that these steroidal oxazole derivatives might exert their insecticidal activity by destroying the mitochondria and nuclear membranes in insect midgut cells. Furthermore, a field trial showed that compound 20g exhibited effects similar to those of the positive controls chlorpyrifos and thiamethoxam against E. lanigerum, reaching a control rate of 89.5% at a dose of 200 μg/mL after 21 days. We also investigated the hydrolysis and metabolism of the target compounds in E. lanigerum by assaying the activities of three insecticide-detoxifying enzymes. Compound 20g at 50 μg/mL exhibited inhibitory action on carboxylesterase similar to the known inhibitor triphenyl phosphate. The above results demonstrate the potential of these steroidal oxazole derivatives to be developed as novel pesticides.
- Bai, Hangyu,Jiang, Weiqi,Li, Qi,Li, Tian,Ma, Shichuang,Shi, Baojun,Wu, Wenjun
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p. 11572 - 11581
(2021/10/12)
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- Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof
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The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain and preparation and application thereof The pleuromutilin derivative with the 1, 3, 4-oxadiazole side chain is a compound shown in a formula 2 or a pharmaceutically acceptable salt thereof, and a solvent compound, an enantiomer, a diastereoisomer and a tautomer of the compound shown in the formula 2 or the pharmaceutically acceptable salt thereof or a mixture of the solvent compound, the enantiomer, the diastereoisomer and the tautomer in any proportion, including a racemic mixture. The pleuromutilin derivative has good antibacterial activity, is especially suitable for being used as a novel antibacterial agent for systemic system infection of animals or human beings, and has good water solubility.
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Paragraph 0055-0056; 0070; 0090; 0092; 0095; 0103
(2021/07/24)
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- Oxazole ring-containing honokiol thioether derivative and preparation method and application thereof
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The invention discloses an oxazole ring-containing honokiol thioether derivative, a preparation method thereof and application of the oxazole ring-containing honokiol thioether derivative as an alpha-glucosidase inhibitor, the chemical structure of the oxazole ring-containing honokiol thioether derivative is shown as a general formula (I), and R is selected from non-substituted or substituted phenyl. Compared with the prior art, the invention provides the novel honokiol thioether derivative containing the oxazole ring, and the honokiol thioether derivative containing the oxazole ring has good inhibitory activity on alpha-glucosidase, provides more possibilities for treating diabetes, and is expected to be used for preparing novel candidate drug molecules for treating diabetes. In addition, the preparation process is simple, the cost is low, and the yield is high.
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Paragraph 0042-0044
(2021/08/11)
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- Development of Novel (+)-Nootkatone Thioethers Containing 1,3,4-Oxadiazole/Thiadiazole Moieties as Insecticide Candidates against Three Species of Insect Pests
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To improve the insecticidal activity of (+)-nootkatone, a series of 42 (+)-nootkatone thioethers containing 1,3,4-oxadiazole/thiadiazole moieties were prepared to evaluate their insecticidal activities against Mythimna separata Walker, Myzus persicae Sulzer, and Plutella xylostella Linnaeus. Insecticidal evaluation revealed that most of the title derivatives exhibited more potent insecticidal activities than the precursor (+)-nootkatone after the introduction of 1,3,4-oxadiazole/thiadiazole on (+)-nootkatone. Among all of the (+)-nootkatone derivatives, compound 8c (1 mg/mL) exhibited the best growth inhibitory (GI) activity against M. separata with a final corrected mortality rate (CMR) of 71.4%, which was 1.54- and 1.43-fold that of (+)-nootkatone and toosendanin, respectively; 8c also displayed the most potent aphicidal activity against M. persicae with an LD50 value of 0.030 μg/larvae, which was closer to that of the commercial insecticidal etoxazole (0.026 μg/larvae); and 8s showed the best larvicidal activity against P. xylostella with an LC50 value of 0.27 mg/mL, which was 3.37-fold that of toosendanin and slightly higher than that of etoxazole (0.28 mg/mL). Furthermore, the control efficacy of 8s against P. xylostella in the pot experiments under greenhouse conditions was better than that of etoxazole. Structure-activity relationships (SARs) revealed that in most cases, the introduction of 1,3,4-oxadiazole/thiadiazole containing halophenyl groups at the C-13 position of (+)-nootkatone could obtain more active derivatives against M. separata, M. persicae, and P. xylostella than those containing other groups. In addition, toxicity assays indicated that these (+)-nootkatone derivatives had good selectivity to insects over nontarget organisms (normal mammalian NRK-52E cells and C. idella and N. denticulata fries) with relatively low toxicity. Therefore, the above results indicate that these (+)-nootkatone derivatives could be further explored as new lead compounds for the development of potential eco-friendly pesticides.
- Cheng, Wanqing,Fan, Jiangping,Guo, Yong,Han, Meiyue,Ma, Nannan,Yan, Xiaoting,Yang, Ruige
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p. 15544 - 15553
(2022/01/03)
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- Design, synthesis, in vitro and in vivo evaluation against MRSA and molecular docking studies of novel pleuromutilin derivatives bearing 1, 3, 4-oxadiazole linker
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A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85–110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 μg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.
- Liu, Jie,Zhang, Guang-Yu,Zhang, Zhe,Li, Bo,Chai, Fei,Wang, Qi,Zhou, Zi-Dan,Xu, Ling-Ling,Wang, Shou-Kai,Jin, Zhen,Tang, You-Zhi
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- Synthesis and biological evaluation of honokiol derivatives bearing 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3h)-ones as potential viral entry inhibitors against sars-cov-2
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The 2019 coronavirus disease (COVID-19) caused by SARS-CoV-2 virus infection has posed a serious danger to global health and the economy. However, SARS-CoV-2 medications that are specific and effective are still being developed. Honokiol is a bioactive component from Magnoliae officinalis Cortex with damp-drying effect. To develop new potent antiviral molecules, a series of novel honokiol analogues were synthesized by introducing various 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3H)-ones to its molecule. In a SARS-CoV-2 pseudovirus model, all honokiol derivatives were examined for their antiviral entry activities. As a result, 6a and 6p demonstrated antiviral entry effect with IC50 values of 29.23 and 9.82 μM, respectively. However, the parental honokiol had a very weak antiviral activity with an IC50 value more than 50 μM. A biolayer interfero-metry (BLI) binding assay and molecular docking study revealed that 6p binds to human ACE2 protein with higher binding affinity and lower binding energy than the parental honokiol. A competitive ELISA assay confirmed the inhibitory effect of 6p on SARS-CoV-2 spike RBD’s binding with ACE2. Importantly, 6a and 6p (TC50 > 100 μM) also had higher biological safety for host cells than honokiol (TC50 of 48.23 μM). This research may contribute to the discovery of potential viral entrance inhibitors for the SARS-CoV-2 virus, although 6p’s antiviral efficacy needs to be validated on SARS-CoV-2 viral strains in a biosafety level 3 facility.
- Bai, Li-Ping,Guo, Yong,Jiang, Zhi-Hong,Liu, Jia-Zheng,Meng, Jie-Ru,Xu, Ting,Zheng, Zhi-Yuan
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- Oxidative Esterification of Aldehydes and Alcohols Catalyzed by Camphor-Based Imidazolium Salts
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Abstract: Sixteen new camphor-based imidazolium salts have been synthesized with renewable camphorsulfonic acid as the starting material. The chemical shifts of the characteristic proton of C2 on the imidazolium ring (N?C=N) were discussed thoroughly and all of these imidazolium salts exhibit good thermal stability. Furthermore, the excellent catalytic performance of the synthesized imidazolium salts were observed in the oxidative esterification between aromatic or aliphatic aldehydes containing electron-withdrawing or electron-donating groups on aromatic ring and primary or secondary alcohol by air as the sole oxidant. Graphic Abstract: [Figure not available: see fulltext.].
- Bian, Tiancen,Feng, Li,Li, Danfeng,Huang, Jiaxin,Zhao, Yuxun,Xu, Xu,Yang, Yiqin,Wang, Shifa
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p. 1812 - 1820
(2020/01/11)
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- Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates
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Epilepsy is a chronic neurological disorder affecting nearly 65–70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30–40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity. The synthesized 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivatives were primarily screened in the maximal electroshock-induced seizure (MES) test in mice. Next, the most promising compounds (17, 22) were investigated in 6 Hz (32 mA) psychomotor seizure model. Protective effect of compound 22 was almost similar to that of levetiracetam. Moreover, these compounds did not induce genotoxic and hemolytic changes in human cells as well as they were characterized by low cellular toxicity. Taking into account the structural requirements for good anticonvulsant activity of 4-alkyl-5-aryl-1,2,4-triazole-3-thiones, it is visible that small electron-withdrawing substituents attached to phenyl ring have beneficial effects both on affinity towards VGSCs and protective activity in the animal models of epilepsy.
- Kaproń, Barbara,?uszczki, Jarogniew J.,Siwek, Agata,Karcz, Tadeusz,Nowak, Gabriel,Zagaja, Miros?aw,Andres-Mach, Marta,Stasi?owicz, Anna,Cielecka-Piontek, Judyta,Kocki, Janusz,Plech, Tomasz
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- Synthesis and antimicrobial activity of new prenylated 2-pyrone derivatives
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A series of new monoprenylated and diprenylated 2-pyrone derivatives with different halogen substituents were synthesized from the corresponding 6-aryl-4-hydroxy-2-pyrones by prenylation reactions. The compounds were evaluated for antibacterial activity and displayed significant in vitro activity with the highest activity shown by the monoprenylated 6-aryl-2-pyrones. All the compounds except the bromine-containing analogs were active against one or more tested bacteria, with Escherichia coli being the most susceptible of the test organisms. With the remarkable antibacterial activity of eight of the compounds against a drug-resistant β-lactamase-producing Klebsiella pneumoniae, a synergistic evaluation between each of these compounds and ampicillin was undertaken. Out of the eight combinations studied, synergistic effects were observed with two compounds, 4-(3-methylbut-2-enoxy)-6-phenyl-2H-pyran-2-one and 6-(4-fluorophenyl)-4-(3-methylbut-2-enoxy)-2H-pyran-2-one. Both compounds, at half the individual MIC values, were able to lower the MIC of ampicillin in combinations from 2500 to 2.4 μg/mL (1/1041 of MIC).
- Chukwujekwu, Jude C.,Obi, Grace,van Heerden, Fanie R.
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- Design, synthesis and biological evaluation of N-hydroxy-aminobenzyloxyarylamide analogues as novel selective κ opioid receptor antagonists
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Aminobenzyloxyarylamide derivatives 1a-i and 2a-t were designed and synthesized as novel selective κ opioid receptor (KOR) antagonists. The benzoyl amide moiety of LY2456302 was changed into N-hydroxybenzamide and benzisoxazole-3(2H)-one to investigate whether it could increase the binding affinity or selectivity for KOR. All target compounds were evaluated in radioligand binding assays for opioid receptor binding affinity. These efforts led to the identification of compound 1c (κ Ki = 179.9 nM), which exhibited high affinity for KOR. Moreover, the selectivity of KOR over MOR and DOR increased nearly 2-fold and 7-fold, respectively, compared with (±)LY2456302.
- He, Guangchao,Peng, Kewen,Song, Qiao,Wang, Junwei,Xu, Anhua,Xu, Yungen,Zhu, Qihua
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- 4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-β-lactamase inhibitors
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Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the μM to sub-μM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the potentiation activity of the compounds was limited by poor outer membrane penetration or efflux. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several β-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.
- Baud, Damien,Bebrone, Carine,Becker, Katja,Benvenuti, Manuela,Cerboni, Giulia,Chelini, Giulia,Cutolo, Giuliano,De Luca, Filomena,Docquier, Jean-Denis,Feller, Georges,Fischer, Marina,Galleni, Moreno,Gavara, Laurent,Gresh, Nohad,Kwapien, Karolina,Legru, Alice,Mangani, Stefano,Mercuri, Paola,Pozzi, Cecilia,Sannio, Filomena,Sevaille, Laurent,Tanfoni, Silvia,Verdirosa, Federica,Berthomieu, Dorothée,Bestgen, Beno?t,Frère, Jean-Marie,Hernandez, Jean-Fran?ois
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supporting information
(2020/09/16)
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- Camphoryl imidazole type ionic liquid and preparation method and application thereof
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The invention discloses a camphoryl imidazole type ionic liquid and a preparation method and application thereof. According to the preparation method, a derivative camphorsulfonic acid of a natural renewable resource camphor is taken as a raw material to prepare 10-iodocamphor; then the 10-iodocamphor and aryl imidazole are subjected to a quaterisation reaction to prepare camphoryl imidazole iodide; then the camphoryl imidazole iodide and sodium hexafluorophosphate, sodium tetrafluoroborate, bis(trifluorosulfonimide)lithium and the like are subjected to ion exchange to prepare camphoryl imidazole hexafluorophosphate, camphoryl imidazole tetrafluoroborate, camphoryl imidazole bis(trifluorosulfonimide)salt and other ionic liquids. The camphoryl imidazole type ionic liquid shows good catalytic activity for an oxidation esterification reaction of aldehyde-alcohol, has the advantages of short reaction time, good reaction selectivity and high product yield, and has a good application prospect.
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Paragraph 0060; 0069
(2019/10/05)
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- Synthesis of novel indole derivatives containing double 1,3,4-oxadiazole moiety as efficient bactericides against phytopathogenic bacterium Xanthomonas oryzae
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Abstract: A series of novel indole derivatives containing double 1,3,4-oxadiazole moiety was designed, synthesized and evaluated for their antibacterial activities in vitro. These compounds were fully characterized by 1H NMR, 13C NMR, and HRMS. Bioassay results indicated that most of title compounds exhibited excellent antibacterial activities against rice bacterial pathogen Xanthomonas oryzae (Xoo). For example, compounds 7d, 7h, 7i, 7j, 7k, 7l and 7m had the half-maximal effective concentration (EC50) values of 52.31, 54.12, 40.65, 38.80, 51.13, 52.75 and 50.66?μg/mL, respectively, which was better than that of commercial product bismerthiazol (BMT) (85.18?μg/mL). The experimental results proved that indole derivatives bearing double 1,3,4-oxadiazole unit are promising candidates for the development of new agricultural bactericides against pathogenic bacterium Xoo. Graphical abstract: [Figure not available: see fulltext.].
- Tian, Kun,Li, Xiao-Qin,Zhang, Li,Gan, Yi-Yuan,Meng, Jiao,Wu, Shou-Qun,Wan, Jin-Lin,Xu, Yang,Cai, Chao-Ting,Ouyang, Gui-Ping,Wang, Zhen-Chao
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- Design and synthesis of new norfloxacin-1,3,4-oxadiazole hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)
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Toward the search of new antibacterial agents to control methicillin-resistant Staphylococcus aureus (MRSA), a class of new norfloxacin-1,3,4-oxadiazole hybrids were designed and synthesized. Antibacterial activities against drug-sensitive bacteria S. aureus and clinical drug resistant isolates of MRSA were evaluated. Compound 5k exhibited excellent antibacterial activities against S. aureus (MIC: 2 μg/mL) and MRSA1–3 (MIC: 0.25–1 μg/mL). The time-kill kinetics demonstrated that compound 5k had an advantage over commonly used antibiotics vancomycin in killing S. aureus and MRSA. Moreover, compound 5k could inhibit the bacteria and destroy their membranes in a short time, and showed very low cytotoxicity to NRK-52E cells. Some interesting structure-activity relationships (SARs) were also discussed. These results indicated that these norfloxacin-1,3,4-oxadiazole hybrids could be further developed into new antibacterial agents against MRSA.
- Guo, Yong,Xu, Ting,Bao, Chongnan,Liu, Zhiyan,Fan, Jiangping,Yang, Ruige,Qin, Shangshang
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- Hypervalent Iodine(III)-Catalyzed Balz–Schiemann Fluorination under Mild Conditions
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An unprecedented hypervalent iodine(III) catalyzed Balz–Schiemann reaction is described. In the presence of a hypervalent iodine compound, the fluorination reaction proceeds under mild conditions (25–60 °C), and features a wide substrate scope and good functional-group compatibility.
- Xing, Bo,Ni, Chuanfa,Hu, Jinbo
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p. 9896 - 9900
(2018/07/31)
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- Facile, highly efficient and environmentally friendly transesterification mediated by platinum dioxide and nickel oxide under essentially neutral conditions
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A practical, facile and highly efficient transesterification reaction under essentially neutral conditions was achieved using platinum dioxide (PtO2) or PtO2/nickel oxide (NiO) as the catalyst. A number of esters and alcohols that contain various functional groups were employed. Good to excellent yields were obtained for different aromatic or aliphatic starting materials. The Pt-alcohol intermediate generated in situ facilitated the exchange of low-alcohol esters to high-alcohol esters.
- Teng, Binhao,Shi, Jiangong,Yao, Chunsuo
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supporting information
p. 2465 - 2471
(2018/06/11)
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- Application of trivalent iodine compounds as catalysts in Bal-Schiemann reaction
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The invention discloses an application of trivalent iodine compounds shown in formula I and/or II in the description and used as catalysts in Bal-Schiemann reaction. The trivalent iodine compounds areused as the catalysts in the Bal-Schiemann reaction, so that the Bal-Schiemann reaction can be conducted at room temperature or near room temperature when a thermochemical method is used, and the reaction has mild reaction conditions, wide substrate use range and short reaction time, and is safe and easy to operate, products are easy to separate, and raw materials are simple and low in toxicity.
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Paragraph 0153; 0158
(2018/10/19)
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- METHOD FOR AROMATIC FLUORINATION
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Disclosed is a fluorination method comprising providing an aryl fluorosuifonate and a fluorinating reagent to a reaction mixture; and reacting the aryl fluorosuifonate and the fluorinating reagent to provide a fluorinated aryl species. Also disclosed is a fluorination method comprising providing, a salt comprising a cation and an aryloxyiate, and SO2F2 to a reaction mixture; reacting the SO2F2 and the ammonium salt to provide a fluorinated aryl species. Further disclosed a fluorination method comprising providing a compound having the structure Ar-OH to a reaction mixture; where A is an aryl or heteroaryl; providing SO2F2 to the reaction mixture; providing a fluorinating reagent to the reaction mixture; reacting the SO2F2, the fluorinating reagent and the compound having the structure Ar-OH to provide a fluorinated aryl species having the structure Ar-F.
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Paragraph 0047-0049
(2017/12/18)
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- Nucleophilic deoxyfluorination of phenols via aryl fluorosulfonate intermediates
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This report describes a method for the deoxyfluorination of phenols with sulfuryl fluoride (SO2F2) and tetramethylammonium fluoride (NMe4F) via aryl fluorosulfonate (ArOFs) intermediates. We first demonstrate that the reaction of ArOFs with NMe4F proceeds under mild conditions (often at room temperature) to afford a broad range of electronically diverse and functional group-rich aryl fluoride products. This transformation was then translated to a one-pot conversion of phenols to aryl fluorides using the combination of SO2F2 and NMe4F. Ab initio calculations suggest that carbon-fluorine bond formation proceeds via a concerted transition state rather than a discrete Meisenheimer intermediate.
- Schimler, Sydonie D.,Cismesia, Megan A.,Hanley, Patrick S.,Froese, Robert D.J.,Jansma, Matthew J.,Bland, Douglas C.,Sanford, Melanie S.
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supporting information
p. 1452 - 1455
(2017/02/10)
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- Noncovalent Interactions in Ir-Catalyzed C-H Activation: L-Shaped Ligand for Para-Selective Borylation of Aromatic Esters
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An efficient strategy for the para-selective borylation of aromatic esters is described. For achieving high para-selectivity, a new catalytic system has been developed modifying the core structure of the bipyridine. It has been proposed that the L-shaped ligand is essential to recognize the functionality of the oxygen atom of the ester carbonyl group via noncovalent interaction, which provides an unprecedented controlling factor for para-selective C-H activation/borylation.
- Hoque, Md Emdadul,Bisht, Ranjana,Haldar, Chabush,Chattopadhyay, Buddhadeb
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supporting information
p. 7745 - 7748
(2017/06/21)
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- Graphene Oxide: An Efficient Acid Catalyst for the Construction of Esters from Acids and Alcohols
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Graphene oxide was found to be an efficient and reusable acid catalyst for the esterification reaction. A wide range of aliphatic and aromatic acids and alcohols were compatible with the standard conditions and afforded the corresponding products in good yields. The heterogeneous catalyst can be easily recovered and recycled in dichloro-ethane solvent with good catalytic activity.
- Chen, Zhengwang,Wen, Yuelu,Fu, Yejuan,Chen, Hai,Ye, Min,Luo, Guotian
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supporting information
p. 981 - 985
(2017/05/05)
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- Design, synthesis and biological evaluation of aminobenzyloxyarylamide derivatives as selective κ opioid receptor antagonists
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Opioid receptors play an important role in both behavioral and mood functions. Based on the structural modification of LY2456302, a series of aminobenzyloxyarylamide derivatives were designed and synthesized as κ opioid receptor antagonists. The κ opioid receptor binding ability of these compounds were evaluated with opioid receptors binding assays. Compounds 1a-d showed high affinity for κ opioid receptor. Especially for compound 1c, exhibited a significant Kivalue of 15.7?nM for κ opioid receptor binding and a higher selectivity over μ and δ opioid receptors compared to (±)LY2456302. In addition, compound 1c also showed potent κ antagonist activity with κ IC50?=?9.32?nM in [35S]GTP-γ-S functional assay. The potential use of the representative compounds as antidepressants was also investigated. The most potent compound 1c not only exhibited potent antidepressant activity in the mice forced swimming test, but also displayed the effect of anti-anxiety in the elevated plus-maze test.
- Wang, Junwei,Song, Qiao,Xu, Anhua,Bao, Yu,Xu, Yungen,Zhu, Qihua
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- 1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases
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Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole–thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.
- Sevaille, Laurent,Gavara, Laurent,Bebrone, Carine,De Luca, Filomena,Nauton, Lionel,Achard, Maud,Mercuri, Paola,Tanfoni, Silvia,Borgianni, Luisa,Guyon, Carole,Lonjon, Pauline,Turan-Zitouni, Gülhan,Dzieciolowski, Julia,Becker, Katja,Bénard, Lionel,Condon, Ciaran,Maillard, Ludovic,Martinez, Jean,Frère, Jean-Marie,Dideberg, Otto,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
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p. 972 - 985
(2017/06/27)
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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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- Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of PKA and a PKB Mimic
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Protein kinases continue to be hot targets in drug discovery research, as they are involved in many essential cellular processes and their deregulation can lead to a variety of diseases. A series of 32 enantiomerically pure inhibitors was synthesized and tested towards protein kinase A (PKA) and protein kinase B mimic PKAB3 (PKA triple mutant). The ligands bind to the hinge region, ribose pocket, and glycine-rich loop at the ATP site. Biological assays showed high potency against PKA, with Ki values in the low nanomolar range. The investigation demonstrates the significance of targeting the often neglected glycine-rich loop for gaining high binding potency. X-ray co-crystal structures revealed a multi-facetted network of ligand-loop interactions for the tightest binders, involving orthogonal dipolar contacts, sulfur and other dispersive contacts, amide-π stacking, and H-bonding to organofluorine, besides efficient water replacement. The network was analyzed in a computational approach.
- Lauber, Birgit S.,Hardegger, Leo A.,Asraful, Alam K.,Lund, Bjarte A.,Dumele, Oliver,Harder, Michael,Kuhn, Bernd,Engh, Richard A.,Diederich, Fran?ois
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supporting information
p. 211 - 221
(2016/01/25)
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- Palladium-Catalyzed Carbonylations of Arylboronic Acids: Synthesis of Arylcarboxylic Acid Ethyl Esters
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An approach for the palladium-catalyzed ethoxycarbonylations of arylboronic acids using diethyl pyrocarbonate as carbon monoxide/carbon dioxide (CO/CO2) surrogate in moderate to good yields has been investigated.
- Liang, Apeng,Han, Shuaijun,Wang, Liang,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
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supporting information
p. 3104 - 3108
(2015/11/03)
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- Synthesis and Biological Activity of Some Novel Aryl-Substituted 1,3,4-Oxadiazole Mannich Bases Containing Pyrimidine Rings
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A series of novel Mannich base derivatives (E1-E15) of 5-aryl-1,3,4-oxadiazole-2-thione with substituted pyrimidine were synthesized and characterized by elemental analysis, IR, 1H-NMR. The antifungal activities of these compounds were also originally studied. The results showed that most of the title compounds exhibited relatively good fungicidal activities. Especially compounds E8 and E13 showed better antifungal activity than comparison compound hymexazol. The relationship of structure and activity revealed that the presence of the methyl group at four and six positions of pyrimidine ring remarkably enhanced the antifungal activity of title compounds.
- Shen, Shengqiang,Sun, Xiaohong,Liu, Yuanfa,Chen, Bang,Jin, Ruyi,Ma, Haixia
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p. 1296 - 1301
(2015/10/06)
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- Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors
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A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔGbind -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔGbind -9.04 and -8.51 kcal/mol, respectively, for BChE.
- Mehr-Un-Nisa,Munawar, Munawar A.,Chattha, Fauzia A.,Kousar, Samina,Munir, Jawaria,Ismail, Tayaba,Ashraf, Muhammad,Khan, Misbahul A.
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p. 6014 - 6024
(2015/11/11)
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- Studying regioisomer formation in the pd-catalyzed fluorination of aryl triflates by deuterium labeling
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Isotopic labeling has been used to determine that a portion of the desired product in the Pd-catalyzed fluorination of electron-rich, non-ortho-substituted aryl triflates results from direct C-F cross-coupling. In some cases, formation of a Pd-aryne intermediate is responsible for producing undesired regioisomers. The generation of the Pd-aryne intermediate occurs primarily via ortho-deprotonation of a L·Pd(Ar)OTf (L = biaryl monophosphine) species by CsF and thus competes directly with the transmetalation step of the catalytic cycle. Deuterium labeling studies were conducted with a variety of aryl triflates.
- Milner, Phillip J.,Kinzel, Tom,Zhang, Yong,Buchwald, Stephen L.
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supporting information
p. 15757 - 15766
(2015/02/02)
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- Cobalt carbonyl as an effective CO source in one-pot synthesis of esters from aryl halides
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For the first time, we have successfully applied Co2(CO) 8 as an effective carbonyl source for the Pd catalysed alkoxycarbonylation of aryl halides affording the corresponding aryl esters under mild microwave conditions. A wide variety of esters and carbonyl derivatives were prepared using this protocol.
- Baburajan,Senthilkumaran,Elango, Kuppanagounder P.
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p. 3050 - 3056
(2013/10/01)
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- Copper-mediated fluorination of arylboronate esters. Identification of a Copper(III) fluoride complex
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A method for the direct conversion of arylboronate esters to aryl fluorides under mild conditions with readily available reagents is reported. Tandem reactions have also been developed for the fluorination of arenes and aryl bromides through arylboronate ester intermediates. Mechanistic studies suggest that this fluorination reaction occurs through facile oxidation of Cu(I) to Cu(III), followed by rate-limiting transmetalation of a bound arylboronate to Cu(III). Fast C-F reductive elimination is proposed to occur from an aryl-copper(III)-fluoride complex. Cu(III) intermediates have been generated independently and identified by NMR spectroscopy and ESI-MS.
- Fier, Patrick S.,Luo, Jingwei,Hartwig, John F.
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p. 2552 - 2559
(2013/03/29)
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- Chemical synthesis, in vitro acetohydroxyacid synthase (AHAS) inhibition, herbicidal activity, and computational studies of isatin derivatives
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Acetohydroxyacid synthase (AHAS) catalyzes the first common step in the biosynthesis of the branched-chain amino acids. As a result of its metabolic importance in plants, it is a target for many commercial herbicides. Virtual screening analysis inspired the evaluation of 19 commercially available isatin analogues and 13 newly synthesized isatin derivatives as novel AHAS inhibitors and for their herbicidal activity. The best compound demonstrated 95% inhibition of the activity of Arabidopsis thaliana AHAS at a concentration of 100 mg L-1, whereas the herbicidal activities of three compounds reached 50% inhibition at a concentration of 10 mg L-1 using the rape root growth test. CoMFA contour models were established to understand the structure-activity relationships for this class of AHAS inhibitor. The compounds were docked to the active site cavity of A. thaliana AHAS using FlexX, and the dominant binding mode was consistent with frontier molecular orbital from DFT calculations. This is the first comprehensive study of isatin derivatives as AHAS inhibitors and provides a valuable starting point for the design of new herbicides.
- Wang, Jianguo,Tan, Haizhong,Li, Yonghong,Ma, Yi,Li, Zhengming,Guddat, Luke W.
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experimental part
p. 9892 - 9900
(2012/01/06)
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- Synthesis of novel triazole derivatives of methyl 3-oxocholanate using microwave irradiation
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An efficient rapid method for the synthesis of new triazole derivatives derived from methyl 3-oxocholanate under microwave irradiation has been developed. These new compounds were characterised by 1H NMR, IR, ESI-MS spectra and elemental analyses. Some of these triazoles were tested for antibacterial activity against Staphylococcus aureus, Candida albicans and Escherichia coli.
- Yang, Jie,Cheng, YuYu,Shi, ZhiChuan,Zhao, ZhiGang
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experimental part
p. 680 - 683
(2011/04/26)
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- Homogeneous electron transfer catalysis of the electrochemical reduction of carbon dioxide. Do aromatic anion radicals react in an outer-sphere manner?
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Electrochemically generated anion radicals of aromatic nitriles and esters possess the remarkable property to reduce carbon dioxide to oxalate with negligible formation of carboxylated products. They may thus serve as selective homogeneous catalysts for the reduction of CO2 in an aprotic medium. The catalytic enhancement of the cyclic voltammetric peaks of these catalysts is used to determine the rate constant of the electron transfer from these aromatic anion radicals to CO2 as a function of the catalyst standard potential. Substituted benzoic esters allowed a particularly detailed investigation of the resulting activation-driving force relationship. Using 14 different catalysts in this series made it possible to finely scan a range of reaction standard free energies of 0.4 eV. Detailed analysis of the resulting data leads to the conclusion that the reaction is not a simple outer-sphere electron transfer. It rather consists in a nucleophilic addition of the anion radical on CO2, forming an oxygen (or nitrogen for the nitriles) - carbon bond, which successively breaks homolytically, generating the parent ester (or nitrile) and the anion radical of CO2, which eventually dimerizes to oxalate.
- Gennaro, Armando,Isse, Abdirisak A.,Savéant, Jean-Michel,Severin, Maria-Gabriella,Vianello, Elio
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p. 7190 - 7196
(2007/10/03)
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- Process for the preparation of alkyl fluorobenzoates in high purity and high yield
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Process for the preparation of alcohol fluorobenzoates of the formula (I) STR1 in which R is an alkyl radical and Fn is 1 to 4 fluorine atoms which, independently of one another, are bonded to the aromatic ring, by reacting a fluorobenzyl chloride of the formula (II) STR2 in which Fn is as defined above, with an at least stoichiometric amount of an alkali metal alcoholate ROM in which R is as defined above and M is an alkali metal from the group consisting of Li, Na and K, in the corresponding alcohol ROH at temperatures from -10° C. to 150° C., the solvent is distilled off, if appropriate, and the alkali metal chloride formed is separated off by treating the mixture with water or by filtration.
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