- Proton Chelating Ligands Drive Improved Chemical Separations for Rhodium
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Current methods for the extraction of rhodium carry the highest carbon footprint and worst pollution metrics of all of the elements used in modern technological applications. Improving upon existing methods is made difficult by the limited understanding of the molecular-level chemistry occurring in extraction processes, particularly in the hydrometallurgical separation step. While many of the precious metals can be separated by solvent extraction, there currently exist no commercial extractants for Rh. This is due to its complicated mixed speciation upon leaching into hydrochloric acid, which gives rise to difficulties in designing effective reagents for solvent extraction. Herein we show that the diamidoamine reagent N-n-hexylbis(N-methyl-N-n-octylethylamide)amine transports Rh(III) from aqueous HCl into an organic phase as the monoaquated dianion [RhCl5(H2O)]2- through the formation of an outer-sphere assembly; this assembly has been characterized by experimentation (slope analysis, FT-IR and NMR spectroscopy, EXAFS, SANS, and ESI-MS) and computational modeling. The paper demonstrates the importance of applying a broad range of techniques to obtain a convincing mode of action for the complex processes involved in anion recognition in the solution phase. A consistent and comprehensive understanding of how the ligand operates to achieve Rh(III) selectivity over the competitor anion Cl- has emerged. This knowledge will guide the design of extractants and thus offers promise for improving the sustainability of metal extraction from both traditional mining sources and the recycling of secondary source materials.
- Narita, Hirokazu,Nicolson, Rebecca M.,Motokawa, Ryuhei,Ito, Fumiyuki,Morisaku, Kazuko,Goto, Midori,Tanaka, Mikiya,Heller, William T.,Shiwaku, Hideaki,Yaita, Tsuyoshi,Gordon, Ross J.,Love, Jason B.,Tasker, Peter A.,Schofield, Emma R.,Antonio, Mark R.,Morrison, Carole A.
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- Photodegradation of metolachlor: Isolation, identification, and quantification of monochloroacetic acid
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The photolysis of metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2- methoxy-l-methylethyl) acetamide] in a sunlight simulator under actinic radiation was investigated. The focus of the study was to determine the extent of monochloroacetic acid (MCA) production. MCA was concentrated and derivatized from photolysate as the n-propyl ester using propanol and sulfuric acid and then identified as the ester using GC/MS and GC/ECD. On the basis of regression analysis, it was shown that the direct photodegradation of ~10 μM metolachlor followed pseudo-first-order kinetics with respect to the metolachlor concentration, and the half-life of the herbicide (~74 h) was independent of the pH of the medium. Photolysis in synthetic field water (SFW) resulted in a significant reduction of photolysis time (t 1/2 ~ 9 h). Direct photolysis experiments indicate a 5.19 ±0.81% (n=3) conversion of metolachlor to MCA, while photolysis in synthetic field water and in a Don River water sample resulted in 29.8 ± 4.6% (n = 3) and 12.6 ± 4.1% (n = 3) conversion, respectively; MCA was shown to be hydrolytically stable over the time course of the photoreaction. The photodegradation of alachlor, butachlor and a model chloroacetanilide, 2-chloro-N-methylacetanilide, in SFW were also investigated.
- Wilson, Ruth I.,Mabury, Scott A.
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- Intramolecular carbene C-H insertion reactions of 2-diazo-2-sulfamoylacetamides
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The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride and secondary amines through acylation followed by sequential treatments with sodium sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The results indicate that: (1) 2-diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide can take the formal aromatic 1,5-C-H insertion in its N-phenylsulfonamide moiety to afford the corresponding 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide derivative; (2) no aliphatic C-H insertions occur for 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides; and (3) for 2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides, the formal aromatic 1,5-C-H insertion in the N-phenylacetamide moiety is favorable to afford the corresponding 3-sulfamoylindolin-2-one derivatives as sole or major products. The intramolecular competitive aromatic 1,5-C-H insertion reactions of 2-diazo-2-sulfamoylacetamides with aryl groups on both amide and sulfonamide groups reveal that the N-aryl substituents on acetamide are more active than those on sulfonamide. The chemoselectivity is controlled by electronic effect of the aryl group.
- Que, Chuqiang,Huang, Peipei,Yang, Zhanhui,Chen, Ning,Xu, Jiaxi
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- Synthesis of asymmetrically substituted cyclen-based ligands for the controlled sensitisation of lanthanides
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A series of unsymmetrical cyclen-based ligands incorporating an antenna and a quencher have been prepared for the complexation of the visible- (Eu, Tb) and near IR-emitting (Nd, Yb) lanthanides. Eu and Tb were sensitised with coumarin 2, and Nd and Yb with rhodamine. Both antennae were paired with nucleoside (uridine and adenosine) quenchers. The interaction between the quencher and the antenna can be regulated by the addition of the complementary base or DNA to the complexes, resulting in changes in the lanthanide luminescence intensity and lifetime. The Royal Society of Chemistry.
- Borbas, K. Eszter,Bruce, James I.
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- Synthesizing method for chloroacetamide compound
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The invention discloses a synthesizing method for a chloroacetamide compound. In a reaction kettle, a secondary amine compound is dissolved in an organic solvent, the mixture is heated for reflux, chloroacetyl chloride is added into the mixture, a reflux reaction is conducted for 0.5-20 hours, and the chloroacetamide compound is obtained. According to the synthesizing method for the chloroacetamide compound, an acid binding agent is not used, discharging of wastewater in the after-treatment process is reduced, by keeping the reflux state of the system, hydrogen chloride gas generated from thereaction is exhausted out of the system and absorbed by water outside the system, high-purity hydrochloric acid is obtained, the waste is turned into wealth, the method comes up to the production standard of safety and environment protection, and discharging of waste gas, waste water and waste residues is reduced; according to the synthesizing method for the chloroacetamide compound, few operationsteps are utilized, the reaction speed is high, the product yield is high, the purity is high, the production cost is low, and the method is safe, friendly to the environment and suitable for industrial large-scale production.
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Paragraph 0043-0045
(2019/10/01)
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- Efficient synthesis, spectroscopic characterization and DFT based studies of novel 1-amide 4-sulfonamide-1,2,3-triazole derivatives
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In the present study, for the first time 1-amide 4-sulfonamide-1,2,3-triazole scaffolds were synthesized by using an azide-alkyne Huisgen cycloaddition reaction. The target products were obtained in moderate to good yields (45–75%) by using catalytic CuI and green system H2O/EtOH. The easy availability of the inexpensive starting materials, avoiding isolation and handling of hazardous organic azides and mild reaction conditions make this method a valuable tool for generating functionalized 1,2,3-triazole derivatives. The unambiguous characterization of synthesized compounds was accomplished by using various spectroscopic techniques such as 1H NMR, 13C NMR, and FT-IR. The information regarding optimized geometry, were obtained by applying DFT/B3LYP-6-31G(d) method. The electrophilicity index, 1H and 13C chemical shift values, lithium and sodium ion affinities of the desired product 3b have been also calculated by the mentioned method. As a whole, the calculated results were found in close agreement to that of experimental data. The studies revealed that the compound 3b possesses good Li+ and Na+ affinity and cation π interaction plays a vital role in the complexation of 3b. For the first time, nucleus–independent chemical shift index was used to confirm the cation π interaction of 3b.
- Bonyad, Sarvenaz Rouhi,Mirjafary, Zohreh,Saeidian, Hamid,Rouhani, Morteza
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p. 164 - 170
(2019/07/18)
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- Palladium-catalyzed olefination of aryl/alkyl halides with trimethylsilyldiazomethane via carbene migratory insertion
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The direct olefination of aryl/alkyl halides with trimethylsilyldiazomethane (TMSD) as a C1- or C2-unit was achieved successfully via a metal carbene migratory insertion process, which offered a new access to afford (E)-vinyl silanes and (E)-silyl-substituted α,β-unsaturated amides in good yields and high chemoselectivity.
- Mu, Qiu-Chao,Wang, Xing-Ben,Ye, Fei,Sun, Yu-Li,Bai, Xing-Feng,Chen, Jing,Xia, Chun-Gu,Xu, Li-Wen
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supporting information
p. 12994 - 12997
(2018/11/23)
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- Latent Bronsted Base Solvent-Assisted Amide Formation from Amines and Acid Chlorides
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Weakly basic amines, including even neutral amines such as nitroaniline and aminocarboxylic acids, react with acid chlorides very efficiently in N, N -dimethylacetamide (DMAC), without addition of a base, to give the corresponding amides in high yields. The role of DMAC and related solvents as latent Bronsted bases was studied in these amidation reactions. Less basic amines, such as aromatic amines, reacted with benzoyl chloride faster than more basic aliphatic amines.
- Otsuka, Rikuto,Maruhashi, Kazuo,Ohwada, Tomohiko
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supporting information
p. 2041 - 2057
(2018/05/04)
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- Synthesis and structure-activity relationships of LP1 derivatives: N-methyl-N-phenylethylamino analogues as novel MOR agonists
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The opioid pharmacological profile of cis-(-)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a-d and 6a-d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(-)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMOR of 6.1 nM in a competitive binding assay, and an IC50 value of 11.5 nM and an Imax of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50 of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(-)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.
- Turnaturi, Rita,Parenti, Carmela,Prezzavento, Orazio,Marrazzo, Agostino,Pallaki, Paschalina,Georgoussi, Zafiroula,Amata, Emanuele,Pasquinucci, Lorella
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- Anti-proliferative activity, molecular modeling studies and interaction with calf thymus DNA of novel ciprofloxacin analogues
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Abstract: In our pursuit to expand new potential anticancer leads, a series of eighteen novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substituted piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues have been synthesized, characterized and evaluated anti-proliferative activity against five human cancer cell lines such as A549 (lung cancer), Mia Paca (pancreatic cancer), HeLa (cervical cancer), MDA MB-231 (breast cancer), MCF-7 (breast cancer) and normal embryonic kidney?cell line (HEK) were carried out using MTT assay. Few of the synthesized analogues exhibited potent anticancer activity against the cancer cell lines at a lower concentration. The synthesized compounds showed the less toxic effect on normal human embryonic kidney?cell line (HEK) compared with doxorubicin. Noticeably, compound 3o exhibited potent activity against all five cancer cell lines compared with ciprofloxacin. Further study exposed that compound 3o could competently intercalate into calf thymus DNA to form 3o-DNA complex which might block DNA replication to apply anti-proliferative activity. Docking simulation studies supported by molecular interactions with DNA type II topoisomerase. These derivates can become lead structures for the development of potential anticancer drugs. Graphical Abstract: Eighteen CP analogues were synthesized and evaluated for anti-proliferative activity. The interactions with DNA topoisomerase II were supported by molecular docking studies. 3o showed promising anticancer activity than CP against MCF7 cell line and interaction with calf thymus DNA was studied by fluorescence spectroscopy.[Figure not available: see fulltext.].
- Suresh, Narva,Suresh, Amaroju,Yerramsetty, Suresh,Bhadra, Manika Pal,Alvala, Mallika,Sekhar, Kondapalli Venkata Gowri Chandra
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- Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
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Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
- Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
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supporting information
p. 8267 - 8276
(2017/06/27)
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- Method for preparing N-methyl-N-phenylacetamide acetate by one-pot method
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The invention discloses a method for preparing N-methyl-N-phenylacetamide acetate by a one-pot method. The method comprises the following steps of (1) under a solvent-free state, dripping N-methylaniline into chloroacetyl chloride, heating to react after dripping is finished, removing hydrogen chloride, and cooling, so as to obtain N-methyl-N-phenylacetamide; (2) under the solvent-free state, directly adding acetic acid and a catalyst into the N-methyl-N-phenylacetamide obtained in the previous step, heating to react, removing the hydrogen chloride, preserving heat until the reaction is finished, and filtering, so as to obtain the N-methyl-N-phenylacetamide acetate, wherein the catalyst is a mixed catalyst of organic alkaline and quaternary ammonium salt. The preparation method has the advantages that a solvent is not used, the water washing is not needed, the green and environment-friendly effects are realized, only one reaction kettle is needed, and the cost is low.
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Paragraph 0012; 0013; 0014; 0015; 0016
(2017/07/21)
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- Efficient syntheses of 1,2,3-triazoloamide derivatives using solid- and solution-phase synthetic approaches
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Efficient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide library was constructed by a parallel solution-phase synthetic route. The synthetic routes rely on amide formation with secondary amines and chloro-acid chlorides; SN2 reaction with sodium azide; and the selective [3 + 2] Hüisgen cycloaddition with appropriate terminal alkynes. The target secondary and tertiary 1,2,3-triazoloamide derivatives were obtained with three-diversity points in excellent overall yields and purities using the reported solid- and solution-phase synthetic routes, respectively.
- Lee, Doohyun,Kim, Daehun,Lee, Seungyeon,Kim, Taegeum,Kim, Joobin,Kim, Sohee,Liu, Kwang-Hyeon,Lee, Sangkyu,Bae, Jong-Sup,Song, Kyung-Sik,Cho, Chang-Woo,Son, Youn Kyung,Baek, Dong Jae,Lee, Taeho
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p. 19984 - 20013
(2015/12/23)
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- Access to newly functionalized imidazole derivatives: Efficient synthesis of novel 5-amino-2-thioimidazoles using propylphosphonic anhydride (T3P)
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We describe here an efficient method to synthesize 5-amino-2-thioimidazole compounds by T3P-mediated cyclization of N-acetamidoisothiourea intermediates. The newly functionalized 5-amino-2-thioimidazole compounds are finally obtained in 5 steps from an amine as starting block.
- Lasalle, Manuel,Picon, Sylvain,Boulahjar, Rajaa,Hoguet, Vanessa,Van Obbergen, Jolien,Roussel, Pascal,Deprez, Benoit,Charton, Julie
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supporting information
p. 1011 - 1014
(2015/02/19)
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- Higher-Affinity Agonists of 5-HT1AR Discovered through Tuning the Binding-Site Flexibility
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Discovery of high-affinity and high-selectivity agonists of 5-HT1AR has become very attractive due to their potential therapeutic effects on multiple 5-HT1AR-related psychological and neurological problems. On the basis of our previously designed lead compound FW01 (Ki = 51.9 nM, denoted as 9a in the present study), we performed large-scale molecular dynamics simulations and molecular docking operations on 5-HT1AR-9a binding. We found the flip-packing events for the headgroup of 9a, and we also found that its tail group could bind flexibly at the agonist-binding site of 5-HT1AR. By finely tuning the flip-packing phenomenon of the 9a headgroup and tuning the binding flexibility of 9a tail group, we virtually designed a series of new 9a derivatives through molecular docking operations and first-principles calculations and predicted that these newly designed 9a derivatives should be higher-affinity agonists of 5-HT1AR. The computational predictions on the new 9a derivatives have been confirmed by our wet-experimental studies as chemical synthesis, binding affinity assays, and agonistic-function assays. The consistency between our computational design and wet-experimental measurements has led to our discovery of higher-affinity agonists of 5-HT1AR, with ~50-fold increase in receptor-binding affinity and ~25-fold improvements in agonistic function. In addition, our newly designed 5-HT1AR agonists showed very high selectivity of 5-HT1AR over subtype 5-HT2AR and also over three subtypes of dopamine receptors (D1, D2, and D3). (Graph Presented).
- Lian, Peng,Li, Linlang,Geng, Chuanrong,Zhen, Xuechu,Fu, Wei
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p. 1616 - 1627
(2015/09/01)
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- Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents
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A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR and MS spectral data. Their inhibition against chitin synthase (CHS) and antifungal activities were evaluated in vitro. Results showed compounds 5b, 5c, 5e, 5f, 5j, 5k, 5l, and 5o had strong inhibitory potency against CHS. Compound 5c, which has the highest potency among these compounds, had a half-inhibition concentration (IC50) of 0.08 mmol/L, while polyoxin B as positive drug had IC50 of 0.18 mmol/L. These IC 50 values of compounds 5i, 5m, 5n, and 5s were greater than 0.75 mmol/L, which revealed that those compounds had weak inhibition activity against CHS. Moreover, most of these compounds exhibited moderate to excellent antifungal activities. In detail, to Candida albicans, the activities of compound 5g and 5k were 8-fold stronger than that of fluconazole and 4-fold stronger than that of polyoxin B; to Aspergillus flavus, the activities of 5g, 5l and 5o were16-fold stronger than that of fluconazole and 8-fold stronger than that of polyoxin B; to Cryptococcus neoformans, the minimum-inhibition- concentration (MIC) values of compounds 5c, 5d, 5e and 5l were comparable to those of fluconazole and polyoxin B. The antifungal activities of these compounds were positively correlated to their IC50 values against CHS. Furthermore, these compounds had negligible actions to bacteria. Therefore, these compounds were promising selective antifungal agents.
- Ji, Qinggang,Yang, Dan,Wang, Xin,Chen, Chunyan,Deng, Qiao,Ge, Zhiqiang,Yuan, Lvjiang,Yang, Xiaolan,Liao, Fei
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p. 3405 - 3413
(2014/06/23)
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- Electrochemical reduction of 2-chloro-N-phenylacetamides at carbon and silver cathodes in dimethylformamide
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Cyclic voltammetry and controlled-potential (bulk) electrolysis have been employed to investigate the direct electrochemical reduction of 2-chloro-N-methyl-N-phenylacetamide (1a), 2-chloro-N-ethyl-N-phenylacetamide (1b), and 2-chloro-N-phenylacetamide (1c) at carbon and silver cathodes, as well as the catalytic reduction of these compounds by electrogenerated nickel(I) salen, in dimethylformamide (DMF) containing 0.050 M tetramethylammonium tetrafluoroborate (TMABF4). Cyclic voltammograms for reduction of 1a and 1b show a single irreversible cathodic peak for cleavage of the carbon-chlorine bond, but two irreversible cathodic peaks are observed in cyclic voltammograms for reduction of 1c. Controlled-potential reduction of 1a and 1b gives mixtures of dechlorinated amide and N-alkyl-N-phenylaniline, whereas bulk electrolyses of 1c afford N-phenylacetamide in almost quantitative yield. In addition, bulk electrolyses of 1a and 1b result in the formation of very small amounts of dimeric species that arise from coupling of the radical intermediate formed by one-electron cleavage of the carbon-chlorine bond. On the basis of the coulometric n values and product distributions, together with computations based on density functional theory, we propose mechanistic pictures for the reduction of 1a and 1b that involve radical intermediates, whereas reduction of 1c involves carbanion intermediates.
- Pasciak, Erick M.,Sengupta, Arkajyoti,Mubarak, Mohammad S.,Raghavachari, Krishnan,Peters, Dennis G.
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p. 159 - 166
(2014/04/03)
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- Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia
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This study explores the possible use of reactive oxygen-activated DNA modifying agents against acute myeloid leukemia (AML). A key amine on the lead agent was investigated via cytotoxicity assays and was found necessary for potency. The two best compounds were screened via the NCI-60 cell panel. These two compounds had potency between 200 and 800 nM against many of the leukemia cancer cell types. Subsequent experiments explored activity against a transformed AML model that mimics the molecular signatures identified in primary AML patient samples. A lead compound had an IC50 of 760 nM against this AML cell line as well as a therapeutic index of 7.7 ± 3 between the transformed AML model cell line and non-cancerous human CD34+ blood stem/progenitor cells (UCB). The selectivity was much greater than the mainstays of AML treatment: doxorubicin and cytarabine. This manuscript demonstrates that this novel type of agent may be useful against AML.
- Bell-Horwath, Tiffany R.,Vadukoot, Anish K.,Thowfeik, Fathima Shazna,Li, Guorui,Wunderlich, Mark,Mulloy, James C.,Merino, Edward J.
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p. 2951 - 2954
(2013/06/27)
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- One-pot synthesis of indolo[2,3-c]quinolin-6-ones by sequential photocyclizations of 3-(2-azidophenyl)-N-phenylacrylamides
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A one-pot synthesis of indolo[2,3-c]quinolin-6(7H)-ones was achieved by sequential photocyclizations of 3-(2-azidophenyl)-N-phenylacrylamides in moderate to high yields. The reactions proceeded via photochemical cyclization of aryl azides to form N-phenylindol-2-carbamides and subsequent 6π-electrocyclic reaction and oxidative aromatization to afford the corresponding indolo[2,3-c]quinolin-6(7H)-ones. Georg Thieme Verlag Stuttgart · New York.
- Li, Zhanshan,Wang, Weixia,Zhang, Xiaotian,Hu, Congcong,Zhang, Wei
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supporting information
p. 73 - 78
(2013/04/24)
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- Photoinduced and N-bromosuccinimide-mediated cyclization of 2-azido-N-phenylacetamides
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An efficient synthesis of quinoxalin-2(1H)-ones or spiro[cyclohexene-1, 2′-imidazol]-4′-ones has been achieved in moderate to high yields by the visible light-induced and N-bromosuccinimide-mediated cyclization reaction of 2-azido-N-phenylacetamides at ambient temperature. Both the regioselectivity and the speed of cyclization are affected by the substituents attached to the phenyl ring. For example, quinoxalin-2-ones are produced as the main products when the substrates bear electron-withdrawing groups at the para-position of the phenyl ring; in contrast, spiro[cyclohexene-1,2′-imidazol]-4′-ones are obtained as the main products when the substrates bear electron-donating groups at the para-position.
- Li, Zhan-Shan,Wang, Wei-Xia,Yang, Ji-Dong,Wu, Yue-Wei,Zhang, Wei
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supporting information
p. 3820 - 3823
(2013/09/02)
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- Design, synthesis, and evaluation of indolebutylamines as a novel class of selective dopamine D3 receptor ligands
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A series of indolebutylamine derivatives were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine 3 receptor. The most potent compound 11q binds to dopamine 3 receptor with a Ki value of 124 nm and displays excellent selectivity over the dopamine 1 receptor and dopamine 2 receptor. Investigation based on structural information indicates that site S182 located in extracellular loop 2 may account for high selectivity of compounds. Interaction models of the dopamine 3 receptor-11q complex and structure-activity relationships were discussed by integrating all available experimental and computational data with the eventual aim to discover potent and selective ligands to dopamine 3 receptor.
- Du, Peng,Xu, Lili,Huang, Jiye,Yu, Kunqian,Zhao, Rui,Gao, Bo,Jiang, Hualiang,Zhao, Weili,Zhen, Xuechu,Fu, Wei
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p. 326 - 335
(2013/09/12)
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- Discovery of novel N -phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis
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In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.
- Flipo, Marion,Willand, Nicolas,Lecat-Guillet, Nathalie,Hounsou, Candide,Desroses, Matthieu,Leroux, Florence,Lens, Zoé,Villeret, Vincent,Wohlk?nig, Alexandre,Wintjens, René,Christophe, Thierry,Kyoung Jeon, Hee,Locht, Camille,Brodin, Priscille,Baulard, Alain R,Déprez, Benoit
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supporting information; experimental part
p. 6391 - 6402
(2012/10/07)
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- HETEROARYL COMPOUNDS AS PDE10A INHIBITORS
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The present invention provides heteroaryl compounds as Phosphodiesterase 10A (PDE I OA) inhibitors. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders by inhibiting Phosphodiesterase 10A enzyme. Also provided herein are processes for preparing compounds described herein, Formula (I), intermediates used in their synthesis, pharmaceutical compositions thereof.
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Page/Page column 48
(2011/11/06)
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- Synthesis and biological evaluation of novel 5-benzylidenethiazolidine-2,4- dione derivatives for the treatment of inflammatory diseases
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Twenty-two compounds based on thiazolidine-2,4-dione moiety were synthesized and evaluated for the inhibitory potency on the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS) activity, and the generation of prostaglandin E2 (PEG2). (Z)-N-(3-Chlorophenyl)-2-(4- ((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acetamide (3I), superior to the commercial anti-inflammatory drug indomethacin, significantly inhibited iNOS activity (IC50 = 8.66 μM), iNOS-mediated NO, and cyclooxygenase (COX)-2-derived PGE2 production (IC50 = 4.16 and 23.55 μM, respectively) on lipopolysaccharide (LPS)-induced RAW 264.7 cells. Docking study revealed that 3I was perfectly docking into the active site of murine iNOS and suppressed the expression of iNOS protein as evidenced by Western blot analysis. At the dose of 50 mg/kg, oral administration of 3I possessed protective properties in both carrageenan-induced paw edema and adjuvant-induced arthritis rat models.
- Ma, Liang,Xie, Caifeng,Ma, Yinghua,Liu, Juan,Xiang, Mingli,Ye, Xia,Zheng, Hao,Chen, Zhizhi,Xu, Qinyuan,Chen, Tao,Chen, Jinying,Yang, Jincheng,Qiu, Neng,Wang, Guangcheng,Liang, Xiaolin,Peng, Aihua,Yang, Shengyong,Wei, Yuquan,Chen, Lijuan
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supporting information; experimental part
p. 2060 - 2068
(2011/06/17)
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- Synthesis and biological activity of novel barbituric and thiobarbituric acid derivatives against non-alcoholic fatty liver disease
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Forty-four barbituric acid or thiobarbituric acid derivatives were synthesized and evaluated for their effects on adipogenesis of 3T3-L1 adipocytes by measuring the expression of adiponectin in vitro. Four compounds (3a, 3o, 3s, 4t) were found to increase the expression of adiponectin and lower the leptin level in 3T3-L1 adipocytes at respective concentration of 10 μM. Among them, 3s showed the most efficacious. Oral administration of 3s effectively reduced body weight, liver weight, and visceral fat and regulated serum levels of biochemical markers in the high-fat/diet-induced Wistar rats. Histopathological evaluation of liver sections by Oil Red O and H&E staining confirmed 3s as a potent, orally active molecule for reducing fat deposition against non-alcoholic fatty liver disease.
- Ma, Liang,Li, Shilin,Zheng, Hao,Chen, Jinying,Lin, Lin,Ye, Xia,Chen, Zhizhi,Xu, Qinyuan,Chen, Tao,Yang, Jincheng,Qiu, Neng,Wang, Guangcheng,Peng, Aihua,Ding, Yi,Wei, Yuquan,Chen, Lijuan
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experimental part
p. 2003 - 2010
(2011/06/25)
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- Evaluation of N-substitution in 6,7-benzomorphan compounds
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6,7-Benzomorphan derivatives, exhibiting different μ, δ, and κ receptor selectivity profiles depending on the N-substituent, represent a useful skeleton for the synthesis of new and better analgesic agents. In this work, an aromatic ring and/or alkyl residues have been used with an N-propanamide or N-acetamide spacer for the synthesis of a new series of 5,9-dimethyl-2′-hydroxy-6,7-benzomorphan derivatives (12-22). Data obtained by competition binding assays showed that the μ opioid receptor seems to prefer an interaction with the 6,7-benzomorphan ligands having an N-substituent with a propanamide spacer and less hindered amide. Highly stringent features are required for δ receptor interaction, while an N-acetamide spacer and/or bulkier amide could preferentially lead to κ receptor selectivity. In the propanamide series, compound 12 (named LP1) displayed high μ affinity (Ki = 0.83 nM), good δ affinity (Ki = 29 nM) and low affinity for the κ receptor (Ki = 110 nM), with a selectivity ratio δ/μ and κ/μ of 35.1 and 132.5, respectively. Further, in the adenylyl cyclase assay, LP1 displayed a μ/δ agonist profile, with IC50 values of 4.8 and 12 nM at the μ and δ receptors, respectively. The antinociceptive potency of LP1 in the tail-flick test after sc administration in rat was comparable with the potency of morphine (ED50 = 2.03 and 2.7 mg/kg, respectively), and was totally reversed by naloxone. LP1, possessing a μ/δ agonist profile, could represent a lead in further developing benzomorphan-based ligands with potent in vivo analgesic activity and a reduced tendency to induce side effects.
- Pasquinucci, Lorella,Prezzavento, Orazio,Marrazzo, Agostino,Amata, Emanuele,Ronsisvalle, Simone,Georgoussi, Zafiroula,Fourla, Danai-Dionysia,Scoto, Giovanna M.,Parenti, Carmela,Arico, Giuseppina,Ronsisvalle, Giuseppe
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experimental part
p. 4975 - 4982
(2010/09/08)
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- Synthesis of benzodiazocine-annulated heterocycles by the implementation of Pd-catalyzed intramolecular Heck reaction
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Synthesis of hitherto unreported benzodiazocine-annulated heterocycles by the implementation of palladium-catalyzed intramolecular Heck reaction has been achieved in excellent yields.
- Majumdar,Ray, Krishanu,Ganai, Sintu
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scheme or table
p. 1736 - 1738
(2010/05/18)
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- Synthesis and antimicrobial activities of some imidazole substituted indoles
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The compounds 1-substituted 2-(imidazol-1-yl)-3-(4,5-diarylimidazol-2-yl) indoles 2, 1-substituted 2-(imidazol-1-yl)-3-(phenanthro[9,10-d]imidazol-2-yl) indoles 3 and 1-substituted 2-(imidazol-1-yl)-3-(benzimidazol-2-yl)indoles 4 have been synthesized from 1-substituted 2-(imidazol-1-yl)-3-formylindole 1. The structural elucidation of the synthesised compounds has been performed by IR, 1H NMR and mass spectroscopic data and elemental analyses. Antimicrobial activities of the compounds are examined and notable antifungal activity is obtained from some of the compounds as expected in comparison with the control agent ketoconazole.
- Benkli, Kadriye,Demirayak, Seref,Gundogdu-Karaburun, Nalan,Kiraz, Nuri,Iscan, Gokalp,Ucucu, Umit
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p. 174 - 179
(2007/10/03)
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- Substitution-reduction: An alternative process for the [ 18F]N-(2-fluoroethylation) of anilines
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Substitution of a halo atom (chloro or bromo) in easily prepared N-haloacetyl-anilines with no-carrier added (NCA) cyclotron-produced [ 18F]fluoride ion (18F, t1/2 = 109.8 min; β+ = 96.9%), followed by reduction with borane-tetrahydrofuran (BH3-THF), provides an alternative route to NCA [ 18F]N-(2-fluoroethyl)-anilines. This two-step and one-pot process is rapid (~50 min) and moderately high yielding (~40% decay-corrected radiochemical yield (RCY) overall). In the nucleophilic substitution reaction, 18-crown-6 is preferred to Kryptofix 222 as complexing agent for the solubilization of the counter-ion (K+), derived from an added metal salt, in acetonitrile. Weakly basic potassium bicarbonate is preferred as the added metal salt. Inclusion of a small amount of water, equating to 4-5 molar equivalents relative to 18-crown-6, base or precursor (held in equimolar ratio), is beneficial in preventing the adsorption of radioactivity onto the wall of the glass reaction vessel and for achieving high RCY in the nucleophilic substitution reaction. BH3-THF is effective for the rapid reduction of the generated [18F]N-fluoroacetyl-aniline to the [ 18F]N-(2-fluoroethyl)-aniline. Copyright
- Briard, Emmanuelle,Pike, Victor W.
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p. 217 - 232
(2007/10/03)
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- Synthesis of substituted oxindoles from α-chloroacetanilides via palladium-catalyzed C - H functionalization
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A novel method for the synthesis of oxindoles is described. In the presence of catalytic palladium acetate and 2-(di-tert-butylphosphino)biphenyl, α-chloroacetanilides are converted to oxindoles in good to excellent yields with high functional group compatibility using triethylamine as a stoichiometric base. The cyclization is highly regioselective, obviating the need for prefunctionalized arenes. Plausible mechanistic pathways for the reaction are discussed. Copyright
- Hennessy, Edward J.,Buchwald, Stephen L.
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p. 12084 - 12085
(2007/10/03)
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- S4N4SbCl5 complex: a useful reagent for conversion of sterically less hindred α-bromo ketones to α-chloro ketones
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The reactions of sterically less hindered α-bromo alkyl and aryl ketones with tetrasulfur tetranitride antimony pentachloride (S4N4SbCl5) complex in toluene at reflux gave the corresponding α-chloro kerones in good to excellent yields.
- Kim, Kil-Joong,Kim, Kyongtae
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p. 4227 - 4230
(2007/10/03)
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- Reaction of Azides in Presence of Aluminium Chloride
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Amidoalkylazides (2) on treatment with aluminium chloride in benzene yield 2-anilino-N-(aryl)acetamides (3) in good yields.
- Ananthanarayanan, C.,Ramakrishnan, V. T.
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p. 156 - 157
(2007/10/02)
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- Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
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Novel compounds of the general formula STR1 and the pharmaceutically acceptable esters and acid addition salts thereof, wherein: R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N-optionally substituted alkylamido, except that when R1 is methyl, R4 is not methyl; or R2 and R3 together form --OCH2 O--; R6, R7, R8, R9 and R10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di-lower alkyl amino; or R6 and R7 together form --CH=CH--CH=CH--; R7 and R8 together form --OCH2 O--; R11 and R12 are each independently hydrogen or lower alkyl; and W is oxygen or sulfur. These cardioselective compounds have calcium entry blockade properties and therefore are useful in therapy in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise induced angina and myocardial infarction.
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- Cycloadditions, 7. Intramolecular Diels-Alder Reactions of Allenecarboxanilides; Variation of the Substituents in the p-Position of the Aniline Nucleus
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The N-methyl-1,2-propadiene-1-carboxanilides 6a-h, differently substituted in the p-position, are synthesized by Wittig reaction of the carbamoylmethylenephosphoranes 5 with ketene.They isomerize by thermolysis in boiling xylene to give the tricycles 7a-h, the products of the intramolecular Diels-Alder reaction, and in some cases also to the quinolones 9, the products of a cyclization reaction.The order of the reaction and the influence of the substituents upon the rate of the intramolecular Diels -Alder reaction are determined by 1H-NMR spectroscopy.
- Diehl, Klaus,Himbert, Gerhard,Henn, Lothar
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p. 2430 - 2443
(2007/10/02)
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- BENZODIOXANYL-HYDROXYETHYLENEAMINO-PIPERIDINYL ACETANILIDES, KETONES, ESTERS AND CARBAMATES WHICH EFFECT IMMUNITY AND CALCIUM ENTRY AND BETA-BLOCKADE
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Novel compounds of the general formula: STR1 and the pharmaceutically acceptable acid addition salts thereof, wherein: R 1, R 2, R 3 and R 4 are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl or lower alkyl sulfonyl;R 5 is hydrogen or lower alkyl;m is 0 or 1;W is alkylene,--CH=CH--,--O--, or--N(R 6)--, where R 6 is lower alkyl or hydrogen;n is 0 or 1; andQ is lower alkyl, cycloalkyl or optionally substituted phenyl. These compounds combine β-blockade and calcium entry blockade properties in the same compound and therefore are useful in therapy in the treatment of cardiovascular diseases, including myocardial infarction, hypertension, arrhythmia and variant and exercise induced angina. The compounds are also useful in immunosuppressant therapy for immune diseases, such as rheumatoid arthritis.
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- Benzodioxanyl-hydroxyethylene-piperazinyl acetanilides which effect calcium entry and β-blockade
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Novel compounds of the general formula: STR1 and the pharmaceutically acceptable esters and acid addition salts thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl; or R2 and R3 together form --OCH2 O--; and R10 and R11 are each independently hydrogen or lower alkyl. These compounds combine β-blockade and calcium entry blockade properties in the same compound and therefore are useful in therapy in the treatment of cardiovascular diseases, including hypertension, arrhythmias and variant and exercise induced angina.
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- Amide phosphorothiolate herbicides
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The present invention relates to new herbicidal phosphorothioate (phosphorodithioate) derivatives and to preparation thereof.
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- Substituted chloroacylanilides
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The invention concerns a process for the preparation of substituted chloroacylanilides of the general formula: SPC1 Wherein R1 represents an alkyl group having from 1 to 4 carbon atoms or a phenyl group; R2 represents a hydrogen atom or halogen atom; R3 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and X1 and X 2 , which may be the same or different, represent a hydrogen atom, a halogen atom, a methyl group or an ethyl group. The process comprises acylating a substituted aniline of the general formula: SPC2 Wherein R1, X1 and X2 are as above defined, in the presence of phosphoryl chloride under substantially anhydrous conditions with a chlorocarboxylic acid of the general formula: EQU1 wherein R2 and R3 are as above defined. Particularly suitable compounds of general Formula II are N-methyl aniline and N-isopropyl aniline, and particularly suitable compounds of general Formula III are chloroacetic acid, dichloroacetic acid and α-chloropropionic acid and α-chlorobutyric acid. The compounds of general Formula I have phytotoxic effects and some are active herbicides.
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