- Structure and absolute configuration of some 5-chloro-2-methoxy-N-phenylbenzamide derivatives
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The absolute configuration of 5-chloro-2-methoxy-N-phenylbenzamide single crystal [compound (1)] and the effect of introducing –[CH2]n–, n?=?1,2 group adjacent to the amide group [compounds (2) and (3)], were studied. Furthermore, the replacement of the methoxy group with a hydroxy group [compound (4)] was defined. Proton and carbon-13 NMR spectrometer were used to record the structural information of the prepared compounds. X-ray single crystal diffractometer were used to elucidate the 3D structural configurations. Intensity data for the studied compounds were collected at room temperature. The X-ray data prove that compound (1) is almost planar, with maximum r.m.s. deviations of 0.210(3)?? corresponds to C13. This planarity starts to disturb by adding –[CH2]n–, n?=?1,2 groups between the NH group and the phenyl ring in compounds (2) and (3), respectively. By replacing the OCH3 group by an OH group in compound (4), the plane of the chlorophenyl moiety is nearly perpendicular to that of the phenyl ring. Such new structural configurations were further illustrated by the infrared, and ultraviolet-visible spectroscopy measurements in the frequency range 400–4000?cm??1 and 190–1100?nm, respectively. Spectroscopic analyses were verified with the help of molecular modeling using density functional theory. The estimated total dipole moment for the prepared compounds reflects its ability to interact with its surrounding molecules. The higher dipole moment for a given structures is combined with the higher reactivity for potential use in medicinal applications.
- Galal, Alaaeldin M F,Shalaby, Elsayed M.,Abouelsayed, Ahmed,Ibrahim, Medhat A.,Al-Ashkar, Emad,Hanna, Atef G
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- Structural Insights of Benzenesulfonamide Analogues as NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization
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NLRP3 inflammasome plays critical roles in a variety of human diseases and represents a promising drug target. In this study, we established the in vivo functional activities of JC124, a previously identified NLRP3 inflammasome inhibitor from our group, in mouse models of Alzheimer's disease and acute myocardial infarction. To understand the chemical space of this lead structure, a series of analogues were designed, synthesized, and biologically characterized. The results revealed the critical roles of the two substituents on the benzamide moiety of JC124. On the other hand, modifications on the sulfonamide moiety of JC124 are well tolerated. Two new lead compounds, 14 and 17, were identified with improved inhibitory potency (IC50 values of 0.55 ± 0.091 and 0.42 ± 0.080 μM, respectively). Further characterization confirmed their selectivity and in vivo target engagement. Collectively, the results strongly encourage further development of more potent analogues based on this chemical scaffold.
- Fulp, Jacob,He, Liu,Toldo, Stefano,Jiang, Yuqi,Boice, Ashley,Guo, Chunqing,Li, Xia,Rolfe, Andrew,Sun, Dong,Abbate, Antonio,Wang, Xiang-Yang,Zhang, Shijun
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- Intermolecular C-H Amidation of Alkenes with Carbon Monoxide and Azides via Tandem Palladium Catalysis
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An atom- and step-economic intermolecular multi-component palladium-catalyzed C-H amidation of alkenes with carbon monoxide and organic azides has been developed for the synthesis of alkenyl amides. The reaction proceeds efficiently without an ortho -directing group on the alkene substrates. Nontoxic dinitrogen is generated as the sole by-product. Computational studies and control experiments have revealed that the reaction takes place via an unexpected mechanism by tandem palladium catalysis.
- Gu, Zheng-Yang,Wu, Yang,Jin, Feng,Bao, Xiaoguang,Xia, Ji-Bao
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supporting information
p. 3361 - 3371
(2021/04/09)
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- Pd-catalyzed amidation of 1,3-diketones with CO and azidesviaa nitrene intermediate
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An efficient Pd-catalyzed amidation of 1,3-diketones has been developed using carbon monoxide and organic azides. This reaction provides a step-economic approach to produce β-ketoamides from readily available compounds under mild ligand-, oxidant-, and base-free conditions. The mechanistic studies showed that the reaction occurred through anin situgenerated isocyanate intermediate.
- Gu, Zheng-Yang,Chen, Jie,Xia, Ji-Bao
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supporting information
p. 11437 - 11440
(2020/10/12)
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- Metal-Free Thermal Activation of Molecular Oxygen Enabled Direct α-CH2-Oxygenation of Free Amines
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Direct oxidation of α-CH2 group of free amines is hard to achieve due to the higher reactivity of amine moiety. Therefore, oxidation of amines involves the use of sophisticated metallic reagents/catalyst in the presence or absence of hazardous oxidants under sensitive reaction conditions. A novel method for direct C-H oxygenation of aliphatic amines through a metal-free activation of molecular oxygen has been developed. Both activated and unactivated free amines were oxygenated efficiently to provide a wide variety of amides (primary, secondary) and lactams under operationally simple conditions without the aid of metallic reagents and toxic oxidants. The method has been applied to the synthesis of highly functionalized amide-containing medicinal drugs, such as O-Me-alibendol and -buclosamide.
- Ghosh, Santanu,Jana, Chandan K.
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p. 260 - 266
(2018/02/19)
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- N-HYDROXY-BENZENE-SULFONAMIDE DERIVATIVES AND THEIR USES THEREOF
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Inhibitors with anti-inflammatory agents are provided, as are methods of using the analogs to inhibit inflammation and prevent or treat diseases and conditions associated with inflammation, such as multiple sclerosis and autoinflammatory diseases.
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Page/Page column 17
(2018/06/30)
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- Room temperature C(sp2)-H oxidative chlorination: Via photoredox catalysis
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Photoredox catalysis has been developed to achieve oxidative C-H chlorination of aromatic compounds using NaCl as the chlorine source and Na2S2O8 as the oxidant. The reactions occur at room temperature and exhibit exclusive selectivity for C(sp2)-H bonds over C(sp3)-H bonds. The method has been used for the chlorination of a diverse set of substrates, including the expedited synthesis of key intermediates to bioactive compounds and a drug.
- Zhang, Lei,Hu, Xile
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p. 7009 - 7013
(2017/10/05)
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- Development and Characterization of a Hydroxyl-Sulfonamide Analogue, 5-Chloro-N-[2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a Novel NLRP3 Inflammasome Inhibitor for Potential Treatment of Multiple Sclerosis
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In our efforts to develop novel small-molecule inhibitors for the NOD-like receptor family pyrin-domain-containing 3 (NLRP3) inflammasome as potential disease-modifying agents to treat neurological disorders including multiple sclerosis (MS), a hydroxyl sulfonamide analogue JC-171 has been rationally designed and biologically characterized both in vitro and in vivo. Our studies established that JC-171 dose dependently inhibited LPS/ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages with an IC50 of 8.45 ± 1.56 μM. Selective inhibition of the NLRP3 inflammasome induced IL-1β release by this compound was also confirmed using mouse bone-marrow-derived macrophages and LPS-challenged mice in vivo. Furthermore, immunoprecipitation study revealed that JC-171 interfered with NLRP3/ASC interaction induced by LPS/ATP stimulation. More importantly, JC-171 treatment delayed the progression and reduced the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, in both prophylactic and therapeutic settings. This coincided with blocking of IL-1β production and a pathogenic Th17 response. Collectively, these results suggest that JC-171 is a selective NLRP3 inflammasome inhibitor with biological activity in vivo, thus strongly encouraging further development of this lead compound as a potential therapeutic agent for human MS.
- Guo, Chunqing,Fulp, Jacob W.,Jiang, Yuqi,Li, Xia,Chojnacki, Jeremy E.,Wu, Jingde,Wang, Xiang-Yang,Zhang, Shijun
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p. 2194 - 2201
(2017/10/23)
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- Product-Derived Bimetallic Palladium Complex Catalyzes Direct Carbonylation of Sulfonylazides
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A novel product-derived bimetallic palladium complex catalyzes a sulfonylazide-transfer reaction with the σ-donor/π-acceptor ligand CO, and is advantageous given its broad substrate scope, high efficiency, and mild reaction conditions (atmospheric pressure of CO at room temperature). This methodology provides a new approach to sulfonylureas, which are present in both pharmaceuticals and agrochemicals. The synthesis of Glibenclamide on a gram scale further revealed the practical utility of this procedure. Mechanistically, the generation of a bridged bimetallic palladium species derived from the product sulfonylurea is disclosed as the crucial step for this catalytic cycle.
- Zhao, Jin,Li, Zongyang,Song, Shaole,Wang, Ming-An,Fu, Bin,Zhang, Zhenhua
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supporting information
p. 5545 - 5549
(2016/05/09)
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- Synthetic process of 4-[2-(5-chloro-2-methoxy benzamide)ethyl]benzsulfamide
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The invention discloses a synthetic process of 4-[2-(5-chloro-2-methoxy benzamide)ethyl]benzsulfamide, and belongs to the technical field of medicinal synthesis processes. According to the process, 5-chloro-2-methoxybenzoic acid and phenylethylamine serve as the raw materials, and a target product is obtained through reactions of four steps including acylating chlorination, amidation, chlor amidation osulfonation and sulfanil amination. By means of the synthesis method, low-price industrial chemicals serve as raw materials and reaction reagents, single-solvent systems are adopted, smooth process connection is achieved, reaction yield is increased, process operation is simplified, and production cost is reduced while raw material cost is reduced.
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Paragraph 0024; 0029; 0030
(2016/11/14)
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- Design and Performance Validation of a Conductively Heated Sealed-Vessel Reactor for Organic Synthesis
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A newly designed robust and safe laboratory scale reactor for syntheses under sealed-vessel conditions at 250 °C maximum temperature and 20 bar maximum pressure is presented. The reactor employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements both online temperature and pressure monitoring in addition to magnetic stirring. Reactions are performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow syntheses to be performed on a 2-6 mL scale. This conductively heated reactor is compared to a standard single-mode sealed-vessel microwave instrument with respect to heating and cooling performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the reaction outcome for a number of different synthetic transformations performed side by side in the new device and a standard microwave reactor suggest that results obtained using microwave conditions can be readily mimicked in the operationally much simpler and smaller conventionally heated device.
- Obermayer, David,Znidar, Desiree,Glotz, Gabriel,Stadler, Alexander,Dallinger, Doris,Oliver Kappe
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p. 11788 - 11801
(2016/12/09)
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- CRYOPYRIN INHIBITORS FOR PREVENTING AND TREATING INFLAMMATION
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Inhibitors that are anti-inflammatory agents are provided, as are methods of using the analogs to inhibit inflammation and prevent or treat diseases and conditions associated with inflammation, such as heart failure and autoimmune diseases.
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Page/Page column 21-22; title; sheet 3
(2014/12/12)
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- Preparation of phenylethylbenzamide derivatives as modulators of DNMT3 activity
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DNA-methyltransferases (DNMTs) are a class of epigenetic enzymes that catalyze the transfer of a methyl moiety from the methyl donor S-adenosyl-l-methionine onto the C5 position of cytosine in DNA. This process is dysregulated in cancers and leads to the hypermethylation and silencing of tumor suppressor genes. The development of potent and selective inhibitors of DNMTs is of utmost importance for the discovery of new therapies for the treatment of cancer. We report herein the synthesis and DNMT inhibitory activity of 29 analogues derived from NSC 319745. The effect of selected compounds on the methylation level in the MDA-MB-231 human breast cancer cell line was evaluated using a luminometric methylation assay. Molecular docking studies have been conducted to propose a binding mode for this series.
- Kabro, Anzhelika,Lachance, Hugo,Marcoux-Archambault, Iris,Perrier, Valerie,Dore, Vicky,Gros, Christina,Masson, Veronique,Gregoire, Jean-Marc,Ausseil, Frederic,Cheishvili, David,Laulan, Nathalie Bibens,St-Pierre, Yves,Szyf, Moshe,Arimondo, Paola B.,Gagnon, Alexandre
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p. 1562 - 1570
(2013/12/04)
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- Investigation of structure-activity relationships in a series of glibenclamide analogues
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In this study, the synthesis of 15 new glibenclamide analogues is described. The conformational trends of these analogues were investigated using Monte Carlo conformational analysis. The conformational analysis results resolved the discrepancy between previous molecular modelling simulations of glibenclamide and allowed rationalizing the effect of aqueous environment on the overall conformation. The 3D-QSAR study was carried out with respect to the compounds' ability to antagonize the [3H]-glibenclamide binging in rat cerebral cortex. Superimposition of the antagonists was performed using the conformations derived from atom-by-atom fit to the glibenclamide crystal structure and this alignment was used to develop CoMFA models. CoMFA provided a good predictability: number of PLS components = 2, q2 = 0.876, R 2 = 0.921, SEE = 0.455 and F = 70. Best CoMFA models showed the steric and lipophilic properties as the major interacting forces whilst the electrostatic property contribution was a minor factor.
- Yuriev, Elizabeth,Kong, David C.M.,Iskander, Magdy N.
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p. 835 - 847
(2007/10/03)
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- Receptor Binding Sites of Hypoglycemic Sulfonylureas and Related benzoic Acids
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The blood glucose level lowering activity of benzoic acid, such as p-benzoic acid (HB699, 2), is discussed in terms of binding at putative insulin-releasing receptor sites of pancreatic β cells.The hypoglycemic potencies fuond for synthetic analogues of 2 indicate that high hypoglycemic activity is only found when a carboxyl group or a group that is readily oxidized to carboxyl in vivo, such as methyl, is attached to the aromatic ring of the phenethyl group.It is proposed that this carboxyl group is able to bind at the same receptor site as the SO2NHCONH group of the sulfonylurea drugs, such as tolbutamide (3).The role of the benzamide group in 2 was attributed to protein binding.
- Brown, George R.,Foubister, Alan J.
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- Process for preparing p-(5-chloro-2-methoxy-benzamidoethyl)-benzene sulfonamide
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A process for preparing p-[5-chloro-2-methoxy-benzamidoethyl]-benzene sulfonamide consisting of treating 5-chlorosalicylic acid or its ester by methylating and aminolysis to form N-phenethyl-5-chloro-2-methoxybenzamide followed by chlorosulfonation and aminolysis.
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