- Synthesis and structure-activity relationships of small-molecular di-basic esters, amides and carbamates as flaviviral protease inhibitors
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Inhibitors of the flaviviral serine proteases, which are crucial for the replication of dengue and West-Nile virus, have attracted much attention over the last years. A dibasic 4-guanidinobenzoate was previously reported as inhibitor of the dengue protease with potency in the low-micromolar range. In the present study, this lead structure was modified with the intent to explore structure-activity relationships and obtain compounds with increased drug-likeness. Substitutions of the guanidine moieties, the aromatic rings, and the ester with other functionalities were evaluated. All changes were accompanied by a loss of inhibition, indicating that the 4-guanidinobenzoate scaffold is an essential element of this compound class. Further experiments indicate that the target recognition of the compounds involves the reversible formation of a covalent adduct.
- Sundermann, Tom R.,Benzin, Clarissa V.,Dra?i?, Tonko,Klein, Christian D.
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p. 187 - 194
(2019/05/21)
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- An unsymmetrical covalent organic polymer for catalytic amide synthesis
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Herein, we present the first report on the Covalent Organic Polymer (COP) directed non-classical synthesis of an amide bond. An economical route has been chosen for the synthesis of APC-COP using p-aminophenol and cyanuric chloride. APC-COP acts as a smart, valuable and sustainable catalyst for efficient access to the amide bond under mild conditions at room temperature in 30 min. APC-COP exhibits selectivity towards carboxylic acids over esters. The key features of this protocol involve the variety of parameters, viz. wider substrate scope, no use of additive and recyclability, which makes this approach highly desirable in gramscale synthesis. Moreover, we have shown the practical utility of the present method in the catalytic synthesis of paracetamol.
- Yadav, Deepika,Awasthi, Satish Kumar
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p. 179 - 186
(2019/12/28)
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- Preparation method of electronic-grade 4,4'-diaminobenzanilide
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The invention discloses a preparation method of electronic-grade 4,4'-diaminobenzanilide. The preparation method comprises the following steps: 1, 4,4'-dinitrobenzanilide is prepared from 4-nitroaniline and 4-nitrobenzoyl chloride through a reaction; 2, crude 4,4'-diaminobenzanilide is obtained from 4,4'-dinitrobenzanilide through catalytic hydrogenation; 3, crude 4,4'-diaminobenzanilide obtainedin step 2, a recrystallization solvent and activated carbon are added to an autoclave simultaneously, recrystallization and activated carbon decoloration are performed simultaneously at 100-150 DEG Cunder nitrogen protection, and electronic-grade 4,4'-diaminobenzanilide is obtained. The appropriate recrystallization solvent is selected and recrystallization and activated carbon decoloration are performed simultaneously, so that electronic-grade 4,4'-diaminobenzanilide with high purity and low ion content is obtained finally, and special requirements of high-performance electronics industry are met.
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Paragraph 0013; 0014; 0026; 0027
(2018/08/28)
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- Biological evaluation and molecular docking studies of nitro benzamide derivatives with respect to in vitro anti-inflammatory activity
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A series of nitro substituted benzamide derivatives were synthesized and evaluated for their potential anti-inflammatory activities in vitro. Firstly, all compounds (1–6) were screened for their inhibitory capacity on LPS induced nitric oxide (NO) production in RAW264.7 macrophages. Compounds 5 and 6 demonstrated significantly high inhibition capacities in a dose-dependent manner with IC50 values of 3.7 and 5.3 μM, respectively. These two compounds were also accompanied by no cytotoxicity at the studied concentrations (max 50 μM) in macrophages. Molecular docking analysis on iNOS revealed that compounds 5 and 6 bind to the enzyme more efficiently compared to other compounds due to having optimum number of nitro groups, orientations and polarizabilities. In addition, 5 and 6 demonstrated distinct regulatory mechanisms for the expression of the iNOS enzyme at the mRNA and protein levels. Specifically, both suppressed expressions of COX-2, IL-1β and TNF-α significantly, at 10 and 20 μM. However, only compound 6 significantly and considerably decreased LPS-induced secretion of IL-1β and TNF-α. These results suggest that compound 6 may be a multi-potent promising lead compound for further optimization in structure and as well as for in vivo validation studies.
- Tumer, Tugba B.,Onder, Ferah Comert,Ipek, Hande,Gungor, Tugba,Savranoglu, Seda,Tok, Tugba Taskin,Celik, Ayhan,Ay, Mehmet
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p. 129 - 139
(2016/12/22)
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- Design, synthesis and biological evaluation of 4-Amino-N-(4-aminophenyl) benzamide analogues of quinoline-based SGI-1027 as inhibitors of DNA methylation
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Quinoline derivative SGI-1027 (N-(4-(2-amino-6-methylpyrimidin-4-ylamino) phenyl)-4-(quinolin-4-ylamino)benzamide) was first described in 2009 as a potent inhibitor of DNA methyltransferase (DNMT) 1, 3A and 3B. Based on molecular modeling studies, performed using the crystal structure of Haemophilus haemolyticus cytosine-5 DNA methyltransferase (MHhaI C5 DNMT), which suggested that the quinoline and the aminopyridimine moieties of SGI-1027 are important for interaction with the substrates and protein, we designed and synthesized 25 derivatives. Among them, four compounds - namely the derivatives 12, 16, 31 and 32 - exhibited activities comparable to that of the parent compound. Further evaluation revealed that these compounds were more potent against human DNMT3A than against human DNMT1 and induced the re-expression of a reporter gene, controlled by a methylated cytomegalovirus (CMV) promoter, in leukemia KG-1 cells. These compounds possessed cytotoxicity against leukemia KG-1 cells in the micromolar range, comparable with the cytotoxicity of the reference compound, SGI-1027. Structure-activity relationships were elucidated from the results. First, the presence of a methylene or carbonyl group to conjugate the quinoline moiety decreased the activity. Second, the size and nature of the aromatic or heterocycle subsitutents effects inhibition activity: tricyclic moieties, such as acridine, were found to decrease activity, while bicyclic substituents, such as quinoline, were well tolerated. The best combination was found to be a bicyclic substituent on one side of the compound, and a one-ring moiety on the other side. Finally, the orientation of the central amide bond was found to have little effect on the biological activity. This study provides new insights in to the structure-activity relationships of SGI-1027 and its derivative. Ep-(igenet)-ic! Guided by modeling studies, derivatives of the known DNA methyltransferase (DNMT) inhibitor SGI-1027 were designed, synthesized and evaluated. Structure-activity relationships were derived from the results, leading to the identification of derivatives with improved potency and potential for further development.
- Rilova, Elodie,Erdmann, Alexandre,Gros, Christina,Masson, Veronique,Aussagues, Yannick,Poughon-Cassabois, Valerie,Rajavelu, Arumugam,Jeltsch, Albert,Menon, Yoann,Novosad, Natacha,Gregoire, Jean-Marc,Vispe, Stephane,Schambel, Philippe,Ausseil, Frederic,Sautel, Francois,Arimondo, Paola B.,Cantagrel, Frederic
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p. 590 - 601
(2014/03/21)
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- Design, synthesis and structure-activity relationship of new HSL inhibitors guided by pharmacophore models
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Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores. Its inhibition may improve insulin sensitivity and blood glucose handling in type 2 diabetes. Accordingly, many small-molecule HSL inhibitors have recently been identified. In continuation of our efforts for discovery of new HSL inhibitors, we prepared a variety of esters, amides, sulfonamides and sulfonate esters capable of fitting two pharmacophore models that we developed and published earlier. The tested compounds were synthesized via coupling reactions of aroyl chlorides or sulfonyl chlorides with phenols, amines and related derivatives. Our efforts led to the identification of interesting compounds of low micromolar anti-HSL bioactivities, which have potential to be developed into effective antidiabetic agents.
- Al-Shawabkeh, Jumana D.,Al-Nadaf, Afaf H.,Dahabiyeh, Lina A.,Taha, Mutasem O.
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p. 127 - 145
(2014/03/21)
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- A catalytic and tert-butoxide ion-mediated amidation of aldehydes with para-nitro azides
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We report here a new catalytic reaction in which, para-nitro azides are acylated by aldehydes to produce amides and molecular nitrogen in a single step. The transformation is believed to proceed via an electron transfer process mediated by the tert-butoxide ion, and catalysed by a thiazolium salt derived species. The Royal Society of Chemistry 2013.
- Carbone, Giorgio,Burnley, James,Moses, John E.
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supporting information
p. 2759 - 2761
(2013/04/10)
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- Green and efficient method for the acylation of amines and phenols in the presence of hydrotalcite in water
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In this study a mild, efficient and environmentally friendly method has been developed for the synthesis of amides and esters in the presence of hydrotalcite in water at room temperature. Different types of amines and phenols have been used and in all cases the products were obtained in moderate to high yields after an easy work-up. This method follows the principles of green chemistry.
- Massah, Ahmad Reza,Toghyani, Mitra,Najafabadi, Batool Hojati
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p. 603 - 605,3
(2020/09/16)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS5A protein
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Page/Page column 257-258
(2011/07/30)
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- Novel 2-phenyl-3-{4'-[N-(4"-aminophenyl)carbamoyl]-phenyl}- quinazoline-4(3H)one-6-sulphonic acid based mono azo reactive dyes
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A series of new heterocyclic mono azo reactive dyes 7a-m were prepared by diazotization of 2-phenyl-3-{4'-[N-(4"-aminophenyl)carbamoyl]-phenyl}- quinazoline-4(3H)-one-6-sulphonic acid (3) and coupling with various cyanurated coupling components 6a-m and their dyeing performance on silk, wool and cotton fibres was assessed. These dyes were found to give a variety of colour shades with very good depth and levelness on the fibres. All the compounds were identified by conventional method (IR and 1H-NMR) and elemental analyses. The percentage dye bath exhaustion on different fibres was reasonably good and acceptable. The dyed fibre showed moderate to very good fastness to light, washing and rubbing.
- Patel, Divyesh R.,Patel, Keshav C.
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scheme or table
p. 177 - 188
(2012/01/02)
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- Silica gel-mediated amide bond formation: An environmentally benign method for liquid-phase synthesis and cytotoxic activities of amides
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An efficient, functional group tolerable, and environmentally benign process for the synthesis of amides was developed. No activation reagents or scavengers are required in this process. Purification of desired compounds is easy, rapid, and cost-effective. This protocol provides an alternative for the combinatorial liquid-phase synthesis of amide libraries for drug discovery. By this method, a number of amides were prepared and evaluated in vitro against a panel of human tumor cell lines. Cinnamic amide IV-4 was found to be the most potent compound synthesized against four human tumor cell lines.
- Yang, Xiao-Dong,Zeng, Xiang-Hui,Zhao, Yuan-Hong,Wang, Xue-Quan,Pan, Zhi-Qiang,Li, Liang,Zhang, Hong-Bin
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scheme or table
p. 307 - 310
(2010/11/18)
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- Colorimetric detection of cyanide with N-nitrophenyl benzamide derivatives
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A series of structurally simple N-nitrophenyl benzamide derivatives have been developed as chemosensors toward cyanide in aqueous environment by taking advantage of the cyanide's strong affinity toward the acyl carbonyl carbon. The high selectivity of these compounds toward CN- makes it a practical system for monitoring CN- concentrations in aqueous samples.
- Sun, Yue,Wang, Guofeng,Guo, Wei
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experimental part
p. 3480 - 3485
(2009/08/15)
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- Synthesis and biological evaluation of thiobenzanilides as anticancer agents
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A series of novel thiobenzanilides is described. These compounds have been previously found to show strong biological activity such as antimycotic and antifungal actions. This is the first demonstration on the mechanism of the anticancer effect of thiobenzanilide agents (4a-c) on human melanoma A375 cells. The cytotoxic studies of compounds 4a-c on human melanoma A375 cells indicate thiobenzanilides induced higher cytotoxicity than nitrobenzanilides (3a-c). In addition, DNA flow cytometric analysis shows that 4a-c displays a significant G2/M phase arrest, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Because cellular apoptosis is often preceded by the disruption of mitochondrial function, the assessment of mitochondrial function in 4a-c-treated cells is worthy of investigation. Our data revealed that treatment of A375 cells with 4a-c resulted in the loss of mitochondrial membrane potential (ΔΨmt), a reduction of ATP synthesis, increased reactive oxygen species (ROS) generation, and activation of caspase-3. Thus, we suggest that 4a-c agents are potent inducers of cell apoptosis in A375 cells.
- Hu, Wan-Ping,Yu, Hsin-Su,Chen, Yan-Ren,Tsai, Yi-Min,Chen, Yin-Kai,Liao, Chao-Cheng,Chang, Long-Sen,Wang, Jeh-Jeng
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p. 5295 - 5302
(2008/12/20)
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- Novel polymer-supported coupling/dehydrating reagents for use in organic synthesis
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Two novel dehydrating reagents 3 and 4, based on a phosphonium anhydride and an oxyphosphonium triflate respectively, were prepared by reaction of the corresponding polymer-supported phosphine oxides with triflic anhydride. Reagent 3, based on the novel phosphorus heterocycle 1,1,3,3-tetraphenyl-2-oxa-1,3- diphospholanium bis(trifluoromethanesulfonate), was found to be a useful reagent for ester and amide formation. A wide range ofcoupling/dehydration-type reactions, such as ester, amide, anhydride, peptide, ether and nitrile formation, were performed in high yield using the more readily prepared polymer-supported triphenylphosphine ditrinate 4, which was easily recovered and re-used several times without loss of efficiency. With primary alcohols, both reagents 3 and 4 provide an alternative to the Mitsunobu reaction, where the use of azodicarboxylates and chromatography to remove the phosphine oxide by-product can be avoided. The use of 4-dimethylaminopyridine allowed the esterification of secondary alcohols with 4 to proceed in high yield but with retention of configuration.
- Fairfull-Smith, Kathryn E.,Jenkins, Ian D.,Longhlin, Wendy A.
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p. 1979 - 1986
(2007/10/03)
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- Amination of Nitrobenzene via Nucleophilic Aromatic Substitution for Hydrogen: Direct Formation of Aromatic Amide Bonds
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The first example of the direct formation of aromatic amide bonds via nucleophilic aromatic substitution for hydrogen is described.Thus, the reaction of benzamide, tetramethylammonium hydroxide dihydrate, and nitrobenzene under anaerobic conditions generates N-(4-nitrophenyl)benzamide (1) (98percent) and azoxybenzene (30percent) in isolated yields.In addition, other substituted benzamides and aliphatic amides are shown to function as nucleophiles in this reaction.A mechanism that is consistent with the simultaneous formation of anilide products and azoxybenzene which requires the oxidation of ?-complex intermediates by nitrobenzene initially generating nitrobenzene radical anions is proposed.By contrast, when the reaction is run under aerobic conditions, the formation of azoxybenzene is completely inhibited due to the trapping of nitroarene radicals by O2.The ability to prepare 1 in high yield and regioselectivity affords a novel route for the direct amination of nitrobenzene that does not require halogenated intermediates or auxiliary leaving groups.Accordingly, treatment of 1 with methanolic ammonia results in the aminolysis of the amide bond producing 4-nitroaniline and regenerates benzamide.
- Stern, Michael K.,Cheng, Brian K.
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p. 6883 - 6888
(2007/10/02)
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- Reaction of N-Aryl- and N-Alkyl-benzimidoyl Chlorides with Silver Nitrate
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N-Arylbenzimidoyl chlorides, in which the N-aryl group is unsubstituted at the ortho- and para-positions, react with AgNO3 to yield N-(nitroaryl)benzamides, in which the NO2 group resides in the ortho- or para-position.N-Arylbenzimidoyl chlorides, in which the N-aryl ring is 2,4,6-trisubstituted, react with AgNO3 to yield the corresponding N-aryl-N-nitrobenzamides.The formation of both types of product can be explained by the intermediacy of an O-nitro imidate.Spectroscopic and chemical evidence is presented for the formation of this intermediate in the reaction of N-(2,4,6-trisubstituted phenyl)benzimidoyl chlorides with AgNO3.Rearrangement of the O-nitro imidate is unimolecular and intramolecular.The rate of rearrangement is independent of the substituent in the C-aryl ring, but increases with the electon-withdrawing ability of the substituents in the N-aryl ring.A mechanism is proposed in which the imidoyl chloride reacts with AgNO3 to produce first a nitrilium ion which goes on to form an O-nitro imidate that subsequently rearranges via a homolytic cleavage of the O-NO2 bond.The ortho:para ratios of N-(nitroaryl)benzamides obtained in the present work indicate that O-nitro imidates are not responsible for the high 1/2ortho:para ratios sometimes observed in the nitration of anilides.N-Alkylbenzimidoyl chlorides react with AgNO3 to form the corresponding N-nitro- and N-nitrosobenzamides.The mechanism of formation of the N-alkyl-N-nitrobenzamide arises from a pathway analogous to that for N-aryl-N-nitrobenzamides, involving a nitrilium ion that gives rise to an O-nitro imidate.The evidence for the formation of the N-nitrosobenzamide points to an alternative reaction of the imidoyl chloride with AgNO3.One possible mechanism for this reaction is described.
- Iley, Jim,Carvalho, Emilia,Norberto, Fatima,Rosa, Eduarda
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p. 281 - 290
(2007/10/02)
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- Rearrangement of Imidoyl Nitrates to N-Nitro Amides: an Intramolecular O-to-N Migration of a Nitro Group
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Imidoyl nitrates, formed by the reaction of imidoyl chlorides with AgNO3, rearrange via a unimolecular, intramolecular mechanism probably involving homolytic fission of the O-N bond to yield N-nitro amides; migration of the nitro group in N-arylimidoyl nitrates to the ortho- and para-positions of the N-aryl ring does not involve a special ortho-directing effect.
- Carvalho, Emilia,Iley, Jim,Rosa, Eduarda
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p. 1249 - 1250
(2007/10/02)
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