- Hydrogenation of nitroaromatics to anilines catalyzed by air-stable arene ruthenium (II)–NNN pincer complexes
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A series of air-stable, phosphine-free arene ruthenium (II)–NNN pincer complexes (RuL, RuL1, RuL2 and RuL3) have been synthesized and characterized by spectroscopic and single-crystal X-ray analysis. Further, arene ruthenium (II)–NNN pincer complexes have been used as catalyst for hydrogenation of nitroaromatics into aniline in the presence of NaBH4 at room temperature. The catalytic process suggested highly chemo-selective nitroreduction with wide functional group tolerance.
- Pitchaimani, Jayaraman,Gunasekaran, Nanjappan,Anthony, Savarimuthu Philip,Moon, Dohyun,Madhu, Vedichi
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Read Online
- AROMATIC AMINE COMPOUND, CURING AGENT FOR EPOXY COMPOUND, CURABLE COMPOSITION, CURED PRODUCT, METHOD FOR PRODUCING CURED PRODUCT, AND METHOD FOR PRODUCING AROMATIC AMINE COMPOUND
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An aromatic amine compound capable of satisfactorily forming a cured product having exceptional alkali resistance by reaction with an epoxy compound; a curing agent for an epoxy compound, the curing agent including the aromatic amine compound; a curable composition including the curing agent for an epoxy compound; a cured product of the curable composition; a method for producing the cured product; and a method for producing the abovementioned aromatic amine compound. The aromatic amine compound has a structure such that a specific position in a central skeleton comprising a fused ring such as a fluorene ring is substituted with a side-chain group including two aromatic groups linked by a flexible bond such as an amide bond, at least one amino group is bonded to the end of the side-chain group, and the structure has no hydroxyl groups.
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Paragraph 0117
(2021/05/07)
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- Synthesis of CoFe2O4@Pd/Activated carbon nanocomposite as a recoverable catalyst for the reduction of nitroarenes in water
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Efficient reduction of nitro compounds into amines is an important industrial transformation. So, it is a great deal to design new catalysts for efficient reduction of the nitro compounds especially in water. In this work, a new magnetic Pd/activated carbon nanocomposite (CoFe2O4@Pd/AC) was synthesized via metal-impregnation-pyrolysis method. The CoFe2O4@Pd/AC was fully characterized by FT-IR, PXRD, FESEM, TEM, VSM, EDX-mapping and BET techniques. The results showed that CoFe2O4@Pd/AC is a highly reactive and easily recoverable magnetic catalyst for the reduction of the nitro compounds by using NaBH4 in water. For instance, aniline was obtained in high yield (99%) after 75 ?min at 25 ?C by using just 6 ?mg of the catalyst. In addition, CoFe2O4@Pd/AC was recovered by a simple magnetic decantation and it exhibits stable activity and remains intact during the catalytic process with no significant loss in activity (8 cycles).
- Hamadi, Hosein,Kazeminezhad, Iraj,Mohammadian, Sara
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- 2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
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Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2. This journal is
- Bayliss, Richard,Boxall, Kathy,Carbain, Benoit,Coxon, Christopher R.,Fry, Andrew M.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Harnor, Suzannah J.,Mas-Droux, Corine,Matheson, Christopher J.,Newell, David R.,Richards, Mark W.,Sivaprakasam, Mangaleswaran,Turner, David,Cano, Céline
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supporting information
p. 707 - 731
(2020/08/24)
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- Heteroleptic 1,4-Diazabutadiene Complexes of Ruthenium: Synthesis, Characterization and Utilization in Catalytic Transfer Hydrogenation
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Reaction of [Ru(trpy)Cl3] with 1,4-diazabutadienes (p-RC6H4N=C(H)-(H)C=NC6H4R-p; R = OCH3, CH3, H and Cl; abbreviated as L-R) in refluxing ethanol in the presence of triethylamine has afforded a family of complexes, isolated as perchlorate salts, of type [Ru(trpy)(L-R)Cl]ClO4 [depicted as complexes 1 (R = OCH3), 2 (R = CH3), 3 (R = H) and 4 (R = Cl)]. Crystal structures of complexes 1, 2 and 4 have been determined, and structure of complex 3 has been optimized by DFT method. The 1,4-diazabutadiene ligand in each complex is bound to ruthenium as a N,N-donor forming five-membered chelate. Complexes 1–4 catalyze transfer hydrogenation of aryl aldehydes to the corresponding alcohols with high (ca. 106) TON. They are also found to catalyze transfer hydrogenation of aryl ketones to corresponding secondary alcohols, but with much less efficiency. Catalytic transfer hydrogenation of nitroarenes to the corresponding amines has also been achieved.
- Saha, Rumpa,Mukherjee, Aparajita,Bhattacharya, Samaresh
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p. 4539 - 4548
(2020/11/30)
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- PARP (poly (ADP-ribose) polymerase)-1 and Tankyrase1/2 multi-target inhibitors as well as preparation method and application thereof
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The invention relates to the field of medicinal chemistry, in particular to PARP (poly (ADP-ribose) polymerase)-1 and Tankyrase1/2 multi-target inhibitors containing a 1(2H)-phthalazinone structure and shown as formula (I) in the description, a preparatio
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Paragraph 0044; 0046; 0047
(2018/09/08)
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- Hemozoin inhibiting 2-phenylbenzimidazoles active against malaria parasites
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The 2-phenylbenzimidazole scaffold has recently been discovered to inhibit β-hematin (synthetic hemozoin) formation by high throughput screening. Here, a library of 325,728 N-4-(1H-benzo[d]imidazol-2-yl)aryl)benzamides was enumerated, and Bayesian statistics used to predict β-hematin and Plasmodium falciparum growth inhibition. Filtering predicted inactives and compounds with negligible aqueous solubility reduced the library to 35,124. Further narrowing to compounds with terminal aryl ring substituents only, reduced the library to 18, 83% of which were found to inhibit β-hematin formation 100 μM and 50% parasite growth 2 μM. Four compounds showed nanomolar parasite growth inhibition activities, no cross-resistance in a chloroquine resistant strain and low cytotoxicity. QSAR analysis showed a strong association of parasite growth inhibition with inhibition of β-hematin formation and the most active compound inhibited hemozoin formation in P. falciparum, with consequent increasing exchangeable heme. Pioneering use of molecular docking for this system demonstrated predictive ability and could rationalize observed structure activity trends.
- L'abbate, Fabrizio P.,Müller, Ronel,Openshaw, Roxanne,Combrinck, Jill M.,de Villiers, Katherine A.,Hunter, Roger,Egan, Timothy J.
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p. 243 - 254
(2018/10/15)
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- TYK2 INHIBITORS, USES, AND METHODS FOR PRODUCTION THEREOF
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The present invention provides compounds useful as inhibitors of Tyrosine Kinase 2 (Tyk2), solid forms and compositions thereof, methods of producing the same, and methods of using the same in the treatment of Tyk2-mediated diseases.
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Paragraph 00231-00232
(2018/09/28)
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- Ultrasensitive near-infrared fluorescence-enhanced probe for in vivo nitroreductase imaging
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Nitroreductase (NTR) can be overexpressed in hypoxic tumors, thus the selective and efficient detection of NTR is of great importance. To date, although a few optical methods have been reported for the detection of NTR in solution, an effective optical probe for NTR monitoring in vivo is still lacking. Therefore, it is necessary to develop a near-infrared (NIR) fluorescent detection probe for NTR. In this study, five NIR cyanine dyes with fluorescence reporting structure decorated with different nitro aromatic groups, Cy7-1-5, have been designed and explored for possible rapid detection of NTR. Our experimental results presented that only a para-nitro benzoate group modified cyanine probe (Cy7-1) could serve as a rapid NIR fluorescence-enhanced probe for monitoring and bioimaging of NTR. The structure-function relationship has been revealed by theoretical study. The linker connecting the detecting and fluorescence reporting groups and the nitro group position is a key factor for the formation of hydrogen bonds and spatial structure match, inducing the NTR catalytic ability enhancement. The in vitro response and mechanism of the enzyme-catalyzed reduction of Cy7-1 have been investigated through kinetic optical studies and other methods. The results have indicated that an electro-withdrawing group induced electron-transfer process becomes blocked when Cy7-1 is catalytically reduced to Cy7-NH2 by NTR, which is manifested in enhanced fluorescence intensity during the detection process. Confocal fluorescence imaging of hypoxic A549 cells has confirmed the NTR detection ability of Cy7-1 at the cellular level. Importantly, Cy7-1 can detect tumor hypoxia in a murine hypoxic tumor model, showing a rapid and significant enhancement of its NIR fluorescence characteristics suitable for fluorescence bioimaging. This method may potentially be used for tumor hypoxia diagnosis.
- Li, Yuhao,Sun, Yun,Li, Jiachang,Su, Qianqian,Yuan, Wei,Dai, Yu,Han, Chunmiao,Wang, Qiuhong,Feng, Wei,Li, Fuyou
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supporting information
p. 6407 - 6416
(2015/06/02)
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- SULFONAMIDE COMPOUNDS AND THEIR USE AS STAT5 INHIBITORS
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The present disclosure relates to compounds having the Formula (Formula (I)) which are inhibitors of STAT5.
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Paragraph 00160; 00171-00172
(2015/12/17)
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- New process for the synthesis of aminaphtone
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The present invention concerns a new process for the synthesis of aminaphtone, which makes use of non-toxic solvents and reagents, under mild reaction and temperature conditions.
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Paragraph 0053; 0054; 0055
(2014/11/13)
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- PROCESS FOR THE SYNTHESIS OF AMINAPHTONE
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The present invention concerns a new process for the synthesis of aminaphtone, which makes use of non-toxic solvents and reagents, under mild reaction and temperature conditions. The aminaphtone obtained with the method of the present invention also has a purity of at least 98% in weight. The method comprises the following steps: a) epoxidating menadione 1 to provide epoxide 2, b) acidifying epoxide 2 to provide hydroxynaphthoquinone 3, c) esterifying between hydroxynaphthoquinone 3 and 4-aminobenzoyl chloride to obtain compound 4, and d) reducing compound 4 in the presence of a reducing agent in water to obtain aminaphtone.
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Paragraph 0069; 0070
(2014/11/11)
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- 3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents
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Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC90 value of 1 μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 μM, indicating its better safety profile.
- Yang, Jianzhong,Pi, Weiyi,Xiong, Li,Ang, Wei,Yang, Tao,He, Jun,Liu, Yuanyuan,Chang, Ying,Ye, Weiwei,Wang, Zhenling,Luo, Youfu,Wei, Yuquan
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supporting information
p. 1424 - 1427
(2013/03/14)
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- Synthesis of some new glutamine linked 2,3-disubstituted quinazolinone derivatives as potent antimicrobial and antioxidant agents
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A series of novel glutamine linked 2,3-disubstituted quinazolinone conjugates was synthesized from methyl anthranilate and different substituted acids and acid chlorides. The compounds 5a-l were prepared in good yields. All compounds were screened for their antibacterial activity against Gram-positive and Gram-negative bacteria and for antifungal activity against Candida albicans and Aspergillus flavus using paper disk diffusion technique. The minimum inhibitory concentrations of the compounds were also determined by agar streak dilution method. The compound 5b was found to exhibit the most potent in vitro anti-microbial activity. When tested for their antioxidant activity, compounds 5i and 5l showed potent radical scavenging activity, while compound 5g had moderate effect against 2,2-diphenyl-1-picrylhydrazyl, hydroxyl, nitric oxide, and superoxide radical scavenging assays. These results suggest that, the three quinazolinone analogs (5g, 5i, and 5l) could be considered as useful templates for future development to obtain more potent antioxidant agents.
- Prashanth,Revanasiddappa
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p. 2665 - 2676
(2013/07/26)
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- Preparation of functionalized indoles and azaindoles by the intramolecular copper-mediated carbomagnesiation of ynamides
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Variations on a theme: A mild and general intramolecular copper-mediated carbomagnesiation procedure for the synthesis of functionalized indoles as well as 4-, 5-, 6-, and 7-azaindoles starts from readily available ynamides. Subsequent reactions with various electrophiles provides polyfunctional N-heterocycles in good yields.
- Frischmuth, Annette,Knochel, Paul
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supporting information
p. 10084 - 10088
(2013/10/01)
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- Synthesis and Preliminary Biologic Evaluation of 5-Substituted-2-(4-substituted phenyl)-1,3-Benzoxazoles as A Novel Class of Influenza Virus A Inhibitors
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The diversity-oriented chemistry synthesis together with the random screening approach has permitted the discovery and optimization of novel antiviral lead compounds. In this paper, a series of novel 5-substituted-2-(4-substituted phenyl)-1,3-benzoxazoles was synthesized and evaluated for their in vitro anti-influenza A virus and anti-influenza B virus activity. The activity was monitored by the MTS assay in the Madin-Darby canine kidney cells. Compound 7h showed excellent inhibitory activity and selective index against A/H3N2 (EC50=37.03μm, SI>5), which were all higher than that of the reference drug oseltamivir (EC50>59.00μm, SI>1). However, no compound displays inhibitory activity against influenza B virus.
- Li, Zhenyu,Zhan, Peng,Naesens, Lieve,Vanderlinden, Evelien,Liu, Ailin,Du, Guanhua,De Clercq, Erik,Liu, Xinyong
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experimental part
p. 1018 - 1024
(2012/07/30)
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- Synthesis, biological evaluation and molecular docking studies of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan as potential antitumor agents
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A series of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan (2a-2s) have been synthesized to screen for FAK inhibitory activity. Compound 2p showed the most potent biological activity against HEPG2 cancer cell line (EC50 = 10.28 μg/mL
- Sun, Juan,Yang, Yu-Shun,Li, Wei,Zhang, Yan-Bin,Wang, Xiao-Liang,Tang, Jian-Feng,Zhu, Hai-Liang
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scheme or table
p. 6116 - 6121
(2011/10/31)
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- Synthesis and docking study of 2-phenylaminopyrimidine Abl tyrosine kinase inhibitors
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Six analogs of imatinib, an Abl kinase inhibitor clinically used as a first-line therapeutic agent for chronic myeloid leukaemia (CML), have been synthesized and characterized. And their potency as Abl kinase inhibitors have been screened by a robust virt
- Lü, Shuang,Luo, Qun,Hao, Xiang,Li, Xianchan,Ji, Liyun,Zheng, Wei,Wang, Fuyi
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experimental part
p. 6964 - 6968
(2012/01/05)
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- 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: Synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation
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A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]- benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2χv) in describing the antimicrobial activity of synthesized compounds (1-20).
- Yadav, Snehlata,Kumar, Pradeep,De Clercq, Erik,Balzarini, Jan,Pannecouque, Christophe,Dewan, Sharwan Kumar,Narasimhan, Balasubramanian
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scheme or table
p. 5985 - 5997
(2011/01/13)
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- QUINAZOLINONES AS PROLYL HYDROXYLASE INHIBITORS
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Quinazolinone compounds of formula (I) are described, which are useful as prolyl hydroxylase inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by prolyl hydroxylase activity. Thus, the compounds may be administered to treat, e.g., anemia, vascular disorders, metabolic disorders, and wound healing.
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Page/Page column 60
(2011/02/18)
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- Synthesis and pharmacological evaluation of novel 1-(2-(benzoyl- substituted-2-phenyl-1h-indol-5-carbony) hydrazinyloxy) vinyl nitrate derivatives as potent non-ulcerogenic, analgesic and anti-inflammatory agents
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Six derivatives of 1-(2-(benzoyl-(substituted)-2-phenyl-1H-indole-5- carbony) hydrazinyloxy) vinyl nitrate were synthesized and tested in vivo for anti-inflammatory, analgesic, and ulcerogenic properties. Synthesized compounds shown significant anti-inflammatory activity comparable to that of Diclofenac sodium in the carrageenan-induced rat paw edema test and all of the compounds were found to be equipotent to Diclofenac sodium in the acetic acid induced writhing analgesic model. Out of six derivatives two derivatives found to produce no ulceration in stomach specimen of rats; nitric oxide seems to contribute to their excellent safety profile which supports several endogenous GIT defense mechanisms, including increase in mucus, bicarbonate secretions, increase in mucosal blood flow, and inhibition of the activation of pro-inflammatory cells by which NO-Indomethacin protects GI mucosa.
- Mokale, Vinod J.,Raut, Mayuresh K.,Burange, Prashant J.,Dhoot, Navneet S.,Bhandari, Shashikant V.,Bothara, Kailash G.,Naik, Jitendra B.
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experimental part
p. 211 - 218
(2011/09/13)
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- Hansch analysis of substituted benzoic acid benzylidene/furan-2-yl-methylene hydrazides as antimicrobial agents
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A series of substituted hydrazide derivatives have been synthesized and screened for their in vitro antimicrobial activities against five representative microorganisms. The results of antimicrobial study indicated that the presence of electron withdrawing groups on the benzoic acid moiety improved antimicrobial activity. Further, the presence of heterocyclic ring furan does not improve the antimicrobial activity of substituted hydrazides. To understand the relationship between physicochemical parameters and antimicrobial activity of substituted hydrazide derivatives, QSAR investigation was performed by the development of one-target and multi-target models. The multi-target model was found to be effective in describing the antimicrobial activity of substituted hydrazides in comparison to the one-target models. Further, it indicated the importance of the topological parameter, valence third order molecular connectivity index (3χv) and the electronic parameter, energy of highest occupied molecular orbital (HOMO) in describing the antimicrobial activity of substituted hydrazides.
- Kumar, Pradeep,Narasimhan, Balasubramanian,Sharma, Deepika,Judge, Vikramjeet,Narang, Rakesh
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experimental part
p. 1853 - 1863
(2009/09/30)
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- Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action
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The related 3C and 3C-like proteinase (3Cpro and 3CLpro) of picornaviruses and coronaviruses, respectively, are good drug targets. As part of an effort to generate broad-spectrum inhibitors of these enzymes, we screened a library of inhibitors based on a halopyridinyl ester from a previous study of the severe acute respiratory syndrome (SARS) 3CL proteinase against Hepatitis A virus (HAV) 3Cpro. Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3Cpro with Kics of 120-240 nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3Cpro and SARS 3CLpro, confirming the identity of the expected products. Mass spectrometric analyses indicated that this hydrolysis proceeded via an acyl-enzyme intermediate. Modeling studies indicated that the halopyridinyl moiety of the inhibitor fits tightly into the S1-binding pocket, consistent with the lack of tolerance of the inhibitors to modification in this portion of the molecule. These compounds are among the most potent non-peptidic inhibitors reported to date against a 3Cpro.
- Huitema, Carly,Zhang, Jianmin,Yin, Jiang,James, Michael N.G.,Vederas, John C.,Eltis, Lindsay D.
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p. 5761 - 5777
(2008/12/21)
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- ANTIFUNGAL AGENTS
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Compounds of formula (I), and pharmaceutically acceptable salts thereof, may be used in therapy, for example as antifungal agents: (I) wherein: Rl, R2, R3, R4, R5, R6, R7, X and X1 are as defined herein. Certain compounds of formula (I) are also provided. Compounds of formula (T), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.
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Page/Page column 45
(2008/06/13)
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- Infrared and Nuclear Magnetic Resonance Properties of Benzoyl Derivatives of Five-membered Monoheterocycles and Determination of Aromaticity Indices
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Benzophenones, 2-benzoylthiophenes, 2-benzoylpyrroles, and 2-benzoylfurans, which have substituents at m- and p-positions of the benzoyl ring were prepared and their ir and nmr spectra were obtained in 0.1 M chloroform-d solution. The chemical shift values of each series were plotted against the Hammett substituent parameters to give good correlation, with the exception of the ortho-Hs and -Cs. The slopes as well as the differences in chemical shift gave sets of meaningful values for the indices of aromaticy.
- Jeon, Kyu Ok,Jun, Jung Ho,Yu, Ji Sook,Lee, Chang Kiu
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p. 763 - 771
(2007/10/03)
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- Synthesis and in Vitro Aldolase Reductase Inhibitory Activity of Compounds Containing an N-Acylglycine Moiety
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A number of N-benzoylglycines (6), N-acetyl-N-phenylglycines (7), N-benzoyl-N-phenylglycines (8), and tricyclic N-acetic acids (9-12) were synthesized as analogues of the N-acylglycine-containing aldolase reductase inhibitors alrestatin and 2-oxoquinoline-1-acetic acid.Derivatives of 6, which represent ring-simplified analogues of alrestatin, are very weak inhibitors of aldolase reductase obtained from rat lens, producing 50percent inhibition only at concentrations exceeding 100 μM.Compounds of series 7 were designed as ring-opened analogues of the 2-oxoquinolines.While this derivatives are more potent than compounds of series 6 (IC 50s of 6-80 μM), they are less active than the corresponding 2-oxoquinolines.Analogues of series 8 were designed as hybrid structures of both alrestatin and the 2-oxoquinoline-1-acetic acids.These compounds are substantially more potent than compounds of series 6 and 7 and display inhibitory activities comparable to or greater than alrestatin or the 2-oxoquinolines (IC 50s of 0.1-10 μM).Of the rigid analogues of 8, the most potent derivative is benzoxindol (12) with an IC 50 of 0.67 μM, suggesting that fusion of the two aromatic rings of 8 in a coplanar conformation may optimize affinity for aldose reductase in this series.
- DeRuiter, Jack,Swearingen, Blake E.,Wandrekar, Vinay,Mayfield, Charles A.
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p. 1033 - 1038
(2007/10/02)
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