- Design, synthesis, and biological evaluation of N-(3-cyano-1H-indol-5/6-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamides and 5-(6-oxo-1,6-dihydropyrimidin-2-yl)-1H-indole-3-carbonitriles as novel xanthine oxidase inhibitors
-
Xanthine oxidase (XO) has been an important target for the treatment of hyperuricemia and gout. The analysis of potential interactions of pyrimidinone and 3-cyano indole pharmacophores present in the corresponding reported XO inhibitors with parts of the XO active pocket indicated that they both can be used as effective fragments for the fragment-based design of nonpurine XO inhibitors. In this paper, we adopted the fragment-based drug design strategy to link the two fragments with an amide bond to design the type 1 compounds 13a–13w,14c, 14d, 14f, 14g, 14j, 14k, and 15g. Compound 13g displayed an evident XO inhibitory potency (IC50 = 0.16 μM), which was 52.3-fold higher than that of allopurinol (IC50 = 8.37 μM). For comparison, type 2 compounds 5-(6-oxo-1,6-dihydropyrimidin-2-yl)-1H-indole-3-carbonitriles (25c–25g) were also designed by linking the two fragments with a single bond directly. The results showed that compound 25c from the latter series displayed the best inhibitory potency (IC50 = 0.085 μM), and it was 98.5-fold stronger than that of allopurinol (IC50 = 8.37 μM). These results suggested that amide and single bonds were applicable for linking the two fragments together to obtain potent nonpurine XO inhibitors. The structure–activity relationship results revealed that hydrophobic groups at N-atom of the indole moiety were indispensable for the improvement of the inhibitory potency in vitro against XO. In addition, enzyme kinetics studies suggested that compounds 13g and 25c, as the most promising XO inhibitors for the two types of target compounds, acted as mixed-type inhibitors for XO. Moreover, molecular modeling studies suggested that the pyrimidinone and indole moieties of the target compounds could interact well with key amino acid residues in the active pocket of XO. Furthermore, in vivo hypouricemic effect demonstrated that compounds 13g and 25c could effectively reduce serum uric acid levels at an oral dose of 10 mg/kg. Therefore, compounds 13g and 25c could be potential and efficacious agents for the treatment of hyperuricemia and gout.
- Zhang, Bing,Duan, Yulin,Yang, Yuwei,Mao, Qing,Lin, Fengwei,Gao, Jun,Dai, Xiwen,Zhang, Peng,Li, Qiuhua,Li, Jinxin,Dai, Ronghua,Wang, Shaojie
-
-
- Trichloroisocyanuric acid (TCCA) and carboxamide interactions in TCCA/NaNO2 triggered nitration of pyrrole and indole in aqueous aprotic media: A kinetic correlation of solvent properties with reactivity
-
This study deals with the trichloroisocyanuric acid (TCCA) interactions with carboxamides like formamide (FMA), N,N′-dimethyl formamide (DMF), and N,N′-dimethyl acetamide (DMA) interactions during the nitration of heterocyclic compounds (HC) like pyrrole and indole in the presence of excess of [NaNO2] over the concentrations of all other reactants. All the reactions were performed in aqueous acetonitrile media containing carboxamide under acid-free conditions. Kinetics of the reactions revealed first order in [nitrating agent] and [HC] under otherwise similar conditions. To gain an insight into the reactive species and role of added carboxamide (FAA, DMF, DMA, etc.), the observed rates of the nitration reaction (log k) were analyzed as a function of (1/D), ([D ? 1]/[2D + 1]), mole fraction (nx), and volume (%) of carboxamide, 1/viscosity, density refractive index function), and Hildebrand solubility parameter plots. Linear regression analysis gave very good correlation coefficients (R2 values), which indicate the importance of several solvent properties in addition to the role of dielectric constant (D) of the reaction media. Multiple linear solvent energy relationships suggested by Abraham, Koppel, Palm, and Taft also afforded very good correlation coefficient (R2 values), showing the importance of cumulative effect of solvent properties. Besides these features, the negative entropies of activation (?S#) suggest greater solvation in the transition state. Isokinetic temperature (β) values for different protocols were very close to the experimental temperature range (303-323 K), indicating the importance of both enthalpy and entropy factors in controlling the reaction.
- Duguta, Govardhan,Muddam, Bhooshan,Kamatala, Chinna Rajanna,Utkoor, Umesh Kumar
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p. 164 - 186
(2020/10/02)
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- N-(indol-5-yl) bicyclic aromatic amide compound as well as preparation method and application thereof
-
The invention belongs to the field of medicines, and relates to an N-(indole-5-yl) bicyclic aromatic amide compound as well as a preparation method and application thereof. The structural general formula of the N-(indol-5-yl) bicyclic aromatic amide compound is shown in the specification. A pharmaceutical composition comprises the N-(indol-5-yl) bicyclic aromatic amide compound, a pharmaceutically acceptable salt, a hydrate or a solvate of the N-(indol-5-yl) bicyclic aromatic amide compound, and a pharmaceutically acceptable carrier. The invention further discloses application of the N-(indol-5-yl) bicyclic aromatic amide compound or the pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition in preparation of anti-hyperuricemia and anti-gout drugs. Tests prove that the compound shows a good effect in an in-vitro xanthine oxidase inhibitory activity test. The preparation method provided by the invention is simple and feasible, relatively high in yield and easy for large-scale production.
- -
-
Paragraph 0044-0045
(2021/05/12)
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- N-(3-cyano-1H-indol-5-yl)isonicotinamide and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide derivatives: Novel amide-based xanthine oxidase inhibitors
-
Our previous work demonstrated that amide is an efficient linker to explore chemical space of xanthine oxidase (XO) inhibitors that are entirely different from febuxostat and topiroxostat. In this effort, with 3-cyano-1H-indol-5-yl as a key moiety, two series of amide-based XO inhibitors, N-(3-cyano-1H-indol-5-yl)isonicotinamides (2a-w) and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamides (3a-i), were designed and synthesized. The structure-activity relationship investigation identified N-(3-cyano-1-cyclopentyl-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (3i, IC50 = 0.62 μM) as the most promising compound, with 14.4-fold higher in vitro inhibitory potency than allopurinol (IC50 = 8.91 μM). Molecular simulations provided reasonable interaction modes for the representative compounds. Furthermore, in vivo activity evaluation demonstrated that compound 3i (oral dose of 12.8 mg/kg) has obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model. Cytotoxicity assay and ADME prediction also supported that 3i is an excellent lead for further exploration of amide-based XO inhibitors.
- Tu, Shun,Zhang, Ting-jian,Zhang, Yi,Zhang, Xu,Zhang, Zhen-hao,Meng, Fan-hao
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-
- Amide-based xanthine oxidase inhibitors bearing an N-(1-alkyl-3-cyano-1H-indol-5-yl) moiety: Design, synthesis and structure-activity relationship investigation
-
Our previous work identified a promising isonicotinamide based xanthine oxidase (XO) inhibitor, N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (1), and concluded that amide is an effective linker in exploring the XO inhibitor chemical space that is completely different from the five-membered ring framework of febuxostat and topiroxostat. Indole, an endogenous bioactive substance and a popular drug construction fragment, was involved in the structural optimization campaign of the present effort. After the installation of some functional groups, N-(1-alkyl-3-cyano-1H-indol-5-yl) was generated and employed to mend the missing H-bond interaction between the 3′-cyano of 1 and Asn768 residue of XO by shortening their distance. In this context, eight kinds of heterocyclic aromatic amide chemotypes were rationally designed and synthesized to investigate the structure-activity relationship (SAR) of amide-based XO inhibitors. The optimized compound a6 (IC50 = 0.018 μM) exhibits 17.2-fold improved potency than the initial compound 1 (IC50 = 0.31 μM). Its potency is comparable to that of topiroxostat (IC50 = 0.013 μM). Molecular docking and molecular dynamics studies proved the existence of the stable H-bond between the cyano group and the Asn768 residue. Moreover, oral administration of a6 (11.8 mg/kg) could effectively reduce serum uric acid levels in an acute hyperuricemia rat model. Liver microsomal stability assay illustrated that compound a6 possesses well metabolic stability in rat liver microsomes. However, the in vivo potency of a6 was much lower than that of topiroxostat, which may be explained by the poor absorption found in the parallel artificial membrane permeability assay (PAMPA). In addition, 6a has non-cytotoxicity against normal cell lines MCF10A and 16HBE. Taken together, this work culminated in the identification of compound 6a as an excellent lead for further exploration of amide-based XO inhibitors.
- Zhang, Ting-jian,Tu, Shun,Zhang, Xu,Wang, Qiu-yin,Hu, Sen-sen,Zhang, Yi,Zhang, Zhen-hao,Wang, Zhao-ran,Meng, Fan-hao
-
-
- N-indole-1,6-dihydropyrimidine-4-carboxamide derivative as well as preparation method and application thereof
-
The invention relates to an N-indole-1,6-dihydropyrimidine-4-carboxamide derivative as well as a preparation method and application thereof, belonging to the technical field of medicines. According to the invention, amide is innovatively applied as a connecting fragment in the design of a non-purine xanthine oxidase inhibitor, and the N-indole-1,6-dihydropyrimidine-4-carboxamide derivative is synthesized. An in-vitro xanthine oxidase inhibitory activity test is carried out on the designed derivative by adopting an ultraviolet spectrophotometric method, and the prepared derivative shows obvious xanthine oxidase inhibitory activity. In an acute hyperuricemia rat model test, the derivative can significantly reduce the uric acid level of serum, and thus has good in-depth research value as the novel xanthine oxidase inhibitor.
- -
-
Paragraph 0068-0069
(2021/07/28)
-
- Design and Synthesis of Pyrano[3,2-b]indolones Showing Antimycobacterial Activity
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Latent Mycobacterium tuberculosis infection presents one of the largest challenges for tuberculosis control and novel antimycobacterial drug development. A series of pyrano[3,2-b]indolone-based compounds was designed and synthesized via an original eight-step scheme. The synthesized compounds were evaluated for their in vitro activity against M. tuberculosis strains H37Rv and streptomycin-starved 18b (SS18b), representing models for replicating and nonreplicating mycobacteria, respectively. Compound 10a exhibited good activity with MIC99 values of 0.3 and 0.4 μg/mL against H37Rv and SS18b, respectively, as well as low toxicity, acceptable intracellular activity, and satisfactory metabolic stability and was selected as the lead compound for further studies. An analysis of 10a-resistant M. bovis mutants disclosed a cross-resistance with pretomanid and altered relative amounts of different forms of cofactor F420 in these strains. Complementation experiments showed that F420-dependent glucose-6-phosphate dehydrogenase and the synthesis of mature F420 were important for 10a activity. Overall these studies revealed 10a to be a prodrug that is activated by an unknown F420-dependent enzyme in mycobacteria.
- Monakhova, Natalia,Korduláková, Jana,Vocat, Anthony,Egorova, Anna,Lepioshkin, Alexander,Salina, Elena G.,Nosek, Jozef,Repková, Eva,Zemanová, Júlia,Jurdáková, Helena,Górová, Renáta,Roh, Jaroslav,Degiacomi, Giulia,Sammartino, José Camilla,Pasca, Maria Rosalia,Cole, Stewart T.,Miku?ová, Katarína,Makarov, Vadim
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-
- Synthesis and in Vitro Evaluation of Novel 5-Nitroindole Derivatives as c-Myc G-Quadruplex Binders with Anticancer Activity
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Lead-optimization strategies for compounds targeting c-Myc G-quadruplex (G4) DNA are being pursued to develop anticancer drugs. Here, we investigate the structure-activity- relationship (SAR) of a newly synthesized series of molecules based on the pyrrolidine-substituted 5-nitro indole scaffold to target G4 DNA. Our synthesized series allows modulation of flexible elements with a structurally preserved scaffold. Biological and biophysical analyses illustrate that substituted 5-nitroindole scaffolds bind to the c-Myc promoter G-quadruplex. These compounds downregulate c-Myc expression and induce cell-cycle arrest in the sub-G1/G1 phase in cancer cells. They further increase the concentration of intracellular reactive oxygen species. NMR spectra show that three of the newly synthesized compounds interact with the terminal G-quartets (5′- and 3′-ends) in a 2 : 1 stoichiometry.
- Nimbarte, Vijaykumar D.,Wirmer-Bartoschek, Julia,Gande, Santosh L.,Alshamleh, Islam,Seibert, Marcel,Nasiri, Hamid Reza,Schnütgen, Frank,Serve, Hubert,Schwalbe, Harald
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p. 1667 - 1679
(2021/03/24)
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- Molecular iodine mediated oxidative cleavage of the C-N bond of aryl and heteroaryl (dimethylamino)methyl groups into aldehydes
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The oxidative cleavage of the C-N bond of aryl and heteroaryl (dimethylamino)methyl groups is achieved by employing molecular iodine as a mild oxidizing agent under ambient conditions in the presence of a mild base. The important reaction of C3 formylation of free NH and substituted indoles containing various substituents is accomplished from the corresponding Mannich bases. This methodology can also be extended for the synthesis of aryl and other heteroaryl aldehydes and ketones. Furthermore, the usefulness of the method is successfully demonstrated on a gram scale.
- Mandrekar, Ketan S.,Tilve, Santosh G.
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supporting information
p. 4152 - 4155
(2021/03/15)
-
- SMALL MOLECULE DIRECT INHIBITORS OF KEAP1-NRF2 PROTEIN-PROTEIN INTERACTION
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This patent document diclsoes novel compounds and methods of preventing or treating diseases or conditions related to Keapl-Nrf2 interaction activity by use of the novel compounds. As direct inhibitors of Keapl-Nrf2 interaction, the compounds disclosed herein are more specific and free of various undesirable effects than existing indirect inhibitors, and are potential dmg candidates of chemopreventive and therapeutic agents for treatment of various diseases or conditions involving oxidative stress and/or inflammation, including but not limited to cancers, diabetes, Alzheimer's, Parkinson's, and inflammatory bowel disease including ulcerative colitis.
- -
-
Paragraph 0492-0493
(2020/07/31)
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- Ferric Chloride Catalyzed 1,3-Rearrangement of (Phenoxymethyl)heteroarenes to (Heteroarylmethyl)phenols
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A highly useful and robust method to (heteroarylmethyl)phenols, derivatives of arylheteroarylmethanes, was developed based on iron(III)-catalyzed 1,3-rearrangement of (phenoxymethyl)heteroarenes. It features cheap catalyst, mild reaction conditions, short
- Tang, Yingzhan,Zhuang, Kaitong,Zhang, Xinhang,Xie, Fukai,Yang, Lu,Lin, Bin,Cheng, Maosheng,Li, Dan,Liu, Yongxiang
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p. 3441 - 3451
(2020/06/01)
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- Access to Polycyclic Sulfonyl Indolines via Fe(II)-Catalyzed or UV-Driven Formal [2 + 2 + 1] Cyclization Reactions of N-((1H-indol-3-yl)methyl)propiolamides with NaHSO3
-
A variety of structurally novel polycyclic sulfonyl indolines have been synthesized via FeCl2-catalyzed or UV-driven intramolecular formal [2 + 2 + 1] dearomatizing cyclization reactions of N-(1H-indol-3-yl)methyl)propiolamides with NaHSO3 in an aqueous medium. The reactions involve the formation of one C-C bond and two C-S bonds in a single step.
- Lu, Lin,Luo, Chenguang,Peng, Hui,Jiang, Huanfeng,Lei, Ming,Yin, Biaolin
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supporting information
p. 2602 - 2605
(2019/04/30)
-
- Synthesis of 3-Formylindoles via Electrochemical Decarboxylation of Glyoxylic Acid with an Amine as a Dual Function Organocatalyst
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A new method for 3-formalytion of indoles has been developed through electrochemical decarboxylation of glyoxylic acid with the amine as a dual function organocatalyst. The amine facilitated both the electrochemical decarboxylation and the nucleophilic reaction efficiently, whose loading can be as low as 1 mol %. This protocol has a broad range of functional group tolerance under ambient conditions. The gram-scale experiment has shown great potential in the synthetic application of this strategy.
- Lin, Dian-Zhao,Huang, Jing-Mei
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supporting information
p. 5862 - 5866
(2019/08/26)
-
- Novel 3,5-di-substituted 1H-indole derivative and synthesis and application thereof
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The invention discloses a novel 3,5-di-substituted 1H-indole derivative and synthesis and application thereof. The structural formula of the novel 3,5-di-substituted 1H-indole derivative is shown in formula 11, in the formula, R is selected from halogen, C1-C6 methyl, C1-C6 methoxyl, -OH, -COOH, -SO3H or -SO2NH2. The invention further provides a method for preparing the compound. The method has eight steps, the reaction yield of every step is higher than 60%, the reaction yields of four of the eight steps are higher than 90%, and the purities of all compounds are greater than 95%, and conformto purity required for later-period anti-tumor cell activity test. The prepared compound 11a-11h has good inhibition activity to pancreatic cell lines BxPC-3, wherein the activity of the compound as shown in formula 11 e is the best, IC50 reaches up to 2.28 mu mol/L, and the compound hardly has toxic or side effects to normal cells of people.
- -
-
Paragraph 0047-0050
(2018/04/28)
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- Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase
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Ribonucleotide reductase (RR), an established cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR reversibly. We herein report the synthesis and biochemical characterization of 25 distinct analogs. We designed each analog through docking to the C-site of hRR based on our 2.7 ? X-ray crystal structure (PDB ID: 5TUS). Broad tolerance to minor structural variations preserving inhibitory potency is observed. E-3f (82% yield) displayed an in vitro IC50 of 5.3 ± 1.8 μM against hRR, making it the most potent in this series. Kinetic assays reveal that E-3a, E-3c, E-3t, and E-3w bind and inhibit hRR through a reversible and competitive mode. Target selectivity toward the R1 subunit of hRR is established, providing a novel way of inhibition of this crucial enzyme.
- Huff, Sarah E.,Mohammed, Faiz Ahmad,Yang, Mu,Agrawal, Prashansa,Pink, John,Harris, Michael E.,Dealwis, Chris G.,Viswanathan, Rajesh
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supporting information
p. 666 - 680
(2018/02/16)
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- Selective nickel-catalyzed dehydrogenative-decarboxylative formylation of indoles with glyoxylic acid
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Herein we present a new strategy for the dehydrogenative-decarboxylative coupling of indoles with glyoxylic acid. A broad range of indoles were transformed into the corresponding 3-formylindoles in moderate to good yields and excellent functional group tolerance. Notably, no N-formylation product was detected under our conditions.
- Yin, Zhiping,Wang, Zechao,Wu, Xiao-Feng
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supporting information
p. 3707 - 3710
(2018/05/31)
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- Method for synthesizing indole -3 - formaldehyde compounds (by machine translation)
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The invention relates to a synthetic indole - 3 - formaldehyde compounds, which belongs to the technical field of organic synthesis. The invention will be indole compound, hexamethylene tetramine, crystalline aluminum trichloride, N, N - dimethyl formamide in proportion in 120 °C reaction under the condition of 1 - 20 the H, then filtered, washing, filtering, concentrating, column chromatography purification and other after-treatment technology, make the refined indole - 3 - formaldehyde compound. The invention overcomes the indole - 3 - benzaldehyde compound of preparation need to use not stabilized peroxide, and for a long time under the high temperature reaction of the defect. And the invention uses the advantages of simple equipment, product yield is high, the resulting yield of a target product can be up to 94%. In addition, the invention relates to a low reaction conditions, less catalyst levels, low energy consumption, the post treatment process is simple and easy to use, without the need of using a high dosage of acid or alkali, post-processing the solvent can be recovered and recycled, industrial "three wastes" is discharged little, suitable for large-scale production. (by machine translation)
- -
-
Paragraph 0041-0044; 0126-0129
(2018/08/28)
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- Diamine monomer containing N-pyrimidinyl indole structure and preparation method thereof
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The invention discloses a diamine monomer containing an N-pyrimidinyl indole structure and a preparation method thereof. The preparation method specifically comprises the following steps of enabling a compound A, a nitrophenylboronic acid compound, silver trifluoroacetate and a catalyst [RhCp*C12]2 to react in methanol, so as to obtain a nitro compound B; under the protection of N2, dissolving the nitro compound B in dimethyl sulfoxide, under conditions of active iron powder and acetic acid, refluxing, and carrying out a reaction, and reducing nitro to amino, so that the diamine monomer C containing the N-pyrimidinyl indole structure is obtained. The diamine monomer containing the N-pyrimidinyl indole structure, which is provided by the invention, is simple in preparation method, easy in the control of a reaction process, further, is higher in yield, can be used as a diamine monomer for synthesizing polyimide, and has potential application values in special fields of high temperature resistance, flexible display substrates and the like.
- -
-
Paragraph 0130; 0131
(2018/03/24)
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- Iron-Catalyzed C3-Formylation of Indoles with Formaldehyde and Aqueous Ammonia under Air
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An efficient iron-catalyzed C3-selective formylation of free (N-H) or N-substituted indoles was developed by employing formaldehyde and aqueous ammonia, with air as the oxidant. This new method gave 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this procedure for catalytic formylation of indoles can be applied to gram-scale syntheses.
- Wang, Qing-Dong,Zhou, Bin,Yang, Jin-Ming,Fang, Dong,Ren, Jiangmeng,Zeng, Bu-Bing
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supporting information
p. 2670 - 2674
(2017/10/06)
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- Iodine-catalyzed C3-formylation of indoles using hexamethylenetetramine and air
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An efficient iodine-catalyzed chemoselective 3-formylation of free (N–H) and N-substituted indoles was achieved by using hexamethylenetetramine (HMTA) in the presence of activated carbon under air atmosphere. This new method could provide 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this catalytic formylation of indoles procedure can be applied to gram-scale synthesis.
- Wang, Qing-Dong,Yang, Jin-Ming,Fang, Dong,Ren, Jiangmeng,Zeng, Bu-Bing
-
supporting information
p. 2877 - 2880
(2017/07/11)
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- Facile Installation of 2-Reverse Prenyl Functionality into Indoles by a Tandem N-Alkylation-Aza-Cope Rearrangement Reaction and Its Application in Synthesis
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An unprecedented tandem N-alkylation-ionic aza-Cope (or Claisen) rearrangement-hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N-alkylation and subsequent microwave-irradiated ionic aza-Cope rearrangement-hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2-reverse quaternary-centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza-Cope rearrangement reaction proceeds highly regioselectively to give the quaternary-centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3-methylene-2,3-dihydro-1Hindole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2-reverse prenylated indoles, such as indolines, indolefused sultams and lactams, and the natural product bruceolline D.
- Chen, Xiaobei,Fan, Huaqiang,Zhang, Shilei,Yu, Chenguang,Wang, Wei
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supporting information
p. 716 - 723
(2016/01/12)
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- Regioselective hydroarylation reactions of C3 electrophilic N-acetylindoles activated by FeCl3: An entry to 3-(Hetero)arylindolines
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A method for the direct and rare umpolung of the 3 position of indoles is reported. The activation of N-acetylindole with iron(III) chloride allows the C-H addition of aromatic and heteroaromatic substrates to the C2-C3 double bond of the indole nucleus to generate a quaternary center at C3 and leads regioselectively to 3-arylindolines. Optimization, scope (50 examples), practicability (gram scale, air atmosphere, room temperature), and mechanistic insights of this process are presented. Synthetic transformations of the indoline products into drug-like compounds are also described.
- Beaud, Rodolphe,Guillot, Regis,Kouklovsky, Cyrille,Vincent, Guillaume
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supporting information
p. 7492 - 7500
(2014/06/23)
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- I2-mediated C3-formylation of indoles by tertiary amine and H2O
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An I2-promoted 3-formylation of free (N-H) and N-substituted indoles with tetramethylethylenediamine (TMEDA) and H2O as the carbonyl source is achieved, providing 3-formylindole in moderate to excellent yields with good functional gr
- Zhang, Bo,Liu, Bin,Chen, Jianbin,Wang, Jiehui,Liu, Miaochang
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supporting information
p. 5618 - 5621
(2014/12/11)
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- Nanomolar e-selectin antagonists with prolonged half-lives by a fragment-based approach
-
Selectins, a family of C-type lectins, play a key role in inflammatory diseases (e.g., asthma and arthritis). However, the only millimolar affinity of sialyl Lewisx (sLex), which is the common tetrasaccharide epitope of all physiological selectin ligands, has been a major obstacle to the development of selectin antagonists for therapeutic applications. In a fragment-based approach guided by NMR, ligands binding to a second site in close proximity to a sLex mimic were identified. A library of antagonists obtained by connecting the sLex mimic to the best second-site ligand via triazole linkers of different lengths was evaluated by surface plasmon resonance. Detailed analysis of the five most promising candidates revealed antagonists with KD values ranging from 30 to 89 nM. In contrast to carbohydrate-lectin complexes with typical half-lives (t1/2) in the range of one second or even less, these fragment-based selectin antagonists show t1/2 of several minutes. They exhibit a promising starting point for the development of novel anti-inflammatory drugs.
- Egger, Jonas,Weckerle, Celine,Cutting, Brian,Schwardt, Oliver,Rabbani, Said,Lemme, Katrin,Ernst, Beat
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supporting information
p. 9820 - 9828
(2013/07/26)
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- Synthesis and quantitative structure-activity relationship (QSAR) study of novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives as nematicidal agents
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In continuation of our program aimed at the discovery and development of natural-product-based pesticidal agents, 54 novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives were prepared, and their structures were well characterized by 1
- Che, Zhiping,Zhang, Shaoyong,Shao, Yonghua,Fan, Lingling,Xu, Hui,Yu, Xiang,Zhi, Xiaoyan,Yao, Xiaojun,Zhang, Rui
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p. 5696 - 5705
(2013/07/26)
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- Discovery of a highly selective FLT3 kinase inhibitor from phenotypic cell viability profiling
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We discovered a novel molecular framework 4 containing a heterobiaryl pyrazolopyridine moiety as a selective FLT3 kinase inhibitor from phenotype-based viability profiling. Compound 4g showed outstanding selectivity in cellular cytotoxicity against MV-4-11 leukemic cells via the induction of apoptosis. The hypothesis-driven deconvolution elucidated that compound 4g selectively blocked the phosphorylation of FLT3 and its downstream effectors, such as ERK and STAT5, only in MV-4-11 cells. The inhibitory effect of 4g on in vitro enzyme function and FLT3 phosphorylation in cells proved that FLT3 kinase is a direct molecular target of 4g. Finally, the kinase activity profiling of 4g verified its excellent selectivity toward FLT3 over 40 representative kinases, including the receptor tyrosine kinase (RTK) family. The Royal Society of Chemistry 2013.
- Lee, Sanghee,Jo, Ala,Park, Seung Bum
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p. 228 - 232
(2013/03/14)
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- Deformylation of indole and azaindole-3-carboxaldehydes using anthranilamide and solid acid heterogeneous catalyst via quinazolinone intermediate
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The deformylation of indole and azaindole-3-carboxaldehydes was achieved in the presence of anthranilamide and a solid acid heterogeneous catalyst under reflux conditions in 25-90% yield. The reaction proceeds via quinazolinone intermediate, which undergoes acid catalyzed cleavage to form deformylated product.
- Yadav, Rammohan R.,Battini, Narsaiah,Mudududdla, Ramesh,Bharate, Jaideep B.,Muparappu, Nagaraju,Bharate, Sandip B.,Vishwakarma, Ram A.
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experimental part
p. 2222 - 2225
(2012/05/20)
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- E-SELECTIN ANTAGONISTS
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Compounds, compositions and methods are provided for inhibiting in vitro and in vivo processes mediated by E-selectin binding. More specifically, particular glycomimetic compounds are described, wherein the compounds are E- selectin antagonists.
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Page/Page column 38
(2012/04/04)
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- Antifungal agents. Part 3: Synthesis and antifungal activities of 3-acylindole analogs against phytopathogenic fungi in vitro
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To find more potent antifungal compounds, twenty 3-acylindole analogs were synthesized and bio-evaluated for their antifungal activities against seven phytopathogenic fungi. Structure-activity relationships investigations revealed that 4- or 6-methyl and 3-acetyl or propionyl groups were the important structural properties of 3-acylindoles for the activities. Especially 4-methyl-3-propionylindole, 12, displayed the more potent activities than hymexazol, a commercially available agricultural fungicide, and might be considered as a new promising lead candidate for further design and synthesis of agricultural fungicides.
- Xu, Hui,Bin Yang, Wen,Wang, Qin
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experimental part
p. 864 - 868
(2012/06/29)
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- A fragment-based in situ combinatorial approach to identify high-affinity ligands for unknown binding sites
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[Figure Presented] In the lead: The title method for the identification of ligands is particularly useful for binding sites where little or no structural information is available. In a fragment-based approach, a suitable pair of first- and second-site ligands is identiled by NMR experiments. By applying a receptor-mediated in situ combinatorial approach, the two ligands are then linked to generate a new high-affinity lead structure (see picture).
- Shelke, Sachin V.,Cutting, Brian,Jiang, Xiaohua,Koliwer-Brandl, Hendrik,Strasser, Daniel S.,Schwardt, Oliver,Kelm, Soerge,Ernst, Beat
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supporting information; experimental part
p. 5721 - 5725
(2010/11/02)
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- Synthesis of 4-, 5-, 6-, and 7-azidotryptamines
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Synthesis of azidotryptamines from commercially available nitroindoles via the corresponding amino tryptamines in good overall yields (15-38%) is presented.
- Friedrich, Anne,Br?se, Stefan,O'Connor, Sarah E.
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supporting information; body text
p. 75 - 76
(2009/04/14)
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- An efficient one-step synthesis of heterobiaryl pyrazolo[3,4-u] pyridines via indole ring opening
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A mild one-step synthetic method to access privileged heterobiaryl pyrazolo[3,4-b]pyridines from indole-3-carboxaldehyde derivatives and a variety of aminopyrazoles has been developed. This novel method constructs heterobiaryls with the wide scope of substrate generality and excellent regioselectivity via indole ring opening.
- Lee, Sanghee,Park, Seung Bum
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supporting information; experimental part
p. 5214 - 5217
(2010/03/04)
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- 1H-Pyrido[3,4-B]indol-1-one and 2,3,4,9-Tetrahydro-1H-Beta-Carbolin-1-one Derivatives
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A compound represented by formula (I) wherein the lines between carbon 3 and carbon 4; and between carbon 4 and carbon 10, represent a single or double bond, R, R1, R2, R3, R4, and R5 are as defined i
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Page/Page column 16
(2009/01/24)
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- (1-Nosyl-5-nitroindol-3-yl)methyl ester: A novel protective group for carboxylic acids
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(Chemical Equation Presented) The usefulness of (1-nosyl-5-nitroindol-3-yl) methyl esters as a novel protective group for carboxylic acid is fully demonstrated. The novel protective group is stable under a broad range of conditions and can easily be deprotected under the mild conditions used for removal of the nosyl (Ns) group. It is orthogonal to the existing protective groups for carboxylic acids such as t-butyl and allyl esters.
- Nishimura, Takuya,Yamada, Kouhei,Takebe, Tohru,Yokoshima, Satoshi,Fukuyama, Tohru
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supporting information; experimental part
p. 2601 - 2604
(2009/05/26)
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- Methylen-oxindole derivatives compositions and tyrosine kinase inhibition therewith
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The invention provides new methylen-indole derivatives of formula (I) STR1 wherein R is a group STR2 in which R4 is hydrogen, hydroxy, C1 -C6 alkoxy, C2 -C6 alkanoyloxy, carboxy, nitro or NHR7, wherein R7 is hydrogen or C1 -C6 alkyl; R5 is hydrogen, C1 -C6 alkyl or halogen; and R6 is hydrogen or C1 -C6 alkyl; n is zero, 1 or 2; R1 is hydrogen, C1 -C6 alkyl or C2 -C6 alkanoyl; R2 is hydrogen, C1 -C6 alkyl, halogen, cyano, carboxyl, nitro or --NHR7 in which R7 is as defined above; R3 is hydrogen, C1 -C6 alkyl or C2 -C6 alkanoyl; and the pharmaceutically acceptable salts thereof; and wherein, when, at the same time, R2 is hydrogen, C1 -C6 alkyl, halogen or cyano and R3 is hydrogen, R1 and n being as defined above, then at least one of R4, R5 and R6 is other than hydrogen, which are useful as tyrosine kinase inhibitors.
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- STUDIES ON THE SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF 5-(3'-INDOLAL)-2-THIOHYDANTOIN DERIVATIVES AS ALDOSE REDUCTASE ENZYME INHIBITORS
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A new series of 5-(3'-indolal)-2-thiohydantoin derivatives was synthesized and tested for the ability to inhibit bovine lens aldose reductase (AR) enzyme.The compounds were prepared by condensation of substituted indole-3-aldehyde derivatives with 2-thiohydantoin.The capacity of inhibiting the semi-purified bovine lens enzyme in vitro was observed for several of the compounds tested.One of them was found to be effective in reducing the enzyme activity compared with a corresponding well-known AR inhibitor.
- Bueyuekbingoel, Erdem,Suezen, Sibel,Klopman, Gilles
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p. 443 - 448
(2007/10/02)
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