- Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer
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Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.
- Wang, Lei,Fang, Kun,Cheng, Junfei,Li, Yu,Huang, Yahui,Chen, Shuqiang,Dong, Guoqiang,Wu, Shanchao,Sheng, Chunquan
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p. 696 - 713
(2020/02/04)
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- Synthesis method for preparing 2-substituted indole derivative
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The invention relates to a synthesis method for preparing a 2-substituted indole derivative. The method includes the following steps: mixing aromatic amine compounds (I), ketone compounds (II) and a drying agent in an organic solvent; adding a palladium catalyst; and reacting in an aerobic weak acid environment to prepare the indole compounds (III). (I), (II) and (III) are as shown in the specification, wherein R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted phenyl, pyridyl and heterocyclic aryl; (I) can be pyridylamine, pyrimidylamine, pyridazinam or pyrazinamide which may further be substituted or unsubstituted; and the substituents are selected fromone or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, amino; and R2 is selected from C1-C6 alkyl, formate groups or C1-C6 alkylamide groups.
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Paragraph 0115-0118
(2019/05/28)
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- 5-Bromo-1-(4-chlorobenzyl)-1h-indole-2-carboxamides as new potent antibacterial agents
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Ten 5-bromoindole-2-carboxamides were synthesized, characterized and evaluated for antibacterial activity against pathogenic Gram-negative bacteria Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Salmonella Typhi using gentamicin and ciprofloxacin as internal standards. Compounds 7a-c, 7g and 7h exhibit high antibacterial activity with a minimum inhibitory concentration (MIC) of 0.35-1.25 μg/mL. Compounds 7a-c exhibit antibacterial activities that are higher than those of the standards against E. coli and P. aeruginosa.
- Mane, Yogesh D.,Patil, Smita S.,Biradar, Dhanraj O.,Khade, Bhimrao C.
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p. 327 - 332
(2018/11/27)
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- Carboxylic Acid-Promoted Single-Step Indole Construction from Simple Anilines and Ketones via Aerobic Cross-Dehydrogenative Coupling
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The cross-dehydrogenative coupling (CDC) reaction is an efficient strategy for indole synthesis. However, most CDC methods require special substrates, and the presence of inherent groups limits the versatility for further transformation. A carboxylic acid-promoted aerobic catalytic system is developed herein for a single-step synthesis of indoles from simple anilines and ketones. This versatile system is featured by the broad substrate scope and the use of ambient oxygen as an oxidant and is convenient and economical for both laboratory and industry applications. The existence of the labile hydrogen at C-3 and the highly transformable carbonyl at C-2 makes the indoles versatile building blocks for organic synthesis in different contexts. Computational studies based on the density functional theory (DFT) suggest that the rate-determining step is carboxylic acid-assisted condensation of the substrates, rather than the functionalization of aryl C-H. Accordingly, a pathway via imine intermediates is deemed to be the preferred mechanism. In contrast to the general deduction, the in situ formed imine, instead of its enamine isomer, is believed to be involved in the first ligand exchange and later carbopalladation of the α-Me, which shed new light on this indolization mechanism.
- Ren, Long,Nan, Guanglei,Wang, Yongcheng,Xiao, Zhiyan
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p. 14472 - 14488
(2018/11/23)
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- Design, synthesis, and antimicrobial activity of novel 5-substituted indole-2-carboxamide derivatives
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Abstract: A series of novel, bioactive 5-substituted indole-2-carboxamide derivatives (10a–t and 14a–k) are synthesized by the coupling of 5-substituted indole-2-carboxylic acids with various amines in the presence of EDC HCl/HOBt in DMF/CH2Cl2 as a solvent. In vitro, antibacterial activity of titled compounds against pathogenic bacteria Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and antifungal activity against pathogenic fungi Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, and Candida parapsilosis are evaluated using gentamicin/ciprofloxacin and fluconazole/oxiconazole as standard drugs, respectively. The majority of the synthesized compounds exhibited good antibacterial activity, but surprisingly none showed antifungal activity. Compounds 10c, 10d, 10i, 10j, 10l–n, 14g, 14h, 14i, 14j, and 14k exhibited high inhibitory antibacterial activity with MIC values in the range of 0.12–6.25?μg/mL. Interestingly, compounds 14i, 14j, and 14k exhibited excellent antibacterial activity against K. pneumoniae and E. coli compare to synthesized compound. All the experimental results promote us to consider this series as a starting point for the development of novel and more potent antibacterial agents in the future. Graphical Abstract: [Figure not available: see fulltext.]
- Mane, Yogesh D.,Sarnikar, Yuvaraj P.,Surwase, Santosh M.,Biradar, Dhanraj O.,Gorepatil, Pratapsinha B.,Shinde, Vishnu S.,Khade, Bhimrao C.
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p. 1253 - 1275
(2017/02/10)
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- Substituted indole - 2 - formic acid (by machine translation)
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This invention relates to a substituted indole - 2 - carboxylic acid synthesis method, is to replace the phenyl hydrazine hydrochloride or arylhydrazines as raw materials, through with pyruvic acid ethyl ester cheng zong, Fischer indole synthesis by reaction of substituted indole - 2 - carboxylic acid ethyl ester, hydrolysis to obtain the substituted - 2 - carboxylic acid. Product purity is greater than 97%, the reaction yield is 64%. Synthesis method of the invention with non-harsh conditions, the operation is simple, and environmental friendliness, it has certain economic benefits. It is a kind of raw materials are easy, simple operation, three wastes, high yield of indole - 2 - carboxylic acid synthesis method. (by machine translation)
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Paragraph 0050; 0052
(2017/10/28)
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- Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators
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Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes. In spite of the theoretical potential of CB1 NAMs, published in vivo studies have generally not been able to demonstrate the expected therapeutically-relevant CB1-mediated effects. Thus, a greater range of molecular tools are required to allow definitive elucidation of the effects of CB1 allosteric modulation. In this study, we show a novel series of indole sulfonamides. Compounds 5e and 6c (ABD1075) had potencies of 4 and 3?nM respectively, and showed good oral exposure and CNS penetration, making them highly versatile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.
- Greig, Iain R.,Baillie, Gemma L.,Abdelrahman, Mostafa,Trembleau, Laurent,Ross, Ruth A.
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p. 4403 - 4407
(2016/08/25)
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- Rh(II)-catalyzed intramolecular annulation of N-sulfonyl 1,2,3-triazoles with indole derivatives: A new method for synthesis pyranoindoles
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A direct and highly stereoselective approach for the synthesis of Z-alkenyl-pyranoindoles had been developed by utilizing Rh(II)-catalyzed intramolecular cyclization of N-sulfonyl-1,2,3-triazoles with indole derivatives. A variety of pyranoindoles were obtained in 44-93% yields. Moreover, a more convenient synthesis of pyranoindoles starting from terminal alkyne was realized via a Cu-Rh sequentially catalyzed one-pot cascade reaction.
- Xie, Hui,Yang, Jian-Xin,Bora, Pranjal Protim,Kang, Qiang
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p. 3014 - 3021
(2016/05/19)
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- Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase
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In order to explore the interactions of bisphosphonate ligands with the active site and an allosteric pocket of the human farnesyl pyrophosphate synthase (hFPPS), substituted indole and azabenzimidazole bisphosphonates were designed as chameleon ligands. NMR and crystallographic studies revealed that these compounds can occupy both sub-pockets of the active site cavity, as well as the allosteric pocket of hFPPS in the presence of the enzyme's Mg2+ ion cofactor. These results are consistent with the previously proposed hypothesis that the allosteric pocket of hFPPS, located near the active site, plays a feed-back regulatory role for this enzyme.
- Gritzalis, Dimitrios,Park, Jaeok,Chiu, Wei,Cho, Hyungjun,Lin, Yih-Shyan,De Schutter, Joris W.,Lacbay, Cyrus M.,Zielinski, Michal,Berghuis, Albert M.,Tsantrizos, Youla S.
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p. 1117 - 1123
(2015/02/19)
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- [Fe(F20TPP)Cl]-catalyzed amination with arylamines and {[Fe(F20TPP)(NAr)](PhI=NAr)}+. Intermediate assessed by high-resolution ESI-MS and DFT calculations
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Amination of C-H bonds catalyzed by transition metal complexes via nitrene/imide insertion is an appealing strategy for C-N bond formation, and the use of iminoiodinanes, or their in situ generated forms from 'PhI-(OAc)2 + primary amides (such as sulfonamides, sulfamates, and carbamates)', as nitrogen sources for the amination reaction has been well documented. In this work, a 'metal catalyst + PhI(OAc)2 + primary arylamines' amination protocol has been developed using [Fe(F20TPP)Cl] (H2F20TPP = meso-tetrakis(pentafluorophenyl)porphyrin) as a catalyst. This catalytic method is applicable for both intra- and intermolecular amination of sp2 and sp3 C-H bonds (> 27 examples), affording the amination products, including natural products such as rutaecarpine, in moderate-to-good yields. ESI-MS analysis and DFT calculations lend support for the involvement of {[Fe(F20TPP)(NC6H4-p-NO2)](PhI=NC6H4-p-NO2)}+. intermediate in the catalysis.
- Liu, Yungen,Chen, Guo-Qiang,Tse, Chun-Wai,Guan, Xianguo,Xu, Zheng-Jiang,Huang, Jie-Sheng,Che, Chi-Ming
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supporting information
p. 100 - 105
(2015/02/19)
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- Gold(I)-catalyzed rearrangement of alkynylaziridine indoles for the synthesis of spiro-tetrahydro-β-carbolines
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Functionalized spiro-tetrahydro-β-carbolines were formed by an efficient gold(I)-catalyzed rearrangement reaction of alkynylaziridine indoles. The reaction involved a Friedel-Crafts type intramolecular reaction of alkynylaziridine indoles, following by hydroamination of aminoallene intermediate.
- Yang, Yan-Fang,Li, Lian-Hua,He, Yu-Tao,Luo, Jian-Yi,Liang, Yong-Min
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p. 702 - 707
(2014/02/14)
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- INDOL-AMIDE COMPOUNDS AS BETA-AMYLOID INHBITORS
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The present invention provides compounds of formula (I), wherein Z, R1, R2, and R3 are as described herein, as well as pharmaceutically acceptable salts and esters thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of Alzheimer's disease.
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Page/Page column 43
(2014/05/07)
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- Indol-amide compounds as beta-amyloid inhbitors
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The present invention provides compounds of formula (I) wherein Z, R1, R2, and R3 are as described herein, as well as pharmaceutically acceptable salts and esters thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of Alzheimer's disease.
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Paragraph 0169
(2014/05/07)
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- Synthesis and biological evaluation of new 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles as PI3Kα inhibitors
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A series of novel 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b] indoles was synthesized through a newly developed approach. All these compounds were evaluated against DYRK1A, CDK5 and PI3Kα and showed promising inhibitory activities against PI3Kα with most IC50 values in the micromolar range. Among them, compound 18 was strongly considered as the most interesting compound with an IC50 value of 0.091 μM. This series exhibited also significant anti-proliferative effects in various human cancer cell lines including those resulting in activation of the PI3K pathway.
- Bruel, Amélie,Logé, Cédric,Tauzia, Marie-Ludivine De,Ravache, Myriam,Le Guevel, Rémy,Guillouzo, Christiane,Lohier, Jean-Fran?ois,Oliveira Santos, Jana Sopkova-De,Lozach, Olivier,Meijer, Laurent,Ruchaud, Sandrine,Bénédetti, Hélène,Robert, Jean-Michel
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p. 225 - 233
(2013/01/15)
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- Synthesis of indoles through highly efficient cascade reactions of sulfur ylides and N-(ortho-chloromethyl)aryl amides
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Batting the ylides: A simple procedure carried out under mild conditions allows the direct and efficient synthesis of structurally diverse indoles. This approach involves a cascade reaction of sulfur ylides and N-(ortho-chloromethyl) aryl amides (see scheme). Copyright
- Yang, Qing-Qing,Xiao, Cong,Lu, Liang-Qiu,An, Jing,Tan, Fen,Li, Bin-Jie,Xiao, Wen-Jing
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supporting information
p. 9137 - 9140
(2012/10/29)
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- Efficient synthesis of 2-ethoxycarbonyl indoles
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An efficient one-pot procedure for the synthesis of 2-ethoxycarbonyl indoles from commercially available materials has been developed. The one-step procedure involves in situ formation of the hydrazones from phenylhydrazine hydrochloride and ethyl pyruvate in the presence of bismuth nitrate followed by Fischer cyclization in polyphosphoric acid and ethanol. This method is efficient and simple.
- Sudhakara,Jayadevappa,Mahadevan,Hulikal, Vijaykumar
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experimental part
p. 2506 - 2515
(2009/12/06)
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- New arylthioindoles and related bioisosteres at the sulfur bridging group. 4. Synthesis, tubulin polymerization, cell growth inhibition, and molecular modeling studies
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New arylthioindoles along with the corresponding ketone and methylene compounds were potent tubulin assembly inhibitors. As growth inhibitors of MCF-7 cells, sulfur derivatives were superior or sometimes equivalent to the ketones, while methylene derivatives were substantially less effective. Esters 24, 27-29, 36, 39, and 41 showed ~50% of inhibition on human HeLa and HCT116/chr3 cells at 0.5 μM, and these compounds inhibited the growth of HEK, M14, and U937 cells with IC50's in the 78-220 nM range. While murine macrophage J744.1 cell growth was significantly less affected (20% at higher concentrations), four other nontransformed cell lines remained sensitive to these esters. The effect of drug treatment on cell morphology was examined by time-lapse microscopy. In a protocol set up to evaluate toxicity on the Saccharomyces cerevisiae BY4741 wild type strain, compounds 24 and 54 strongly reduced cell growth, and 29, 36, and 39 also showed significant inhibition. 2009 American Chemical Society.
- La Regina, Giuseppe,Sarkar, Taradas,Bai, Ruoli,Edler, Michael C.,Saletti, Roberto,Coluccia, Antonio,Piscitelli, Francesco,Minelli, Lara,Gatti, Valerio,Mazzoccoli, Carmela,Palermo, Vanessa,Mazzoni, Cristina,Falcone, Claudio,Scovassi, Anna Ivana,Giansanti, Vincenzo,Campiglia, Pietro,Porta, Amalia,Maresca, Bruno,Hamel, Ernest,Brancale, Andrea,Novellino, Ettore,Silvestri, Romano
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experimental part
p. 7512 - 7527
(2010/05/18)
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- Monocyte chemoattractant protein-1 inhibitor compounds
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The invention concerns the use of a compound of the formula (I) in which Z, X, T, A, R1, R2, p and q have any of the meanings defined herein, and their pharmaceutically acceptable salts or in vivo hydrolysable esters, in the treatment of a disease or condition mediated by monocyte chemoattractant protein-1 (MCP-1). Certain of the components of formula (I) are novel and are provided, together with pharmaceutical compositions thereof, as further features of the invention.
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- Aromatic amidine derivatives useful as selective thrombin inhibitors
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The present invention relates to a novel thrombin inhibitor which is effective even when orally administered. More specifically, the present invention relates to an aromatic amidine derivative represented by formula (I) and the salts thereof, which show potent selective inhibitory activity for thrombin in which (a), R, R1, R2, R3, A, W, Y and n are defined as described in the specification.
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