- Carbazole compound and application thereof in preparation of medicines for treating fatty liver and 2 type diabetes and other metabolic related diseases
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The invention relates to a carbazole compound and application thereof in preparation of drugs for treating metabolic related diseases such as fatty liver and 2 type diabetes, wherein the structural general formula of the carbazole compound is as shown in
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Paragraph 0072-0075
(2021/09/21)
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- Design, synthesis and biological activity evaluation of novel carbazole-benzylpiperidine hybrids as potential anti Alzheimer agents
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Alzheimer's disease (AD) as the most common form of dementia in aged people, is an intricate neurodegenerative disease. Therefore, a novel strategy so-called multi-target-directed ligand has received much attention for the effective treatment of AD. In this study a series of novel carbazole-benzylpiperidine hybrids 9a-m was designed, synthesized and evaluated as acetylcholinesterase and butyrylcholinesterase inhibitors. Moreover, some of these compounds were evaluated for anti β-secretase (BACE1) activity and metal chelation properties. Among the synthesized compounds, compounds 9b (IC50 = 16.5 μM for AChE and IC50 = 0.59 μM for BuChE) and 9c (IC50 = 26.5 μM for AChE and IC50 = 0.18 μM for BuChE) showed the highest inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Furthermore, these compounds (9b and 9c) displayed interaction with Zn2+ ion and compound 9c showed moderate inhibitory activity against BACE1 (24.5% at 50 μM). Kinetic and docking studies exhibited that these compounds likely act as a non-competitive inhibitor able to interact with the catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase simultaneously.
- Edraki, Najmeh,Faghih, Zeinab,Iraji, Aida,Nadri, Hamid,Rezaei, Zahra,Sadeghian, Batool,Sadeghian, Issa,Sakhteman, Amirhossein
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- With chiral center carbazolyl isopropanolamine derivatives of the preparation method and application of (by machine translation)
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The invention relates to a with chiral center carbazolyl isopropanolamine derivatives of the preparation method and application. This compound has the general formula (I) indicated by the structure: The compound such as [...] Phaeosphaeria, tobacco wilt b
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Paragraph 0056; 0057; 0062; 0067
(2019/05/04)
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- Identification of racemic and chiral carbazole derivatives containing an isopropanolamine linker as prospective surrogates against plant pathogenic bacteria: In vitro and in vivo assays and quantitative proteomics
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Recent observations on the emergence of drug-resistant plant pathogenic bacteria have highlighted and elicited an acute campaign to develop novel, highly efficient antibiotic surrogates for managing bacterial diseases in agriculture. Thus, a type of racemic and chiral carbazole derivative containing an isopropanolamine pattern was systematically synthesized to discover low-cost and efficient antibacterial candidates. Screening results showed that compounds 2f, 6c, and 2j could significantly suppress the growth of tested plant pathogens, namely Xanthomonas oryzae pv oryzae, X. axonopodis pv citri, and Pseudomonas syringae pv actinidiae, and provided the corresponding EC50 values of 1.27, 0.993, and 0.603 μg/mL, which were significantly better than those of existing commercial drugs. In vivo studies confirmed their prospective applications for controlling plant bacterial diseases. Label-free quantitative proteomics analysis indicated that compound 2f could dramatically induce the up- and down-regulation of a total of 247 differentially expressed proteins, which was further validated by the parallel reaction monitoring technique. Moreover, fluorescence spectra and SEM images were obtained to further explore the antibacterial mechanism.
- Zhao, Yong-Liang,Huang, Xing,Liu, Li-Wei,Wang, Pei-Yi,Long, Qing-Su,Tao, Qing-Qing,Li, Zhong,Yang, Song
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p. 7512 - 7525
(2019/08/21)
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- Potential Antimicrobial Isopropanol-Conjugated Carbazole Azoles as Dual Targeting Inhibitors of Enterococcus faecalis
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A series of isopropanol-bridged carbazole azoles as potential antimicrobial agents were designed and synthesized from commercial carbazoles. Bioassay revealed that 3,6-dichlorocarbazolyl triazole 3f could effectively inhibit the growth of E. faecalis with minimal inhibitory concentration of 2 μg/mL. The active molecule 3f showed lower propensity to trigger the development of resistance in bacteria than norfloxacin and exerted rapidly bactericidal ability. Compound 3f also exhibited low cytotoxicity to normal mammalian RAW264.7 cells. Further mechanism exploration indicated that conjugate 3f was membrane active against E. faecalis and could form 3f-DNA complex by intercalating into DNA of resistant E. faecalis, which might be responsible for its antimicrobial action. Molecular docking showed an efficient binding of triazole derivative 3f with DNA gyrase enzyme through noncovalent interactions.
- Zhang, Yuan,Tangadanchu, Vijai Kumar Reddy,Cheng, Yu,Yang, Ren-Guo,Lin, Jian-Mei,Zhou, Cheng-He
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supporting information
p. 244 - 249
(2018/03/21)
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- Carbazole alkamine compound and preparation method thereof and application for parasitic disease resistance
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The invention provides a carbazole alkamine compound and a preparation method thereof and application for a parasitic disease resistance aspect. Specifically, the invention provides a racemic modification of the compound shown as type (A) and an enantiomer or salt capable of being accepted by pharmacy of the enantiomer. The compound has excellent anti-schistosoma and anti-hydatid cyst activity. According to the carbazole alkamine compound and the preparation method thereof and the application for the parasitic disease resistance aspect, the design is reasonable, the source of used raw materials is wide, the preparation method is easy and convenient and suitable for utility and can be applied to parasitic disease resistance drug preparation. Type A (please see the specifications for the chemical structural formula)
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Paragraph 0182; 0183; 0184; 0187; 0188
(2017/05/10)
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- Novel carbazole aminoalcohols as inhibitors of β-hematin formation: Antiplasmodial and antischistosomal activities
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Malaria and schistosomiasis are two of the most socioeconomically devastating parasitic diseases in tropical and subtropical countries. Since current chemotherapeutic options are limited and defective, there is an urgent need to develop novel antiplasmodials and antischistosomals. Hemozoin is a disposal product formed from the hemoglobin digestion by some blood-feeding parasites. Hemozoin formation is an essential process for the parasites to detoxify free heme, which is a reliable therapeutic target for identifying novel antiparasitic agents. A series of novel carbazole aminoalcohols were designed and synthesized as potential antiplasmodial and antischistosomal agents, and several compounds showed potent in?vitro activities against Plasmodium falciparum 3D7 and Dd2 strains and adult and juvenile Schistosoma japonicum. Investigations on the dual antiparasitic mechanisms showed the correlation between inhibitory activity of β-hematin formation and antiparasitic activity. Inhibiting hemozoin formation was identified as one of the mechanisms of action of carbazole aminoalcohols. Compound 7 displayed potent antiplasmodial (Pf3D7 IC50?=?0.248?μM, PfDd2 IC50?=?0.091?μM) and antischistosomal activities (100% mortality of adult and juvenile schistosomes at 5 and 10?μg/mL, respectively) and exhibited low cytotoxicity (CC50?=?7.931?μM), which could be considered as a promising lead for further investigation. Stoichiometry determination and molecular docking studies were also performed to explain the mode of action of compound 7.
- Wang, Weisi,Li, Qiang,Wei, Yufen,Xue, Jian,Sun, Xiao,Yu, Yang,Chen, Zhuo,Li, Shizhu,Duan, Liping
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p. 191 - 199
(2017/04/13)
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- Bromomethylthioindole Inspired Carbazole Hybrids as Promising Class of Anti-MRSA Agents
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Series of N-substituted carbazole analogues bearing an indole ring were synthesized as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents from a molecular hybridization approach. The representative compound 19 showed an MIC = 1 μg/mL against a panel of MRSA clinical isolates as it possessed comparable in vitro activities to that of vancomycin. Moreover, compound 19 also exhibited MIC = 1 μg/mL activities against a recent identified Z172 MRSA strain (vancomycin-intermediate and daptomycin-nonsusceptible phenotype) and the vancomycin-resistant Enterococcus faecalis (VRE) strain. In a mouse model with lethal infection of MRSA (4N216), a 75% survival rate was observed after a single dose of compound 19 was intravenously administered at 20 mg/kg. In light of their equipotent activities against different MRSA isolates and VRE strain, the data underscore the importance of designed hybrid series for the development of new N-substituted carbazoles as potential anti-MRSA agents.
- Cheng, Chia-Yi,Chang, Chun-Ping,Lauderdale, Tsai-Ling Yang,Yu, Guann-Yi,Lee, Jinq-Chyi,Jhang, Yi-Wun,Wu, Chien-Huang,Ke, Yi-Yu,Sadani, Amit A.,Yeh, Ching-Fang,Huang, I-Wen,Kuo, Yi-Ping,Tsai, De-Jiun,Yeh, Teng-Kuang,Tseng, Chen-Tso,Song, Jen-Shin,Liu, Yu-Wei,Tsou, Lun K.,Shia, Kak-Shan
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supporting information
p. 1191 - 1196
(2016/12/18)
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- Carbazole-rivastigmine diad and pharmaceutical composition and application thereof
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The invention provides compounds of the structure as shown in the description or pharmaceutical salt, a pharmaceutical composition and application of the compounds. The compounds relate to a series of carbazole and rivastigmine diads. The carbazole and ri
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Paragraph 0024
(2016/12/26)
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- Synthesis and biological evaluation of novel 1,2,4-triazine derivatives bearing carbazole moiety as potent α-glucosidase inhibitors
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A new series of 1,2,4-triazine derivatives bearing carbazole moiety 7a-7p were designed, synthesized, and evaluated for their α-glucosidase inhibitory activity. The majority of the screened compounds displayed potent α-glucosidase inhibitory activity, with IC50 values in the range of 4.27 ± 0.07-47.75 ± 0.25 μM as compared to the standard drug acarbose. Among the series, compound 7k represented the most potent α-glucosidase inhibitory activity with IC50 values of 4.27 ± 0.07 μM. Kinetic analysis revealed that compound 7k is a non-competitive inhibitor with a Ki of 4.43 μM. Furthermore, the binding interactions of compound 7k with α-glucosidase was confirmed through molecular docking. This study showed these 1,2,4-triazine derivatives bearing carbazole moiety as a new class of α-glucosidase inhibitors.
- Wang, Guangcheng,Wang, Jing,He, Dianxiong,Li, Xin,Li, Juan,Peng, Zhiyun
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p. 2806 - 2809
(2016/06/09)
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- Carbazole Aminoalcohols Induce Antiproliferation and Apoptosis of Human Tumor Cells by Inhibiting Topoisomerase I
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Novel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine-chain-substituted compounds showed the most promising antiproliferative activity, with IC50values in the single-digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds. Results of comet assays and molecular docking indicate that the representative compounds may act as topo I poisons, causing single-strand DNA damage by stabilizing the topo I–DNA cleavage complex. In particular, the most potent compound, 1-(butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol (6), was shown to be able to induce G2-phase cell-cycle arrest and apoptosis in HeLa cells.
- Wang, Weisi,Sun, Xiao,Sun, Deheng,Li, Shizhu,Yu, Yang,Yang, Tingyuan,Yao, Junmin,Chen, Zhuo,Duan, Liping
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p. 2675 - 2681
(2016/12/23)
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- Pro-neurogenic compounds
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This invention relates generally to stimulating neurogenesis (e.g., post-natal neurogenesis, e.g., post-natal hippocampal neurogenesis) and protecting from neuron cell death.
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Page/Page column 88
(2015/09/22)
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- Computer-aided structure-based design of multitarget leads for Alzheimer's disease
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Alzheimer's disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates. We used a combination of docking and molecular dynamics protocols in order to discard nonbinders, optimize the best candidates, and provide a rationale for their potential as inhibitors. To provide a proof of concept, we proceeded to screen the literature and databases, a task that allowed us to identify a set of carbazole-containing compounds that initially showed affinity only for the cholinergic targets in our experimental assays. Two cycles of design based on our protocol led to a new set of analogues that were synthesized and assayed. The assay results revealed that the designed inhibitors had improved affinities for BACE-1 by more than 3 orders of magnitude and also displayed amyloid aggregation inhibition and affinity for AChE and BuChE, a result that led us to a group of multitarget amyloid cascade inhibitors that also could have a positive effect at the cholinergic level.
- Domnguez, Jos L.,Fernndez-Nieto, Fernando,Castro, Marian,Catto, Marco,Paleo, M. Rita,Porto, Silvia,Sardina, F. Javier,Brea, Jos M.,Carotti, Angelo,Villaverde, M. Carmen,Sussman, Fredy
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p. 135 - 148
(2015/02/05)
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- Discovery of a neuroprotective chemical, (S)- N -(3-(3,6-Dibromo-9 H -carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(-)-P7C3-S243], with improved druglike properties
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(-)-P7C3-S243 is a neuroprotective aminopropyl carbazole with improved druglike properties compared with previously reported compounds in the P7C3 class. It protects developing neurons in a mouse model of hippocampal neurogenesis and protects mature neurons within the substantia nigra in a mouse model of Parkinsons disease. A short, enantioselective synthesis provides the neuroprotective agent in optically pure form. It is nontoxic, orally bioavailable, metabolically stable, and able to cross the blood-brain barrier. As such, it represents a valuable lead compound for the development of drugs to treat neurodegenerative diseases and traumatic brain injury.
- Naidoo, Jacinth,De Jesus-Cortes, Hector,Huntington, Paula,Estill, Sandi,Morlock, Lorraine K.,Starwalt, Ruth,Mangano, Thomas J.,Williams, Noelle S.,Pieper, Andrew A.,Ready, Joseph M.
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p. 3746 - 3754
(2014/05/20)
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- Development of a scalable synthesis of P7C3-A20, a potent neuroprotective agent
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A scalable synthesis of the neuroprotective agent P7C3-A20 is described. The synthesis has provided hundred-gram batches of the final compound for biological evaluation in rodents primates. The synthesis can be performed without chromatographic purificati
- Naidoo, Jacinth,Bemben, Christopher J.,Allwein, Shawn R.,Liang, Jue,Pieper, Andrew A.,Ready, Joseph M.
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supporting information
p. 4429 - 4431
(2013/07/26)
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- Development of proneurogenic, neuroprotective small molecules
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Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apopotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.
- MacMillan, Karen S.,Naidoo, Jacinth,Liang, Jue,Melito, Lisa,Williams, Noelle S.,Morlock, Lorraine,Huntington, Paula J.,Estill, Sandi Jo,Longgood, Jamie,Becker, Ginger L.,McKnight, Steven L.,Pieper, Andrew A.,De Brabander, Jef K.,Ready, Joseph M.
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supporting information; experimental part
p. 1428 - 1437
(2011/04/16)
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- Heparanase inhibitors and uses thereof
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The invention provides heparanase inhibitors suitable for treatment of diseases and disorders caused by or associated with heparanase catalytic activity such as cancer, inflammatory disorders and autoimmune diseases.
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Page/Page column 20
(2008/06/13)
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- 3,6-Dibromocarbazole piperazine derivatives of 2-propanol as first inhibitors of cytochrome C release via bax channel modulation
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There is compelling evidence that Bax channel activity stimulates cytochrome c release leading ultimate]y to cell death, which is a key event in ischemic injuries and neurodegenerative diseases. Here 3,6-dibromocarbazole piperazine derivatives of 2-propan
- Bombrun, Agnes,Gerber, Patrick,Casi, Giulio,Terradillos, Olivier,Antonsson, Bruno,Halazy, Serge
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p. 4365 - 4368
(2007/10/03)
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- N-Alkylation of 1H-indoles and 9H-carbazoles with alcohols
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A comparative study of N-alkylation of 1H-indole and 9H-carbazole derivatives with alcohol derivatives was performed using classic Mitsunobu reaction conditions, i.e. DEAD/PPh3, azodicarboxamide derivatives such as TMAD in the presence of PBus
- Bombrun, Agnes,Casi, Giulio
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p. 2187 - 2190
(2007/10/03)
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