51997-51-4Relevant academic research and scientific papers
Design, synthesis, crystal structure, biological evaluation and molecular docking studies of carbazole-arylpiperazine derivatives
Xu, Wei,Huang, Junjun,Shao, Binhao,Xu, Xingjie,Jiang, Renwang,Yuan, Mu
, p. 5565 - 5572 (2016)
Subtype-selective α1-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α1-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α1Dsubtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α1B-AR (pA27.13) with a poor selectivity for α1Aand α1Dsubtypes. Compound 1 exhibited enhanced antagonistic effect on α1Dsubtype (pA27.06) and excellent selectivity for α1Dover α1B(α1D/α1Bratio?=?79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α1receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α1D-selective antagonists.
Discovery of a novel multifunctional carbazole–aminoquinoline dimer for Alzheimer's disease: copper selective chelation, anti-amyloid aggregation, and neuroprotection
Zhang, Xiao,Wang, Ying,Wang, Sheng-nan,Chen, Qiu-he,Tu, Ya-lin,Yang, Xiao-hong,Chen, Jing-kao,Yan, Jin-wu,Pi, Rong-biao,Wang, Yan
, p. 777 - 784 (2018)
A novel multifunctional carbazole–aminoquinoline dimer PZ001 was designed, synthesized, and evaluated. The results indicated that PZ001 possessed selective copper chelation, and inhibited copper-induced Aβ1–42 aggregation. Furthermore, PZ001 exerted powerful neuroprotection against glutamate-induced HT22 cell death. These results suggest that PZ001 may be a promising multifunctional anti-AD compound.
Fine-tuning hydroxylamines as single-nitrogen sources for Pd(0)-catalyzed diamination of o-bromo(or chloro)-biaryls
Bai, Jiaxing,Ding, Pin,Han, Lingbo,Liu, Jingjing,Luan, Xinjun
, (2022/03/19)
Transition metal-catalyzed diamination by hydroxylamines is a common approach for making three-membered aziridines, while its use for building the larger N-heterocycles is still underdeveloped. Herein, we report an efficient Pd(0)-catalyzed inter-molecular [4+1] annulation of o-bromo(or chloro)-biaryls with bifunctional secondary hydroxylamines for the one-step assembly of synthetically useful carbazoles. Noteworthily, a linchpin for this domino reaction was the judicious selection of both the amino-sources and Pd(0)-catalysts for enabling the prerequisite oxidative addition of aryl halides to Pd(0)-species in the presence of hydroxylamines with a labile N-O bond. [Figure not available: see fulltext.].
Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents
Chang, Qi,Long, Jing,Hu, Liqing,Chen, Zhuo,Li, Qianbin,Hu, Gaoyun
, (2020/04/09)
Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied β adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98–3.70 μM), compared to propranolol (59.5–75.8 μM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 μM for 5m, partially inhibited at 50 μM for propranolol), induce cell apoptosis and cell cycle arrest in the G2/M phase (both observed at 1 μM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.
Design, Synthesis, and Biological Evaluation of a New Series of Carvedilol Derivatives That Protect Sensory Hair Cells from Aminoglycoside-Induced Damage by Blocking the Mechanoelectrical Transducer Channel
O'Reilly, Molly,Kirkwood, Nerissa K.,Kenyon, Emma J.,Huckvale, Rosemary,Cantillon, Daire M.,Waddell, Simon J.,Ward, Simon E.,Richardson, Guy P.,Kros, Corné J.,Derudas, Marco
, p. 5312 - 5329 (2019/06/07)
Aminoglycosides (AGs) are broad-spectrum antibiotics used for the treatment of serious bacterial infections but have use-limiting side effects including irreversible hearing loss. Here, we assessed the otoprotective profile of carvedilol in mouse cochlear cultures and in vivo zebrafish assays and investigated its mechanism of protection which, we found, may be mediated by a block of the hair cell's mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel. One derivative was found to confer greater protection than carvedilol itself in cochlear cultures and also to bind more tightly to the MET channel. At higher concentrations, both carvedilol and this derivative were toxic in cochlear cultures but not in zebrafish, suggesting a good therapeutic window under in vivo conditions.
Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents
Xu, Yao,Chen, Shujun,Cao, Ying,Zhou, Pingzheng,Chen, Zhipeng,Cheng, Kui
, p. 253 - 266 (2018/05/29)
Toll-like receptor 4 (TLR4) initiates innate immune response to release inflammatory cytokines and has been pathologically linked to variety of inflammatory diseases. Recently, we found that Carvedilol, as the classic anti-heart failure and anti-inflammatory clinic drug, could inhibit the TLR4 signaling in the TLR4 overexpressed cells. Herein, we have designed and synthesized a small library of novel Carvedilol derivatives and investigated their potential inhibitory activity. The results indicate that the most potent compound 8a (SMU-XY3) could effectively inhibited TLR4 protein and the LPS triggered alkaline phosphatase signaling in HEK-Blue hTLR4 cells. It down regulated the nitric oxide (NO) in both RAW264.7 cells and BV-2 microglial cells, in addition to blocking the TNF-α signaling in ex-vivo human peripheral blood mononuclear cells (PBMC). More interestingly, 8a shows higher affinity to hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) over HCN2, which probably indicates the new application of TLR4 inhibitor 8a in heart failure, coronary heart disease, and other inflammatory diseases.
8-aminoquinoline-hydroxyl carbazole heterozygote and preparation method and pharmaceutical composition thereof
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Paragraph 0019; 0020, (2017/08/29)
The invention relates to synthesis of a series of 8-aminoquinoline-hydroxyl carbazole heterozygote. According to the 8-aminoquinoline-hydroxyl carbazole heterozygote, copper ion can be selectively chelated, and a good nerve cell protection effect can be realized. Therefore, the 8-aminoquinoline-hydroxyl carbazole heterozygote can serve as candidate compound of AD treating medicine development.
Preparation method of carvedilol phosphate hemihydrate
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Paragraph 0011; 0044; 0045; 0046; 0053; 0054, (2017/02/02)
The invention provides a preparation method of carvedilol phosphate hemihydrates. The preparation method comprises the following steps: carrying out mixing reaction on a compound with a structure as shown in a formula (II) and 2-(2-methoxy phenoxy) ethylamine to obtain reaction liquid containing a compound with the structure as shown in a formula (III); directly adding phosphoric acid in the reaction liquid obtained in the step (1) so that 2-(2-methoxy phenoxy) ethylamine phosphate and filtrate can be obtained; adding phosphoric acid in the filtrate obtained in the step (2) to obtain the carvedilol phosphate hemihydrates. The reaction liquid obtained in the step (1) is not required to be treated, the phosphoric acid is added in the same reaction system in two steps, excessive 2-(2-methoxy phenoxy) ethylamine is recycled and can be continued to be used for reaction, and furthermore, the purity and the yield of the prepared carvedilol phosphate hemihydrates as a target product are quite high. In addition, preparation of the compound with the structure as shown in the formula (II) and the carvedilol phosphate hemihydrate as the target product is realized through a one-pot method, and a synthesis method is simple.
Suppression of store overload-induced calcium release by hydroxylated metabolites of carvedilol
Malig, Thomas,Xiao, Zhichao,Chen, S.R. Wayne,Back, Thomas G.
, p. 149 - 153 (2015/12/18)
Carvedilol is a drug widely used in the treatment of heart failure and associated cardiac arrhythmias. A unique action of carvedilol is its suppression of store overload-induced calcium release (SOICR) through the cardiac ryanodine receptor (RyR2), which can trigger ventricular arrhythmias. Since the effects of carvedilol metabolites on SOICR have not yet been investigated, three carvedilol metabolites hydroxylated at the 3-, 4′ and 5′-positions were synthesized and assayed for SOICR inhibition in mutant HEK 293 cells expressing the RyR2 mutant R4496C. This cell line is especially prone to SOICR and calcium release through the defective RyR2 channel was measured with a calcium-sensitive fluorescent dye. These results revealed that the 3- and 4′-hydroxy derivatives are slightly more effective than carvedilol in suppressing SOICR, while the 5′-analog proved slightly less active. Metabolic deactivation of carvedilol via these hydroxylation pathways is therefore insignificant.
Design and synthesis of 3-(3-((9 H-carbazol-4-yl)oxy)-2-hydroxypropyl)-2-phenylquinazolin-4(3 H)-one derivatives to induce ACE inhibitory activity
Venkatesh, Ramineni,Kasaboina, Suresh,Gaikwad, Hanmant K.,Janardhan, Sridhara,Bantu, Rajashaker,Nagarapu, Lingaiah,Sastry, G. Narahari,Banerjee, Sanjay K.
, p. 22 - 29 (2015/04/22)
In an attempt to develop a new class of cardiovascular drugs, a series of novel carbazolyloxy phenylquinazoline derivatives 9a-g have been synthesized and evaluated as angiotensin converting enzyme (ACE) inhibitors. Most of these compounds exhibited activity as significant ACE inhibitors and three compounds (9b, 9c & 9e) showed maximum inhibitory potency in enzyme based assays. To render support to the experimental results, a series of quinazolinone derivatives were docked into active site of ACE and identified the probable binding modes compared to Lisinopril. Also we have identified common pharmacophore hypothesis (AAADDRR) among the best docked conformers of most potent compounds in a series of compounds. The most potent 9b, 9c, 9e compounds shared common active site with the Lisinopril binding site and retained the key active site residue interactions. The obtained results from pharmacological and molecular modeling studies can be utilized for further optimization of identified hits for selective inhibition of ACE.
