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Synthesis and Evaluation of 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides as Novel GSK‐3β Inhibitors and Anti‐Ischemic Agents 下载免费PDF全文
Qing Ye Qiu Li Yubo Zhou Lei Xu Weili Mao Yuanxue Gao Chenhui Li Yuan Xu Yazhou Xu Hong Liao Luyong Zhang Jianrong Gao Jia Li Tao Pang 《Chemical biology & drug design》2015,86(4):746-752
A series of novel 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides were designed, synthesized, and biologically evaluated for their GSK‐3β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK‐3β protein. Among them, compounds 5n , 5o , and 5p significantly reduced GSK‐3β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK‐3β activity. In the in vitro neuronal injury models, compounds 5n , 5o , and 5p prevented neuronal death against glutamate, oxygen–glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK‐3β inhibitors with potential neuroprotective activity against brain ischemic stroke. 相似文献
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Synthesis and Anti‐neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2‐nitro‐1‐phenyl‐1H‐Indole Derivatives as p38α MAPK Inhibitors 下载免费PDF全文
Bao Cheng Yongsheng Lin Ming Kuang Sai Fang Qiong Gu Jun Xu Laiyou Wang 《Chemical biology & drug design》2015,86(5):1121-1130
Inhibition of p38 mitogen‐activated protein kinases (MAPKs) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease (AD). Inspired from the pharmacophore of natural NF‐κB and p38α MAPK inhibitor 5,6‐dehydrokawain and p38α MAPK inhibitors 1a, 1‐pyrazolyl‐3‐(4‐((2‐anilinopyrimidin‐4‐yl)oxy)napththalen‐1‐yl)ureas, and 1b , a class of indole–pyrimidinyl compounds which were patented respectively, we designed, de novo synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2‐nitro‐1‐phenyl‐1H‐indole derivatives in an effort to develop pharmacologically tractable agents to alleviate the progression of AD. Fourteen of the seventeen synthesized compounds exhibit significant inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS)‐induced microglia activation with IC50 less than the control 5,6‐dehydrokawain. Notably, compound 27 , 6‐methoxy‐2‐nitro‐1‐(1H‐1, 2, 3‐triazol‐1‐yl)‐1H‐indole, with IC50 values of 1.6 μ m can markedly inhibit p38 α MAPK and NO release in BV‐2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound 27 inhibits p38 α MAPK through binding to the Glu71 and Asp168 residues. Moreover, in vitro study shows that all compounds can easily cross the blood–brain barrier (BBB) and did not exhibit any acute cellular toxicity checked by MTT assay. These investigations provide promising chemical lead candidate as anti‐neuroinflammatory agents for AD. 相似文献
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Synthesis and Pharmacological Activity of a New Series of 1‐(1H‐Indol‐4‐yloxy)‐3‐(2‐(2‐methoxyphenoxy)ethylamino)propan‐2‐ol Analogs 下载免费PDF全文
Marek Bednarski Monika Otto Magdalena Dudek Marcin Kołaczkowski Adam Bucki Agata Siwek Grażyna Groszek Elżbieta Maziarz Piotr Wilk Jacek Sapa 《Archiv der Pharmazie》2016,349(3):211-223
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The synthesis of a new series of 1β‐methylcarbapenems having pyrrolidine and piperidine moieties is described. Their in‐vitro antibacterial activities against both Gram‐positive and Gram‐negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound III b having an oxime‐pyrrolidine moiety showed the most potent antibacterial activity. 相似文献
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Discovery of Novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole Derivatives as Potential Anti‐Inflammatory Agents 下载免费PDF全文
Xinning Wang Yang Zong Leilei Zhao Junhao Xing Jinpei Zhou Huibin Zhang 《Chemical biology & drug design》2015,86(4):509-516
A novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 5 with good anti‐inflammatory activity was identified from our in‐house library. Based on hit compound 5 , two series of 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 6a – g and 7a – h were designed and synthesized as novel anti‐inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF‐α production in LPS‐stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC50 = 0.86 μm ) and TNF‐α (IC50 = 1.87 μm ) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti‐inflammatory activity than ibuprofen did on xylene‐induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF‐κB in LPS‐stimulated RAW 264.7 macrophages. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2005,48(5):323-330
2‐[14C]‐N‐(6‐Chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide (9A , also referred to as [14C]‐PS‐1145) was synthesized from [14C]‐paraformaldehyde in five steps in an overall radiochemical yield of 15%. The key intermediate 1‐[14C]‐6‐chloro‐1,2,3,4‐tetrahydro‐β‐carboline was obtained by Pictet–Spengler cyclization of chlorotryptamine with [14C]‐paraformaldehyde. Similar reactions were conducted with tryptamine to address the generality of the methodology. Copyright © 2005 John Wiley & Sons, Ltd. 相似文献
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Design,Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives as Anti‐inflammatory Agents against Lipopolysaccharide‐induced Acute Lung Injury in Rats 下载免费PDF全文
Lili Dong Zhe Wang Lingfeng Chen Dandan Liang Dengjian Shi Xiaoou Shan Guang Liang 《Chemical biology & drug design》2015,85(6):672-684
Quinazoline has been reported to exhibit multiple bioactivities. The aim of this study was to discover new quinazoline derivatives with preventive effect on lipopolysaccharide‐induced acute lung injury via anti‐inflammatory actions. Thirty‐three 4‐amino quinazolin derivatives were synthesized and screened for anti‐inflammatory activities in lipopolysaccharide‐induced macrophages. The most potent four compounds, 6h, 6m, 6p , and 6q , were shown dose‐dependent inhibition against lipopolysaccharide‐induced TNF‐α and IL‐6 release. Then, the preliminary structure–activity relationship and quantitative structure–activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide‐induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation of lipopolysaccharide. The results showed that 6m and 6q, especially 6q , obviously alleviated lung histopathological changes, inflammatory cells infiltration, and cytokines mRNA expression initiated by lipopolysaccharide. Taken together, this work suggests that 6m and 6q suppressed the lipopolysaccharide‐induced acute lung injury through inhibition of the inflammatory response in vivo and in vitro, indicating that quinazolines might serve as potential agents for the treatment of acute lung injury and deserve the continuing drug development and research. 相似文献
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Alexandre V. Ivachtchenko Eugene B. Frolov Oleg D. Mitkin Volodymyr M. Kysil Alexander V. Khvat Sergey E. Tkachenko 《Archiv der Pharmazie》2009,342(12):740-747
Synthesis, biological evaluation, and structure‐activity relationships (SAR) for a series of novel γ‐carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro‐γ‐carboline 5b (2,8‐dimethyl‐5‐[cis‐2‐pyridin‐3‐ylvinyl]‐2,3,4,5‐tetrahydro‐carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H1 and serotonin 5‐HT6 receptors (IC50 < 0.45 μM and IC50 = 0.73 μM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity. 相似文献
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Abstract: A protected tridehydropeptide containing (Z)‐β‐(3‐pyridyl)‐α,β‐dehydroalanine (ΔZ3Pal) residue, Boc‐Leu‐ΔZ3Pal‐Leu‐OMe ( 1 ), was synthesized via Erlenmeyer azlactone method. X‐ray crystallographic analysis revealed that the peptide 1 adopts an extended conformation, which is similar to that of a ΔZPhe analog, Boc‐Leu‐ΔZPhe‐Leu‐OMe ( 2 ). 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2006,49(9):789-799
[14C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [14C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐14C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐13C4]‐ethyl acetoacetate and [D4]‐methanol in six steps in an overall yield of 2%. [13C4]‐2‐methylnicotic acid, was prepared by condensation of [13C4]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 John Wiley & Sons, Ltd. 相似文献
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Jixia Yang Gongzheng Zhang Zhaoyang Wang Zhanxiong Xiao Hongliang Wen 《Journal of labelled compounds & radiopharmaceuticals》2019,62(14):920-924
Parkinson disease (PD) is a neurodegenerative disorder characterized by the accumulation of α‐synuclein into Lewy bodies. 3‐Benzylidine‐indolin‐2‐one represents a class of compounds, which are known to inhibit the accumulation of α‐synuclein. In this paper, we report the synthesis of [13C] and [15N] labelled 1‐benzyl‐(Z)‐3‐(benzylidene)indolin‐2‐one from commercially available [13C2]‐chloroacetic acid and [15N]‐aniline in five steps. The product will be used to study its metabolites in human liver microsomes by liquid chromatography‐tandem mass spectrometry. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2003,46(14):1261-1268
Nicotinic acetylcholine receptors are widely distributed throughout the human brain and are believed to play a role in several neurological and psychiatric disorders. In order to identify an effective PET radioligand for in vivo assessment of the α4β2 subtype of nicotinic receptor, we synthesized [18F]3‐[1‐(3‐fluoropropyl)‐(S)‐pyrrolidin‐2‐ylmethoxy]pyridine (NicFP). The in vitro KD of NicFP was determined to be 1.1 nM, and the log P value obtained by HPLC analysis of the unlabelled standard was found to be 2.2. The radiosynthesis of [18F]NicFP was carried out by a nucleophilic substitution reaction of anhydrous [18F]fluoride and the corresponding mesylate precursor. After purification by HPLC, the radiochemical yield was determined to be 11.3±2.1% and the specific activity was 0.47±0.18 Ci/μmol (EOS, n = 3). The time of synthesis and purification was 99±2 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright © 2003 John Wiley & Sons, Ltd. 相似文献
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Design,Synthesis, and Biological Evaluation of Thiazolidine‐2,4‐dione Conjugates as PPAR‐γ Agonists 下载免费PDF全文
Syed Nazreen Mohammad Sarwar Alam Hinna Hamid Mohammad Shahar Yar Abhijeet Dhulap Perwez Alam Mohammad Abdul Qadar Pasha Sameena Bano Mohammad Mahboob Alam Saqlain Haider Chetna Kharbanda Yakub Ali Kolakappi Pillai 《Archiv der Pharmazie》2015,348(6):421-432