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1.
To develop new drugs with the effects of lowering blood-fat and blood pressure, compounds 1~7 and 10 were synthesized by the reactions of 2-methyl-2-[4-(4-chlorobenzoyl)phenoxy]propionyl chloride with a hydroxyl group in 1,4dihydropyridines. Compounds 8 and 9 were obtained by the reactions of 2-methyl-2-[4-(4- chlorobenzoyl)phenoxy]propionyl chloride with salicylic aldehyde first, and then with β-aminocrotonates. All 1~10 are new compounds, and their structures were elucidated by means of 1HNMR and MS. The effects of compounds 1~10 on lowering cholesterol, triglyceride and blood pressure were investigated, and some of which were found to have the effects of lowering triglyceride and blood pressure. 相似文献
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New Constitutents from the Fresh Stems of Opuntia Dillenii 总被引:2,自引:0,他引:2
Aim:To study the chemical composition of Opuntia dillenii Haw.Methods:Many kinds of chromatography methods were used in the isolation procedure,while the structures of isolated compounds were determined on the aids of NMR and MS spectral analysis.Result:Three new compounds,together with 14 known compounds,were isolated form the 80% ethanolic extract of its stems.Conclusion:The three new compounds,opuntioside I(2),4-ethoxyl-6-hydroxymethyl.a-pyrone(3) and kaempferol 7-O-β-D-glucopyranosyl (1→4)-β-D-glucopyranoside(4),wene characterized. 相似文献
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Yue WANG ;Ming YAN ;Guang-yao ZHENG ;Ling HE ;Huan YANG 《Acta pharmacologica Sinica》2014,35(7):957-966
Aim: The aim of this study was to identify K-opioid receptor (KOR) agonists from a library of 80 000 small-molecule compounds and provide the experimental basis for the development of new analgesic candidates. Methods: The cell-based, high-throughput screen for human KOR agonists was based on the LANCETM cAMP assay. Preliminary structure-activity relationship (SAR) analysis was applied according to the compounds' structures. An acetic acid twisting experiment was used to verify the pharmacodynamics. Results: In total, 31 compounds were identified as KOR agonists after preliminary and secondary screening. Of these compounds, five demonstrated significant KOR-stimulating activity that was comparable to U-50,488, a selective KOR agonist. The ECho values for I-7, I-8, 1-10, 11-5, and 11-8 were 13.34±1.65, 14.01±1.84, 9.57±0.19, 14.94±0.64, and 8.74±0.72 nmol/L, respectively. Based on SAR studies, the stimulating activity of compounds with 5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyrimidine (group I) and 3,4-dimethoxy-N-(2-oxoethyl)-N-p-tolylbenzenesulfonamide (group II) parent structures were higher than the compound with a 5-hydroxy-2-methylbenzofuran-3-carboxylic acJd (group III) parent structure. PharmacodynarnJc experiments JndJcated that 20-40 μg/kg ip of compounds 1-10 and 11-8 significantly decreased the number of writhes induced by acetic acid; this finding is consistent with the SAR studies. Furthermore, the analgesic effects of compounds I-10 and II-8 were significantly antagonized in the presence of the selective KOR antagonist nor-BNI. Conclusion: These findings collectively indicate that compounds I-10 and II-8 exhibit significant analgesic activities, providing evidence, at least in part, for their clinical application as new analgesic drugs. 相似文献
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Aim: To study the Central pharmacological effect of the water - and chloroform - extract compounds from Cynanchum Chinese R. Br. Methods: The minimal neurotoxicity of the extract - compounds were measured by rotorod test. The Independent activity test and the hypnotic synergism test by under threshold hypnotic dosage of pentobarbital were employed to evaluate the central pharmacological action of the extract - compounds. All the extract - compounds were evaluated for anticonvulsant activity by maximal electroshock (MES) and subcutaneous metrazol (MET) induced seizure. Result: The extract - compounds significantly inhibited the spontaneous motor activity dose - dependently in mice after intraperitoneal administration. The two extract - compounds promoted the hypnotic effect by under threshold hypnotic doses of pentobarbital, and the ED50 values were 2.36 g/kg and 0. 75 g/kg, respectively. Meanwhile, the water - extract compounds exhibited significant protection after intraperitoneal (ip) administration in MET - induced seizures and the ED50 value was 2.34 g/kg; however, the chloroform - extract compounds did not produced protective effect in this seizure model. On the other hand, the chloroform - extract compounds exhibited significant protection in MES and the ED50 value was 1.34 g/kg; the water- extract compounds had no protective effect. Both extract -compounds showed no neurotoxicity as compared with phenytoin. Conclusion : The extract compounds from Cynanehum Chinese R. Br show inhibition effect on CNS, and the water - and chloroform - extract compounds show different anticonvulsant activities in different seizure models in mice. 相似文献
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Aim: Both endothelin ETA receptor antagonists and angiotensin AT1 receptor antagonists lower blood pressure in hypertensive patients. A dual AT1 and ETA receptor antagonist may be more efficacious antihypertensive drug. In this study we identified the mode and mechanism of binding of imidazole series of compounds as dual AT1 and ETA receptor antagonists. Methods: Molecular modeling approach combining quantum-polarized ligand docking (QPLD), MM/GBSA free-energy calculation and 3D-QSAR analysis was used to evaluate 24 compounds as dual AT1 and ETA receptor antagonists and to reveal their binding modes and structural basis of the inhibitory activity. Pharmacophore-based virtual screening and docking studies were performed to identify more potent dual antagonists. Results: 3D-QSAR models of the imidazole compounds were developed from the conformer generated by QPLD, and the resulting models showed a good correlation between the predicted and experimental activity. The visualization of the 3D-QSAR model in the context of the compounds under study revealed the details of the structure-activity relationship: substitution of methoxymethyl and cyclooctanone might increase the activity against AT~ receptor, while substitution of cyclohexone and trimethylpyrrolidinone was important for the activity against ETA receptor; addition of a trimethylpyrrolidinone to compound 9 significantly reduced its activity against AT~ receptor but significantly increased its activity against ETA receptor, which was likely due to the larger size and higher intensities of the H-bond donor and acceptor regions in the active site of ETA receptor. Pharmacophore-based virtual screening followed by subsequent Glide SP, XP, QPLD and MM/GBSA calculation identified 5 potential lead compounds that might act as dual AT1 and ETA receptor antagonists. Conclusion: This study may provide some insights into the development of novel potent dual ETA and AT1 receptor antagonists. As a result, five compounds are found to be the best dual antagonists against AT1R and ETA receptors. 相似文献
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Yi-ping ZHU ;Kun XIAO ;Hai-ping YU ;Lan-ping MA ;Bing XIONG ;Hai-yan ZHANG ;Xin WANG ;Jing-ya LI ;Jia LI ;Jing-kang SHEN 《中国药理学报》2009,(2):259-269
Aim: The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease β-secretase (BACE-1) bearing hydroxyethylene (HE) framework. Methods: First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode. Results: Thirteen new compounds (6-18) have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance (NMR) spectra, low-and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study. Conclusion: This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer's disease. 相似文献
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N. Najafi M. Pirali R. Dowlatabadi M. Bagheri N. Rastkari M. Abdollahi 《Pharmaceutical Chemistry Journal》2005,39(12):641-643
Several new N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides have been synthesized and characterized
with respect to acute toxicity (LD50), analgesic and antiinflammatory properties (formalin-and carrageenan-induced foot edema models), and interaction with morphine-induced
antinociception in mice. The new compounds were prepared by acyl coupling of 2-aminobenzophenones with α-(benzotriazol-1-yl)-N-acylglycines
followed by displacement of the benzotriazole ring with ammonia and cyclization of the resulting monoacyl aminals. The LD50 of the synthesized compounds exceeds 1000 mg/kg. Three compounds produced significant analgesic action in doses 100–150 μg/kg
in the early (painful) phase of the formalin test and potentiated the morphine-induced antinociception in this test. The synthesized
drugs neither showed antinociception in the second (inflammatory) phase of the formalin test nor decreased the carrageenan-induced
foot edema growth. Thus, the synthesized compounds produce analgesic action but do not possess antiinflammatory properties.
The analgesic activity is probably due to the interaction with μ-and δ-opioid receptors.
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Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 12, pp. 21–23, December, 2005. 相似文献
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Qiang QU Jian QU Lu HAN Min ZHAN Lan-xiang WU Yi-wen ZHANG Wei ZHANG Hong-hao ZHOU 《Acta pharmacologica Sinica》2014,35(5):685-696
Aim: Herbal products have been widely used, and the safety of herb-drug interactions has aroused intensive concerns. This study aimed to investigate the effects of phytochemicals on the catalytic activities of human CYP2D6*1 and CYP2D6*10 in vitro. Methods: HepG2 cells were stably transfected with CYP2D6*1 and CYP2D6*10 expression vectors. The metabolic kinetics of the enzymes was studied using HPLC and fluorimetry. Results: HepG2-CYP2D6*1 and HepG2-CYP2D6*10 cell lines were successfully constructed. Among the 63 phytochemicals screened 6 compounds, including coptisine sulfate, bilobalide, schizandrin B, iuteolin, schizandrin A and puerarin, at 100 pmol/L inhibited CYP2D6*1- and CYP2D6*10-mediated O-demethylation of a coumarin compound AMMC by more than 50%. Furthermore, the inhibition by these compounds was dose-dependent. Eadie-Hofstee plots demonstrated that these compounds competitively inhibited CYP2D6*1 and CYP2D6*10. However, their K1 values for CYP2D6*I and CYP2D6*IO were very close, suggesting that genotype- dependent herb-drug inhibition was similar between the two variants. Conclusion: Six phytochemicals inhibit CYP2D6*1 and CYP2D6*lO-mediated catalytic activities in a dose-dependent manner in vitro. Thus herbal products containing these phytochemicals may inhibit the in vivo metabolism of co-administered drugs whose primary route of elimination is CYP2D6. 相似文献
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Objective To determine the inhibitory effects of 21 resveratrol derivatives and 3 natural curcuminoids on lipopolysaccharide(LPS)-induced Nitric oxide(NO)and tumor necrosis factor-alpha(TNF-α)production in microglia and their structure-activity relationships.Methods Cell viability was evaluated by the MTT reduction assay.Accumulation of nitrite(NO2-)in culture supernatant fluids was measured by the Griess reaction.Sodium nitroprusside(SNP)(2.5 mM)solution was used to determine the scavenging activities of these compounds.The levels of TNF-α in the culture medium were measured by using an ELISA kit.Semi-quantitative RT-PCR analysis was used to determine the mRNA levels of inducible NOS(iNOS)and TNF-α.Results It was found,for the first time,that certain resveratrol derivatives that have 3,5-dimethoxyl groups in the A-ring,such as(E)-4-(3,5-dimethoxystyryl)phenol(pterostilbene,compound 2),or have substituted the B-ring of resveratrol with quinolyl,such as(E)-5-[2-(quinolin-4-yl)vinyl]benzene-1,3-diol(compound 18)and(E)-4-(3,5-dimethoxystyryl)quinoline(compound 19),strongly inhibited NO production.Compounds 2,18,and 19 reduced LPS-induced protein and mRNA expression of inducible NO synthase(iNOS),but did not display direct NO-scavenging activity up to 30 μM in sodium nitroprusside(SNP)solution.Moreover,compounds 2,18,and 19 could also significantly inhibit the production of TNF-α by LPS-activated microglia.Furthermore,we found the demethoxy derivatives of curcumin have more potent inhibition activity on NO and TNF-α releasing in activated-microglia.Conclusions In the present study we compared the activated-microglia inhibition effect of resvertrol,curcumin and their derivatives and provided a glance of the structure-activity relationships of these compounds,the information is beneficial to design new potent compounds which can provide better therapeutic implications for various neurodegenerative diseases. 相似文献
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LIJi-ren BAIYan-jing WANGBin CHENGang AITie-min ZHAOYu-ying 《中国药学》2003,12(4):181-183
Aim To separate and identify chemical constituents of Ehinacea purpurea. Methods Five compounds were isolated from the plant using chromatography. Their structures were elucidated by spectroscopy. Results Five compounds were isolated and their structures were identified as 2, 6-dimethyl-7-octene-2, 3, 6-triol-2-O-β-D-gtucopyranoside (1), 7, 8-furocoumarin (2), 6-methoxy-7-hydroxycoumarin (3), caffeic acid (4), methyl catfeate (5), and ethyl catfeate(6). Conclusion All these compounds were obtained from the plant for the first time. 相似文献
11.
1. A series of 1-(2-chloroacyl)ureas, related to the sedative-hypnotic drugs brom-valetone and carbromal, was synthesized and tested in mice to determine central depressant and acute toxic effects. Four 1-(2-bromoacyl)ureas and two 3-halo compounds were included for comparison. 2. Large variations in potency were seen between the compounds. Much of this can be ascribed to differences in lipophilicity. Among homologous 1-(2-chloroacyl)ureas, those with 6 acyl carbons had maximal potency. Among groups of structural isomers, the most potent were 2-halo, 3-alkyl substituted compounds. 3. The most potent compounds were also those with the largest ratios of hypnotic to lethal activity. 4. The variation in the onset and duration of action of these compounds enables a choice to be made for a compound with a particular set of characteristics. 相似文献
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2-去氧-2,3-去氢-N-三氟乙酰基神经氨酸8,9-二硫酸酯衍生物的合成 总被引:2,自引:0,他引:2
目的:合成2-去氧-2,3-去氢-N-三氟乙酰基神经氨酸(Neu5FA2en) 8,9-二硫酸酯衍生物。从中筛选有唾液酸酶抑制活性化合物。方法:以氢氧化钡脱除2-去氧-2,3-去氢-N-乙酰基神经氨酸(Neu5Ac2en)的N-乙酰基后,以三氟乙酸乙酯为三氟乙酰化试剂;以三氧化硫三甲胺复合物为硫酸酯化剂,合成目标化合物。结果:得到Neu5FA2en衍生物7个,均为新化合物。 结论:初步生物活性试验表明,所得化合物均具有一定的酶抑制活性,其中(10)的酶抑制活性较强。Neu5FA2en分子中三氟乙酰氨基与硫酸酯基具有协同作用,可增强对酶的抑制活性。 相似文献
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2-吲哚醛西佛碱化合物的合成及其抗癌活性研究 总被引:3,自引:0,他引:3
目的:合成一系列吲哚-2-位西佛碱衍生物,通过药理筛选寻找具有抗癌活性的化合物。方法:通过亲核取代、还原、氧化、亲核加成等反应得到目的化合物。结果:设计合成了22个吲哚-2-位西佛碱新化合物,药理筛选结果显示2个化合物(5,14)对KB癌细胞株有抑制作用。结论:药理筛选结果表明,一些化合物显示了一定的抗癌活性,值得进一步研究。 相似文献
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两头尖的化学成分研究 总被引:9,自引:0,他引:9
目的研究两头尖的化学成分。方法通过硅胶柱色谱,大孔树脂柱色谱及高压液相色谱等方法分离两头尖各部分提取物,根据理化性质和光谱分析鉴定化学结构。结果从两头尖根茎中分离得到9个化合物,分别鉴定为:27-hydroxyolean-12(13)-en-28-oic-acid-3-o-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside (1),五加苷K(eleutheroside K, 2),oleanolic acid-3-O-α-L-rhamnopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-α-L-arabinopyranoside (3),桦树脂醇(betulin, 4),桦树脂酸(betulic acid, 5),乙酰齐敦果酸(acetyloleamolic acid, 6),卫矛醇(evonymitol, 7),齐敦果酸(oleamolic acid, 8),薯蓣皂苷元(diosgenin, 9)。结论化合物1为新化合物,命名为raddeanoside 12。化合物3~7为首次自该植物中得到。 相似文献