1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物的合成及其抗惊厥活性

目的寻找具有抗惊厥活性的1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物.方法以邻苯二甲酸酐为原料,先制备酞乙酸,再依次与氯化亚砜、胺反应合成9个(Z)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物;以氯乙酸为起始原料,依次与氯化亚砜、胺、三苯基膦反应制得季磷盐,再与邻苯二甲酸酐经Wittig反应又合成9个(E)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物.所有目标化合物的结构均经IR和1H-NMR确证.采用最大电休克发作实验(MES)对目标化合物进行抗惊厥活性筛选.结果合成了18个未见文献报道的新化合物.5e、5h和5i的抗惊厥活性ED50值分别为155.6、184.6和170.4mg·kg-1.结论 E型异构体较Z型异构体具有较好的抗惊厥活性,其构效关系和药理作用机制值得进一步研究.     

4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其对血小板聚集的抑制作用

目的:合成新的哒嗪酮类化合物,并研究其抗血小板凝集活性.方法:在6-(4-氯乙酰氨基苯基)-4,5-二氢-3(2H)哒嗪酮引入不同取代哌嗪,合成一系列化合物,并经过1H-NMR等确证;参考Born方法进行体外药理实验.结果:所有化合物都具有抗血小板凝集的活性,其中化合物(1)、(4)的抗血小板凝集活性明显优于MCI-154.结论:4-位取代哌嗪环基的引入对化合物抗血小板凝集的活性有显著影响.     

（E）-1（3H）-异苯并呋喃酮-△3-乙酰胺类化合物的合成及抗惊活性

目的 设计合成了(E)-1(3H)-异苯并呋喃酮-△3-乙酰胺类化合物，寻找具有抗惊活性的化合物。方法 以氯乙酸为起始原料，依次与氯化亚砜、胺、三苯膦反应制得季磷盐，再与邻苯二甲酸酐经Wittig反应制得目标化合物，硅胶柱色谱得纯品。通过最大电休克发作实验(MES)。对目标化合物进行抗惊活性筛选。结果 合成了9个新化合物，用IR和^1H-NMR进行结构确证，其中3个化合物有良好的抗惊活性。结论 E型异构体具有抗惊活性。     

(E)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物的合成及抗惊活性

目的设计合成了(E)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物,寻找具有抗惊活性的化合物.方法以氯乙酸为起始原料,依次与氯化亚砜、胺、三苯膦反应制得季磷盐,再与邻苯二甲酸酐经Wittig反应制得目标化合物,硅胶柱色谱得纯品.通过最大电休克发作实验(MES),对目标化合物进行抗惊活性筛选.结果合成了9个新化合物,用IR和1H-NMR进行结构确证,其中3个化合物有良好的抗惊活性.结论 E型异构体具有抗惊活性.     

西酞普兰中间体5-腈基异苯并呋喃-1-酮的合成研究

目的以简单易得的原料合成西酞普兰的中间体5-腈基异苯并呋喃-1-酮。方法以邻苯二甲酰亚胺为原料,通过硝化、还原、开环、环合、Sandmeyer反应、取代等6步反应制得5-腈基异苯并呋喃-1-酮。结果目标化合物经熔点测定、红外光谱、核磁共振氢谱等确证其化学结构。结论原料易得,方法简单,值得推广。     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED50值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED₅₀值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

6-芳香基-5-氧代-3(2H)-哒嗪酮的合成及其血小板聚集抑制作用的评价

分别以β-苯甲酰-γ-丁内酯(1a)和β-噻吩甲酰-γ-丁内酯(1b)为原料合成6-苯基-5-羟甲基-3(2H)-4,5-二氢哒嗪酮(2a)和6-(2-噻吩基)-5-羟甲基-3(2H)-4,5-二氢哒嗪酮(2b);将2a脱氢得6-苯基-5-羟甲基-3(2H)-哒嗪酮(5);将化合物5氧化得5位为甲醛基取代的化合物6,将6氧化为5位为羧基取代的化合物8;将2a氧化成5位为甲醛基取代的化合物7,将7氧化为5位为羧基取代的化合物9。通过体外进行各化合物对由ADP、凝血酶和胶原蛋白诱导的血小板聚集的抑制作用实验来评价其活性强度。结果表明,这类化合物对血小板聚集的抑制作用强烈地依赖于其5位的氧化程…     

《中南药学》2007年第5卷关键词索引

(E)-6-0-P-香豆酰鸡屎藤苷甲酯白花蛇舌草2种主要香豆酸类化学成分的含量测定5-4701(3H)-异苯并呋喃酮3-取代-~光学异构体的合成及抗血小板活性初步研究5-43310,11-二氢-10-羟基卡马西平反相高效液相色谱法测定血清中奥卡西平的代谢产物单羟基衍生物1-2824-dien-21-oic acid KT     

4,5-二氢-3(2H)-哒嗪酮衍生物的合成及抑制血小板聚集作用

目的设计并合成6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮衍生物,并对其抗血小板聚集活性进行初步评价.方法以苯酚为原料,经多步反应合成目标化合物,并以Born比浊法测试目标化合物的抗血小板聚集活性.结果共合成16个新化合物,经MS、1H-NMR确证其结构.其中12个化合物具有一定的抗血小板聚集活性.结论中间连接链的长度影响此类化合物抑制血小板聚集活性.当n=3、4时,所有化合物均具有一定的活性;当n=2时,仅有两个化合物具有活性.     

Synthesis and potential biological activity of some novel 3-[(N-substituted indol-3-yl)methyleneamino]-6-amino-4-aryl-pyrano(2,3-c)pyrazole-5-carbonitriles and 3,6-diamino-4-(N-substituted indol-3-yl)pyrano(2,3-c)pyrazole-5-carbonitriles

Starting from N-substituted indole-3-carboxaldehydes (1a-g) a series of new 3-[(N-substituted indol-3-yl)methyleneamino]-6-amino-4-aryl-pyrano(2,3-c)pyrazole-5-carbonitriles (3a-g and 4a-g) have been synthesized via the acid catalyzed condensation reaction of 1a-g with 3-amino-5-pyrazolone, followed by the reaction with arylidene malononitriles. A series of new 3,6-diamino-4-(N-substituted indol-3-yl)pyrano(2,3-c)pyrazole-5-carbonitriles (7a-g) have been prepared either via the base catalyzed condensation reaction of 1a-g with 3-amino-5-pyrazolone to give 6a-g, followed by the reaction with malononitrile or by the reaction of N-substituted-3-indolylidene malononitriles (5a-g) with 3-amino-5-pyrazolone. According to the obtained results, the newly synthesized compounds possess significant anti-inflammatory, analgesic and anticonvulsant activities. The anticonvulsant potency of certain tested compounds was more pronounced than both anti-inflammatory and analgesic activities. Moreover, most of the newly synthesized compounds possess potential antimicrobial activity against Escherichia coli and Pseudomonas aeruginosa.     

Synthesis and antimicrobial activity of acyclo C-nucleosides: 3-(alditol-1-yl)-7-oxo-5-phenyl-1,2,4-triazolo[4,3-a]pyrimidines

Condensation of 2-hydrazino-4-oxo-6-phenylpyrimidine (1) with aldopentoses 2a-d or aldohexoses 2e-g gave the corresponding aldehydo-sugar (4-oxo-6-phenylpyrimidin-2-yl)hydrazones 3a-g which were acetylated to the corresponding poly-O-acetyl-aldehydo-sugar (3-acetyl-4-oxo-6-phenylpyrimidin-2-yl)hydrazones 4a-g. The latter compounds underwent oxidative cyclization with bromine in acetic acid and in the presence of sodium acetate to the corresponding 8-acetyl-3- (poly-O-acetyl-alditol-1-yl)-7-oxo-5-phenyl-1,2,4-triazolo[4,3-a]pyrimid ines 6a-g. Compounds 6a-g were also obtained by consecutive one-pot oxidative cyclization/acetylation in which the parent hydrazones 3a-g were treated with bromine/acetic acid/sodium acetate followed by acetic anhydride. Deacetylation of 6a-g with ammonium hydroxide in methanol gave the title compounds 7a-g. The antibacterial and antifungal activities of compounds 3c, 3f, 7c and 7f are reported.     

Non-nucleoside HIV reverse transcriptase inhibitors, Part 6[1]: synthesis and anti-HIV activity of novel 2-[(arylcarbonylmethyl)thio]-6-arylthio DABO analogues

2-(Arylcarbonylmethyl)thio-6alpha-naphthylmethyl derivatives of dihydro-alkoxy-benzyl-oxopyrimidines (DABO) were newly found to exhibit activity against both HIV-1 and HIV-2. To further explore their structure-activity relationship, the modified S-DABO analogues (5a-g and 6e-f) with a 1-naphthylthio or phenylthio group at the C-6 position were synthesized. S-Alkylation of 5-ethyl-2-thiouracil with substituted 2-bromo-acetophenones provided crude 2-[(arylcarbonylmethyl)thio]-5-ethyl-(3H)-uracil 2a-e, which was directly subjected to toluenesulfonylation with TsCl to afford disulfonate 4a-e. Substitution of 4a-e with arylthiol afforded the desired S-DABO analogues 5a-g and 6e-f. The compounds were evaluated for their in vitro anti-HIV activity in MT-4 cells. The IC(50) values for anti-HIV-1 activity fall into the range 0.37-29.50 microM, and the IC(50) values for anti-HIV-2 activity fall into the range 23.11-181.07 microM. The results indicated that these compounds are moderately active against HIV-1 and HIV-2.     

Synthesis, antimicrobial, and anti-inflammatory activities of novel 2-[3-(1-adamantyl)-4-substituted-5-thioxo-1,2,4-triazolin-1-yl] acetic acids, 2-[3-(1-adamantyl)-4-substituted-5-thioxo-1,2,4-triazolin-1-yl]propionic acids and related derivatives

The reaction of 3-(1-adamantyl)-4-substituted-1,2,4-triazoline-5-thiones 3a-g with sodium chloroacetate, in ethanolic sodium hydroxide yielded the corresponding N1-acetic acid derivatives 4a-g. The interaction of 3a-g with ethyl 2-bromopropionate in acetone, in the presence of potassium carbonate, yielded the corresponding N1-ethyl propionate derivatives 5a-g, which upon hydrolysis with aqueous sodium hydroxide afforded the corresponding propionic acid derivatives 6a-g. Similarly, the reaction of 3-(1-adamantyl)-4-amino-1,2,4-triazoline-5-thione 7 with sodium chloroacetate in ethanolic sodium hydroxide yielded the corresponding N1-acetic acid derivative 8. On the other hand, the reaction of 2-(1-adamantyl)-1,3,4-oxadiazoline-5-thione 9 with sodium chloroacetate yielded the corresponding S-acetic acid derivative 10. Compounds 4a-g, 5b, 5c, 5g, 6a-g, 8 and 10 were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives produced good or moderate activities particularly against Bacillus subtilis. In addition, the in vivo anti-inflammatory activities of these compounds were determined using the carrageenin-induced paw oedema method in rats. Compounds 4a, 4b, 4e, 4f, 6f, 6g and 10 produced good dose-dependent anti-inflammatory activities.     

6-(4-取代乙酰氨基苯基)-4,5-二氢-3(2H)-哒嗪酮衍生物的合成及其抗血小板凝集活性

目的研究引入仲胺类基团对6-（4-取代乙酰氨基苯基）-4，5-二氢-3（2H）-哒嗪酮类化合物抗血小板凝集活性的影响。方法设计合成未见报道的目标化合物13个，用。H—NMR、IR、MS确证结构，参考Bom方法进行体外药理实验。结果与结论所有化合物都具有抗血小板凝集的活性，其中化合物6b、6g的抗血小板凝集活性明显优于MCI-154。仲胺类基团的空间位阻和亲水性对化合物抗血小板凝集的活性有影响。     

Synthesis and In Vitro Antioxidant Activity of New 3-Substituted-2-Oxindole Derivatives

A series of new 1,3-dihydro-3-hydroxy-3-(2-phenyl-2-oxoethyl)-2H-indol-2-ones (1a-g) and 1,3-dihydro-3-(2-phenyl-2-oxoethylidene)-2H-indol-2-ones (2a-g) were synthesised by Knoevenagel condensation of substituted indole-2,3-diones (isatins) with various acetophenones. The synthesised compounds were characterised by their physical data, elemental, IR, ¹H NMR, ¹³C NMR and mass spectral analyses and their in vitro antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay. These compounds showed moderate to good antioxidant activities as compared with the standard, ascorbic acid. The antioxidant potential of 3-hydroxy-3-substituted oxindoles (1a-g) increased in a concentration-dependent manner from 10 to 500 μg/ml with 5-fluoro and 5-methyl analogues showing maximum activity. Of 3-aroyl methylene indol-2-ones (2a-g), majority of compounds with halogen substitution at position 5 of isatin ring exhibited good antioxidant activity within a concentration range of 5-100 μg/ml and the maximum activity was observed at 20 and 25 μg/ml concentrations. Thus, our study provides evidence that some newly synthesised isatin derivatives exhibit substantial antioxidant activity at low concentrations.     

Synthesis, modelling, and mu-opioid receptor affinity of N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicycl

A series of N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes (1a-g) and of reverted N-3-propionyl-N-9-arylpropenyl isomers (2a-g), as homologues of the previously reported analgesic 3,8-diazabicyclo[3.2.1]octanes (I-II), were synthesized and evaluated for the binding affinity towards opioid receptor subtypes mu, delta and kappa. Compounds 1a-g and 2a-g exhibited a strong selective mu-affinity with Ki values in the nanomolar range, which favourably compared with those of I and II. In addition, contrary to the trend observed for DBO-I, II, the mu-affinity of series 2 is markedly higher than that of the isomeric series 1. This aspect was discussed on the basis of the conformational studies performed on DBN which allowed hypotheses on the mode of interaction of these compounds with the mu receptor.     

Antiplatelet effect and selective binding to cyclooxygenase by molecular docking analysis of 3-alkylaminopropoxy-9,10-anthraquinone derivatives

In an effort to develop potent cytotoxic inhibitors of cyclooxygenase (COX), a series of cytotoxic 3-alkylaminopropoxy-9,10-anthraquinone derivatives was screened to evaluate their antiplatelet effect on washed rabbit platelets and human platelet-rich plasma (PRP). Thrombin, arachidonic acid (AA), collagen, and platelet-activating factor (PAF) induced platelet aggregations were potently inhibited by compounds 1, 2, and 3 (each at 300 microM). Of the compounds tested in human PRP, compounds 1, 8, and 10 showed significant inhibition of primary and secondary aggregation induced by epinephrine and had a weak inhibitory effect on cyclooxygenase-1 (COX-1). Molecular docking studies revealed that compounds, 1, 8, and 10 were bound in the active sites of COX-1. This indicated that the antiplatelet effect of these three compounds was partially mediated through the suppression of COX-1 activity and reduced thromboxane formation. It is concluded that the cytotoxic compounds 1, 8, and 10 may interfere the conversion of arachidonic acid to prostaglandin (PG)H(2) in the active site of COX-1.     

Synthesis of 2,3,5,6-tetrahydro-3H-imidazo[2,1-b] [1,3,5]benzotriazepines and their oxidative ring contraction into 1-(4,5-dihydro-1H-imidazol-2-yl)-1H-benzimidazoles

Syntheses of novel 5-aryl-2,3,5,6-tetrahydro-3H-imidazo[2,1-b] [1,3,5]benzotriazepine derivatives 3a-g were performed by reacting 2-(2-aminoarylimino)imidazolidines 1a-b with corresponding aryl aldehydes. The compounds 3 incorporating aminal group upon treatment with 2,3-dichloro-5,6-dicyano-1,2-benzoqinone (DDQ) underwent the oxidative ring contraction to give 1-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-benzimidazoles 4a-g. Reactions of the compounds 1a-c with carbonyldiimidazole (CDI) afforded novel 2,3,5,6-tetrahydro-1H-imidazo[2,1-b] [1,3,5]benzotriazepin-5-ones 5a-c which when heated in boiling methanol gave the corresponding 1-(4,5-dihydro-1H-imidazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-ones 6a-c. Radioligand binding studies using rat central imidazoline I2 receptors and alpha2-adrenoceptors demonstrated that benzimidazoles 4a-g display a low affinity (microM) for these receptors while benzimidazol-2-ones 6a-b elicited a moderate affinity for I2 receptor with Ki values of 490 and 220 nM, respectively.     

Synthesis and anticonvulsant activity of a new series of 1,4-dihydropyridine derivatives

A series of 1,4-dihydropyridine derivatives (1a-g) were prepared from three compounds condensation of Hantzsch synthesis. A new series of 2,2'-{[4-(aryl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]dicarbonyl}dihydrazinecarbothioamide (2a-g) were prepared from compounds diethyl 4-(aryl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1a-g) reacted with thiosemicarbazide to give the corresponding compounds (2a-g) by hydrazinolysis method. The synthesized compounds were confirmed by IR, (1)HNMR, (13)CNMR, mass spectral and elemental analyses. The newly synthesized compounds (2a-g) were screened for anticonvulsant activity against in swiss albino rat. The test was evaluated by maximal electrode induced convulsion method. Synthesized compounds were used two (50 and 100 mg/kg) concentrations. Compounds (1a-g) were inactive while compounds (2a-g) have moderate anti-convulsant activity compared with standard phenytoin drug. The compound 2,2'-{[4-(furan-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]dicarbonyl} dihydrazinecarbothioamide (2a) has highly active compared with other compound (2b-2g).