半合成头孢菌素抗生素的研究——Ⅱ.7-(7-或8-取代香豆素-3-甲酰胺基)头孢菌素的合成

本文报道了以7-或8-取代香豆素-3-羧酸为侧链酸,用酰氯法和Vilsmeier试剂法与7-ADCA,7-ACA和7-ACT缩合,合成了17个7-或8-取代香豆素-3-甲酰胺头孢菌素类衍生物,通过有机溶媒、葡聚糖凝胶(Sephadex LH-20)及离心薄层层析纯化精制,得到纯品。初步抑菌试验结果表明:化合物V_2,V_3,V_8,V_9,V_(14)和V_(15)对耐药性金黄色葡萄球菌有较强的作用。     

4-喹诺酮-2-羧酸衍生物的合成及抗过敏作用

合成了一些7-位和5,8-位取代4-喹诺酮-2-羧酸衍生物。经药理筛选,发现化合物(24)(18)对大鼠被动皮肤过敏(PCA)的保护作用分别为98.5%和93.3%。     

3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与乙酰胆碱酯酶抑制活性

目的初步探讨在7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物母核C-3位苯环侧链中引入二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及其乙酰胆碱酯酶抑制活性。方法以取代的苯甲醛和乙酰甘氨酸为初始原料,经Erlenmeyer-Plchl反应、缩合反应、水解反应、缩合反应,生成6-芳甲基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮反应,得到6-芳甲基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物;以芳基乙烯为原料,经温和的氧化反应、缩合反应得到3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮在乙酸中反应得到6-芳基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。两条合成路线得到的3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物进一步经Williamson反应制备得到10个3-(烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。所有目标化合物结构均经质谱、红外光谱和核磁共振氢谱确证。采用Ellman法对目标化合物进行体外乙酰胆碱酯酶抑制活性筛选。结果根据前期已筛选化合物的活性数据和总结出的初步构效关系,设计并合成了10个C-3位苯环侧链中含有二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。体外乙酰胆碱酯酶抑制活性筛选表明,所有目标化合物均具有乙酰胆碱酯酶抑制活性,其中7个化合物在10μmol.L-1浓度水平抑制活性超过了50%。结论根据体外重组人源AChE(rhAChE)抑制活性的测试结果,发现C-3位苯环侧链中含有二乙胺基团的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物均具有较好的rh-AChE抑制活性。在这一位置的侧链中引入二乙胺基团,可以增强化合物对rhAChE的抑制活性。     

半合成头孢菌素抗生素的研究——Ⅱ.7-(7-或8-取代香豆素-3-甲酰胺基)头孢菌素的合成

本文报道了以7-或8-取代香豆素-3-羧酸为侧链酸,用酰氯法和Vilsmeier试剂法与7-ADCA,7-ACA和7-ACT缩合,合成了17个7-或8-取代香豆素-3-甲酰胺头孢菌素类衍生物,通过有机溶媒、葡聚糖凝胶(Sephadex LH-20)及离心薄层层析纯化精制,得到纯品。初步抑菌试验结果表明:化合物V₂,V₃,V₈,V₉,V₁₄和V₁₅对耐药性金黄色葡萄球菌有较强的作用。     

恩诺沙星C-3上1,2,4-三唑硫基乙酰腙类化合物的合成及抗肿瘤活性

目的基于氟喹诺酮的作用机制和结构特征设计抗肿瘤氟喹诺酮化合物。方法 1,2,4-三唑杂环作为恩诺沙星C-3上羧基的电子等排体,硫基乙酰腙作为功能修饰侧链,设计合成了新的1,2,4-三唑硫基乙酰腙类氟喹诺酮C-3衍生物(7a-7l),其结构经元素分析和光谱数据确证,用M TT[3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide]方法评价了体外对SMMC-7721、L1210和HL60共3种癌细胞的抗增殖活性。结果合成了12个新目标物,对3种癌细胞抗肿瘤活性强于母体恩诺沙星。构效关系表明,2-羟基苯环基或吸电子基取代苯基类化合物的活性强于其他取代基的化合物,其中对SMMC-7721细胞的活性与对照阿霉素相当。结论硫基乙酰腙功能基修饰的1,2,4-三唑杂环替代氟喹诺酮C-3上羧基有利于提高抗肿瘤活性。     

3-取代-1(3H)-异苯并呋喃酮光学异构体的合成及抗血小板活性初步研究

目的为开发高效、低毒的新型抗脑卒中药物,设计一系列3-取-代1(3H)-异苯并呋喃酮衍生物,研究这类化合物的抗血小板活性。方法以邻苯二甲酸酐为起始原料合成了一系列3-取代-1(3H)-异苯并呋喃酮6a-g以及7a-g,拆分了化合物6a-g。使用Born氏法体外实验评价了这类化合物的抗血小板活性。结果抗血小板活性强弱顺序为:l-异构体>dl消旋体>d-异构体;烷基苯酞的活性要强于相应的烯基苯酞。所合成的目标化合物活性均弱于正丁基苯酞(NBP,6c)及阿司匹林(Asp)。结论异苯并呋喃酮类化合物抗血小板活性可能与分子大小及构型有关,不同取代基作用强度总体趋势随取代基增大而减弱,体内生物大分子可能对该类化合物存在立体选择性。     

异黄酮衍生物的合成Ⅱ.7-氯和6-氯-7-甲氧基-3′-(N,N-二乙胺甲基)-4′-羟基异黄酮的合成

合成了7-氯和-6-氯-7-甲氧基-3′-(N,N-二乙胺甲基)-4′-羟基异黄酮(1478和1481)。它们的合成是由间-氯苯酚或3-羟基-4-氯苯酚与对-硝基苯乙酰氯反应,制得取代的脱氧安息香。它们与原甲酸乙酯环合得到取代的-4′-硝基异黄酮,再将化合物中的硝基用锌粉还原成氨基,再经重氮化和水解,得到取代的-4′-羟基异黄酮。它们经Mannich反应,最后制得7-氯和6-氯-7-甲氧基-3′-(N,N-二乙胺甲基)-4′-羟基异黄酮。它们耐氧作用不如已合成的7-甲氧基-3′-(N,N-二烷胺甲基)-4′-羟基异黄酮。     

2-取代胺甲基-5(6)-(E)-取代亚甲基环戊(己)酮盐酸盐类化合物的设计、合成及其抗肿瘤活性

目的设计合成20个2,5(6)-双取代环戊(己)酮类化合物,进行抗肿瘤活性研究。方法以WB852为先导化合物,设计合成了20个2-取代胺甲基-5(6)-(E)-取代亚甲基环戊(己)酮盐酸盐类化合物。利用MTT法对其中17个化合物进行了体外细胞毒活性筛选,所用肿瘤细胞株为人乳腺癌细胞T47D、MCF-7、MCF-7/Adr;通过Habig的酶动力学方法,测试了部分目标化合物细胞外对GSTπ活性的影响。结果与结论合成了20个2-取代胺甲基-5(6)-(E)-取代亚甲基环戊(己)酮盐酸盐类化合物,其中16个为未见文献报道的新化合物,其结构均经1H-NMR、MS和IR确证。体外抗肿瘤活性筛选结果,17个化合物对3种肿瘤细胞均有不同程度的生长抑制活性,A-16、A-17、A-18、A-19等4个化合物活性显著,值得进行深入研究。9个化合物均有不同程度地抑制GSTπ的活性,其中A-4、8、9、11和15等5个化合物对GSTπ的抑制作用强于WB852。取代胺甲基部分、取代亚甲基侧链的改变以及环的大小对抗肿瘤活性和选择性影响不大,但显著影响对GSTπ的抑制作用。A-16、A-17、A-18、A-19对MCF-7/Adr的生长抑制作用与WB852相当,但均低于对MCF-7细胞的活性,对耐药细胞的活性与GSTπ抑制无关。     

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…     

4-甲基-香豆素及4-甲基喹啉-2(1H)-酮的7位羟基、巯基与炔丙基卤代物的不同反应性

目的合成具有抗HIV活性的三环杂环化合物的关键中间体.方法 7-羟基-4-甲基-香豆素、7-羟基-4-甲基喹啉-2(1H)-酮、7-巯基-4-甲基-香豆素分别与3-氯-3-甲基-1-丁炔、3-溴丙炔反应得到相应产物,其结构经波谱确证.结果 4-甲基-香豆素的7位羟基发生正常的双分子亲核取代反应(SN2),得到炔丙基醚产物4、7和10,进一步热环合得到三环杂环化合物5、8和11;7-巯基-4-甲基-香豆素、7-巯基-4-甲基喹啉-2(1H)-酮与3-氯-3-甲基-1-丁炔反应分别得丙二烯醚双分子亲核取代反应(SN2′)产物聚集双键硫醚化合物12和14,且不能进一步热环合成三环杂环.结论 4-甲基-香豆素及4-甲基喹啉-2(1H)-酮的7位羟基、巯基与炔丙基卤代物表现出不同的反应性.     

2-甲酰(乙酰)取代喹啉缩氨基硫脲的合成

缩氨基硫脲类化合物有抗肿瘤、抗病毒和抗菌等多种药理活性。Barret等首次报道了乙二醛二缩氨基硫脲(Ⅰ)的抗疟活性。Klayman等研究了缩     

Synthesis and analgesic and antiinflammatory activity of methyl 6-substituted-3(2h)-pyridazinone-2-ylacetate derivatives

A series of methyl 6-substituted-3(2H)-pyridazinone-2-ylacetates 9 were synthesized and their analgesic and anti-inflammatory effects were evaluated in the phenylbenzoquinone-induced writhing test (PBQ test) and carrageenan-induced paw edema method, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. Methyl 6-(4-(4-fluorophenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9e was found to be more active than acetylsalicylic acid (ASA). Methyl 6-(4-(2-ethoxyphenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9c has shown an anti-inflammatory activity as compared to the standard compound indometacin at the carrageenan-induced paw edema method.A significant dependence of the anti-inflammatory effect on the substituents has been observed. The pharmacological study of these compounds confirms that modification of the chemical group at the position 6 of the 3(2H)-pyridazinone system influences analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and (1)H-NMR spectra and elemental analysis.     

Antibacterial activity of morin and its complexes with La(III), Gd(III) and Lu(III) ions

The antibacterial activity of morin, sodium salt of morin-5"-sulfonic acid (NaMSA) and new complexes of La (II), Gd (III) and Lu (III) with morin were tested against three bacterial strains: Escherichia coli G (-), Klebsiella pneumoniae G (-), Staphylococcus aureus G (+) and compared with the activity of penicillin. All of the complexes possess inhibitory action against the tested strains. The activity of the studies compounds depends on their concentration. The complexes at a concentration of 10 microg/cylinder demonstrated higher activity than morin alone, but at a concentration of 100 microg/cylinder morin was the most effective inhibitor against the strains used in this investigation.     

Synthesis and evaluation of anti-inflammatory and analgesic activity of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-ones

A novel series of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-one (7a–i) were synthesized by the condensation between the appropriately substituted 5-substituted-1,3,4-oxadiazolyl-2-thione (4a–i) derived from various existing NSAIDs and 3-(2-bromoacetyl)-2H-chromen-2-one (6) under reflux in the presence of sodium ethoxide. Structure of the synthesized compounds was established on the basis of physicochemical, elemental analysis, and spectral data. The title compounds were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 200 mg/kg bw. Among the series, four compounds 7c, 7e, 7f, and 7h were found to possess a significant anti-inflammatory and analgesic activity profile. In addition, these compounds were also found to possess a less degree of ulcerogenic potential as compared to standard NSAIDs.     

Synthesis and analgesic and anti-inflammatory activity of ethyl (6-substituted-3 (2H)-pyridazinone-2-yl)acetate derivatives

A number of 6-substituted-3(2H)-pyridazinones and the corresponding methyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives carrying the arylpiperazinyl structure present in potent antinociceptive agents reported in the literature were synthesized. As part of a programme a series of diverse arylpiperazine derivatives of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate were prepared and tested for their in vivo analgesic and anti-inflammatory activity by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference non-steroidal anti-inflammatory drugs (NSAIDs). On the basis of available data, the structure-activity relationship in the series of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives was also discussed. When compared to parent 6-substituted-3(2H)-pyridazinones, the new ester derivatives, for example ethyl (6-4-[(2-fluoro)phenyl]piperazine-3(2H)-pyridazinone-2-yl)acetate exhibited better analgesic and anti-inflammatory activity and a lower ulcerogenic effect.     

Synthesis of some new quinoxalines and 1,2,4-triazolo[4,3-a]-quinoxalines for evaluation of in vitro antitumor and antimicrobial activities

Two novel series of quinoxalines derived from 3-phenylquinoxalin-2(1H)-one and 2-hydrazino-3-phenylquinoxaline, namely 1-substituted-3-phenylquinoxaline-2(1H)-ones, 2a-c, 3a-d, and 4; 2-(3-oxo-3,3a,4,5,6,7-hexahydroindazol-2-yl)-3-phenylquinoxaline 6; N- cyclopentylidene or benzylidene-N'-(3-phenylquinoxaline-2-yl)hydrazines, 7 and 18; 1-substituted-4-phenyl-1,2,4-triazolo[4,3-a]quinoxalines, 9, 10, 12, 13, 14, and 16 have been synthesized in order to evaluate their antitumor and antimicrobial activities. Preliminary screening at NCI showed that compounds 2b, 2c, 3b, 3c, and 9 exhibited a moderate to strong growth inhibition activity on various tumor panel cell lines between 10(-6) to 10(-5) molar concentrations. Compound 3b was the most active with a broad spectrum of activity. Compound 3c showed selectivity towards CNS-cancer SF-639, leukemia CCRF-CEM, and melanoma SK-MEL-5 (GI(50) = 4.03, 6.46, and 4.17 microM, respectively). On the other hand, the in vitro microbiological data revealed that the prepared compounds showed mild antimicrobial activity.     

Synthesis of some 1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones with potential analgesic and antiinflammatory activities

Starting from 3-substituted-1,2,4-triazole-5-thiones (la-h), eight new 5-carbomethoxy-2-substituted-7H-1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones (2a-h) were synthesized and characterized by spectral and elementary analysis. The obtained compounds were submitted to preliminary pharmacological assay to evaluate their antiinflammatory and analgesic activities as well as gastrointestinal irritation liability and acute toxicity. Among the compounds studied, compounds 2c, 2d, 2e and 2h showed most remarkable antiinflammatory activity in the carrageenan and serotonin induced edema and in the inhibition of castor oil-induced diarrhea tests. The analgesic activity of these active compounds correlated with their antiinflammatory activities in the inhibition of acetic acid-induced writhing test. In gastric ulceration studies, the compounds were found safety at low dose levels (10 and 20 mg/kg).     

Synthesis of some halogen-containing 1,2,4-triazolo-1,3,4-thiadiazines and their antibacterial and anticancer screening studies--part I

A series of 7-arylidene-6-(2,4-dichloro-5-fluorophenyl)-3-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (3) were prepared by the condensation of 4-amino-5-mercapto-3-substituted-1,2,4-triazoles (1) and 3-aryl-1-(2,4-dichloro-5-fluorophenyl)-2-bromo-2-propen-1-one (2). An alternative route for the synthesis of the title compound 3 has been described. The newly synthesised compounds were characterised on the basis of N-analyses, IR, 1H NMR and mass spectral data. Some of the newly synthesised compounds were tested for their antibacterial activities against Gram + ve and Gram - ve bacteria. Among the tested compounds 3n showed the highest degree of antibacterial activity against S. aureus and evaluation of the LD50 value of this compound was carried out. Some of the newly synthesised compounds were also screened for their anticancer activities. Among these, compounds 3b, 3g, 3n and 3p are found to be active against NCI-H460 (lung), MCF7 (breast), SF 268 (CNS) in the preliminary anticancer screening studies. Further, 60-cell-line anticancer studies of these compounds were carried out. The results of such studies are discussed in this paper.     

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 2. Derivatives of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoic (-heptanoic) acids

A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)- enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibiti 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The most potent compounds exceeded mevinolin's activity in vitro and in vivo.