吡嗪类碳酰肼化合物与CT-DNA相互作用及体外抑菌

以5-氯吡嗪-2-羧酸甲酯和水合肼为原料,经亲核取代和脱水缩合反应合成了3种新型吡嗪类碳酰肼化合物C13H14N6O(a)、C13H14N6O2(b)和C12H12N6O2(c)。采用元素分析与核磁共振氢谱对化合物a~c进行了表征,结果表明合成的产物即为目标化合物。通过溶剂挥发法培养得到了化合物a的单晶并利用X-射线单晶衍射测定化合物a的晶体结构为单斜晶系。根据紫外-可见光谱可知,化合物a~c均以插入模式与CT-DNA作用。利用微量热实验测定了化合物a~c与CT-DNA的相互作用,发现反应过程放热,热效应ΔH依次为-5.77×103、 -5.50×103和-5.96×103 kJ·moL-1,反应时间均小于40 min。通过分子对接模拟计算明确了化合物a和b与DNA的具体结合位点包括A链DC4和DG5以及B链DC4、 DG5和DA6,化合物c与DNA的具体结合位点包括A链DC4和DG5以及B链DC4和DG5。采用牛津杯法测定了化合物a~c对枯草芽孢杆菌、金黄色葡萄球菌、铜绿假单胞菌以及大肠杆菌四种细菌的抑菌活性,结果表明化合物a~c均对铜绿假单胞菌表现出优于阳性对照组四环素的抑菌活性。     

二茂铁基查尔酮衍生物的超快三阶非线性光学响应

合成三例二茂铁基查尔酮衍生物:1-二茂铁基-3-(5-溴噻吩-2-基)-2-丙烯-1-酮(1)、1-二茂铁基-3-(4-溴噻吩-2-基)-2-丙烯-1-酮(2)和1-二茂铁基-3-(5-氯噻吩-2-基)-2-丙烯-1-酮(3);采用1H NMR、13C NMR和HR-MS对化合物1～3进行了结构表征,并测定了其热学性质;运用密度泛函理论方法进行结构优化,并计算得到了它们的分子轨道能量和极化率;采用紫外-可见吸收光谱与Z-扫描技术(532nm,180fs)分别测定了三种化合物的线性和非线性光学性质。结果表明,化合物1～3的紫外吸收波长发生明显红移,且1的非线性吸收幅度、极化率和分子超极化率最大; 1、2和3均存在分子内电荷转移现象,表现出超快三阶非线性光学响应。     

Synthesis and in-vitro antioxidant activities of some coumarin derivatives containing 1,2,3-triazole ring

A new green protocol was developed for the S-alkylation of 2-mercapto-1,3,4-oxadiazole by the reaction of 5-substituted-2-mercapto-1,3,4-oxadiazole with propargyl bromide in sodium bicarbonate in water. The newly synthesized 5-[(substitutedphenoxy)methyl]-2-[(prop-2-yn-1-yl)sulfanyl]-1,3,4-oxadiazole when reacted with azidomethyl coumarins underwent regioselective reaction yielding 4-(((4-((5-((substitutedphenoxy)methyl)-1,3,4-oxadiazol-2-yl)sulfanylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methyl)-2H-chromene-2-one or 1-((4-((5-((substitutedphenoxy)methyl)-1,3,4-oxadiazol-2-yl)sulfanylmethy)-1H-1,2,3-triazol-1-yl-)methyl)-3H-benzo[f]chromene-3-one. Structures of the newly synthesized compounds were confirmed by spectral and analytical data. The compounds were screened for their in-vitro antioxidant property.     

Synthesis and biological evaluation of some new substituted benzoxazepine and benzothiazepine as antipsychotic as well as anticonvulsant agents

Various 2-((2-((5-benzylideneamino)-1,3,4-oxa/thiadiazol-2-yl)methyl)hydrazinyl) methyl)benzo[b][1,4]oxa/thiazepin-4(5H)-ones (4a–4l), 2-((2-((5-(4-oxo-2-substitutedphenyl thiazolidin-3-yl)-1,3,4-oxa/thiadiazol-2-yl)methyl)hydrazinyl)methyl)benzo [b] [1,4]oxa/thiazepin-4(5H)-ones (5a–5l) and 2-((2-((5-(3-chloro-2-(substitutedphenyl)-4-oxoazetidin-1-yl)-1,3,4-oxa/thia diazol-2-yl)methyl)hydrazinyl)methyl)benzo[b][1,4]oxa/thiazepin-4(5H)-ones (6a–6l) have been synthesized. The structures of these compounds have been established by elemental (C, H, N) and spectral (IR, ¹H-NMR and Mass) analysis. The synthesized compounds were screened for their antipsychotic and anticonvulsant activities. Compound 5l was found to be the most active compound of this series.     

Synthesis and pesticidal activities of novel anthranilic diamides containing pyridylpyrazole and iminodithiocarbamate or thiosemicarbazone motifs

Abstract

A series of novel anthranilic diamide derivatives containing pyridylpyrazole and iminodithiocarbamate or thiosemicarbazone motifs were synthesized via multi-step reactions. The structures of seven title compounds (methyl 2-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3- methylbenzylidene)hydrazinecarbodithioate 7 and 3-bromo-N-(2-((2-substitutedcarbamothioylhydrazono)methyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide 8a-8f) were confirmed by melting points, IR, ¹H NMR, ¹³C NMR, and HRMS. The bioassays showed that some of the compounds exhibited modest insecticidal activities against oriental armyworm (Mythimna separata Walker), particularly, compound 8b (3-bromo-N-(4-chloro-2-methyl-6-((2-(methylcarbamothioyl)hydrazono)methyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide) held 100% and 30% larvicidal activity at the concentration of 25?mg/L and 10?mg/L, respectively. In addition, several compounds displayed favorable fungicidal activities against Alternaria solani Sorauer and Physalospora piricola at 50?μg/mL, and were comparable with the controls Chlorothalonil and Triadimefon. The results in this paper will provide important information for further research and development of sulfur-containing heterocyclic agrochemicals.     

Rhenium tricarbonyl core complexes of thymidine and uridine derivatives

Thymidine and uridine were modified at the C2' and C5' ribose positions to form amine analogues of the nucleosides (1 and 4). Direct amination with NaBH(OAc)3 in DCE with the appropriate aldehydes yielded 1-{5-[(bis(pyridin-2-ylmethyl)amino)methyl]-4-hydroxytetrahydrofuran-2-yl}-5-methyl-1H-pyrimidine-2,4-dione (L1), 1-{5-[(bis(quinolin-2-ylmethyl)amino)methyl]-4-hydroxytetrahydrofuran-2-yl}-5-methyl-1H-pyrimidine-2,4-dione (L2), and 1-[3-(bis(pyridin-2-ylmethyl)amino)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1H-pyrimidine-2,4-dione (L5), while standard coupling procedures of 1 and 4 with 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid (2) and 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid (3) in the presence of HOBT-EDCI in DMF provided a second novel series of bifunctional chelators: 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid [(3-hydroxy-5-(5-methyl-4-oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl] amide (L3), 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid [(3-hydroxy-5-(5-methyl-4-oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl] amide (L4), 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid [2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl] amide (L6), and 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid [2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl] amide (L7). The rhenium tricarbonyl complexes of L1-L4, L6, and L7, [Re(CO)3(LX)]Br (X=1-4, 6, 7: compounds 5-10, respectively), have been prepared by reacting the appropriate ligand with [NEt4][Re(CO)3Br3] in methanol. The ligands and their rhenium complexes were obtained in good yields and characterized by common spectroscopic techniques including 1D and 2D NMR, HRMS, IR, cyclic voltammetry, UV, and luminescence spectroscopy and X-ray crystallography. The crystal structure of complex 6.0.5NaPF6 displays a facial geometry of the carbonyl ligands. The nitrogen donors of the tridentate ligand complete the distorted octahedral spheres of the complex. Crystal data: monoclinic, C2, a = 24.618(3) A, b = 11.4787(11) A, c = 15.5902(15) A, beta = 112.422(4) degrees , Z = 4, D(calc) = 1.562 g/cm3.     

新多取代吡啶类化合物的合成及生物活性

为寻找具有农用生物活性的新颖化合物,以2-氰基硫代乙酰胺为起始原料经由三步反应,设计并合成出了一系列新颖的多取代吡啶衍生物2-甲基-5-氰基-6-炔丙硫基-4-(2-呋喃基或噻吩基)吡啶-3-甲酸甲酯或乙酯和6-甲基-5-乙酰基-2-炔丙硫基-4-(2-呋喃或噻吩基)吡啶-3-乙腈.所有新化合物均经过1H NMR和元素分析确证.初步生物活性测定表明:化合物7有一定的除草和杀菌活性.     

硝基呋喃亚甲基哌啶类化合物的合成与抗结核活性

结核是由结核分枝杆菌引起的一种慢性呼吸道传染病,对人类的健康构成严重威胁。 本文利用药效团拼接原理,将片段硝基呋喃和苯基噻唑组合,得到了19个2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)噻唑(5)和2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)-4-苯噻唑(6)系列化合物,测试了所有化合物在1和0.1 μmol/L浓度下对结核分枝杆菌H37Ra的抑制率。 构效关系分析表明,苯环上有取代基有利于活性,且苯环上对位取代普遍优于间位和邻位取代,对位吸电子基团取代活性优于对位供电子基团取代活性。在苯环对位吸电子基团取代中,—CF₃取代的化合物2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)-4-(4-三氟甲基)苯基)噻唑(6f)活性最高,在1和0.1 μmol/L浓度下,抑制率分别为99.6%和93.4%。 鉴于新化合物具有抗结核高活性,化合物6f可作为抗结核候选化合物进一步研究。     

Design,Ultrasonic-assisted Synthesis and Evaluation In vitro Antimicrobial Activity of Bis-isoxazole Derivatives Bearing Chloro-pyridinyl Group

An ultrasonic-assisted synthesis of bis-isoxazole derivatives was developed. Eight 3-(6-chloropyridin-3-yl)-5-{[(3-aryli-soxazol-5-yl)methoxy]methyl}isoxazoles were synthesized by 1,3-dipolar cycloaddition reaction between substituted isoxazolyl alkyne compounds and 6-chloro-N-hydroxynicotinimidoyl chloride. The structures of the synthesized compounds were confirmed by HRMS, FTIR, ¹H and ¹³C NMR spectroscopy. Wherein, the antifungal and antibacterial activities of target compounds were tested. The synthesized compounds 6a and 6h exhibited better antifungal activity in comparison with the standard drug itraconazole. The minimum inhibitory concentrations(MICs) of both compound 6a and compound 6h were both 4 μg/mL against Candida albicans ATCC 10231.     

含苯并噻唑砌块的2,4,6-三取代嘧啶衍生物的合成及抗肿瘤活性评价(英文)

为了寻找高效的抗肿瘤药物,设计并合成了一系列含苯并噻唑砌块的2,4,6-三取代嘧啶衍生物.采用噻唑蓝(MTT)法对目标化合物在人类四种癌细胞[EC-109(人食管癌细胞)、MGC-803(人胃癌细胞)、PC-3(人前列腺癌细胞)、Hep G-2(人肝癌细胞)]、GES-1(人正常胃黏膜上皮细胞)和HEEC(人正常食管细胞)中进行抗肿瘤活性评价,结果显示部分化合物对MGC-803和PC-3细胞表现出中度至强效的抗肿瘤活性.其中2-(((4-(4-(吡啶-2-基)哌嗪-1-基)-6-(三氟甲基)嘧啶-2-基)硫基)甲基)苯并[d]噻唑(13h)和2-(((4-(4-(嘧啶-2-基)哌嗪-1-基)-6-(三-氟甲基)嘧啶-2-基)硫代)甲基)苯并[d]噻唑(13i)对PC-3表现出比较好的抗肿瘤活性, IC50值分别3.82和2.29μmol/L,且化合物13h和13i对GES-1的细胞增值毒性明显小于阳性对照5-氟尿嘧啶.     

新型α1受体拮抗剂先导化合物的寻找(I): 5-氯-2-(4-(芳氧烷基)哌嗪-1-基)苯并噁唑类化合物的设计、合成及生物活性研究

为寻找用于治疗良性前列腺增生的新型α1受体拮抗剂, 以本研究组发现的2-[(4-(2-(2-氯苯氧基)乙基)哌嗪-1-基)甲基]-5-甲基苯并噁唑(wb5c)为先导化合物, 结合已构建的α1-AR拮抗剂药效团模型, 通过骨架改造, 设计出以苯并噁唑-2-基哌嗪为母核的目标物, 然后以5-氯-2-氨基酚和取代苯酚为原料, 经缩合、卤代、氨化、Williamson醚合成、取代等反应共合成11个新目标化合物, 结构经ESI-MS, 1H NMR, IR及HRMS确证. 初步药理活性实验表明, 目标物具有中等强度α1受体拮抗活性, 符合我们提出的三元素药效团模型. 5-氯-2-[4-(芳氧烷基)哌嗪-1-基]类化合物是一类新的具有潜在开发价值的α1受体拮抗剂.     

Synthesis and some transformations of methyl [4-(oxoacetyl)phenyl]carbamate

The oxidation of methyl (4-acetylphenyl)carbamate with selenium dioxide in dioxane–water (30: 1) gave methyl [4-(oxoacetyl)phenyl]carbamate whose condensation with ethyl acetoacetate or diethyl malonate and hydrazine hydrate afforded ethyl 3-methyl-6-[4-(methoxycarbonylamino)phenyl]pyridazine-4-carboxylate and methyl {4-[5-(hydrazinecarbonyl)-6-oxo-1,6-dihydropyridazin-3-yl]phenyl}carbamate, respectively. The reaction of methyl [4-(oxoacetyl)phenyl]carbamate with o-phenylenediamine in dimethylformamide–ethanol on heating led to the formation of methyl [4-(quinoxalin-2-yl)phenyl]carbamate. Methyl {4-(5,7-dioxo- 4,4a,5,6,7,8-hexahydropyrimido[4,5-c]pyridazin-3-yl)phenyl}carbamate and methyl {4-(5-oxo-7-sulfanylidene- 4,4a,5,6,7,8-hexahydropyrimido[4,5-c]pyridazin-3-yl)phenyl}carbamate were synthesized by reactions of methyl [4-(oxoacetyl)phenyl]carbamate with barbituric and thiobarbituric acids, respectively, and hydrazine hydrate in the presence of zirconyl chloride octahydrate at room temperature.     

芳基噻唑联哌啶酰胺类化合物的合成及生物活性

为了寻找具有生物活性的新型芳香基噻唑联哌啶酰胺类先导化合物,设计并合成了15个未见文献报道的芳基噻唑联哌啶酰胺类化合物,其结构经1HNMR、13CNMR和HRMS确证,生物活性测定结果显示,部分目标化合物表现出高效的抑菌和杀虫活性,如在200μg/mL浓度下,5-(3-溴苯基)-4-甲基-2-(1-((4-硝基苯基)磺酰基)哌啶-4-基)噻唑(6b)对黄瓜霜霉病的抑菌活性为100%,优于嘧菌酯,5-(4-溴苯基)-2-(1-((4-氯苯基)磺酰基)哌啶-4-基)-4-甲基噻唑(6c)对水稻纹枯病的抑菌活性为58.86%,与嘧菌酯相当;在500μg/m L浓度下,(4-(5-(3-溴苯基)-4-甲基噻唑-2-基)哌啶-1-基)(间甲基苯基)酮(6h)对粘虫的杀虫活性为100%.     

Assessment of the in vivo genotoxicity of new lead compounds to treat sickle cell disease

The compounds 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl nitrate (C1), (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl nitrate (C2), 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (C3), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (C4), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (C5), and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate (C6) were evaluated with a micronucleus test using mouse peripheral blood to identify new candidate drugs for the treatment of sickle cell disease (SCD) that are safer than hydroxyurea. The compounds induced an average frequency of micronucleated reticulocytes (MNRET) of less than six per 1,000 cells at 12.5, 25, 50, and 100 mg/kg, whereas hydroxyurea induced an average MNRET frequency of 7.8, 9.8, 15, and 33.7 per 1000 cells respectively, at the same concentrations. Compounds C1-C6 are new non-genotoxic in vivo candidate drugs for the treatment of SCD symptoms.     

A Convenient Synthesis and Herbicidal Activity of N-phosphonoalkylpyrazolo[4,3-e][1,2,4]-triazolo[1,5-d]pyrimidines

An important building block, diethyl [(5-amino-4-cyano-3-methylsulfanyl-pyrazol-1-yl)–(4-fluorophenyl)methyl] phosphonate (3) was efficiently synthesized via the condensation of 1-hydrazino-1-(4-fluorophenyl)methyl phosphonate (1) with 2-[bis(methylthio)methylene]malononitrile (2).3 reacted with triethyl orthoformate to afford diethyl [(4-cyano-5-ethoxymethyleneamino-3-methylsulfanyl-pyrazol-1-yl)-(4-fluorophenyl)methyl] phosphonate (4), which reacted with various acyl hydrazines in refluxing 2-methoxyethanol to provide the target compounds (5) in good yields directly. The results of preliminary bioassay indicated that compounds 5 possess potent herbicidal activity against the roots of monocotyledonous (barnyard grass) and dicotyledonous (oil rape) plants, and could be further developed as potential herbicides.     

N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)酰胺类新化合物的合成及生物活性

以N-吡啶基吡唑甲酸和2-氨基-3-甲基苯甲酸为起始原料,经由亲核加成、环化和酰化等多步反应合成了一系列结构新颖的N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)酰胺类化合物.测试了所合成化合物的杀虫及抑菌活性,结果表明,新化合物大多化合物在200 mg·L^-1浓度下对东方粘虫(Mythimna separataWalker)具有一定的杀虫活性,尤其是N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)乙酰胺(8a)和N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)-3-氯-2,2-二甲基丙酰胺(8e)致死率可达70%;部分化合物在50 mg·L^-1浓度下对油菜菌核病菌的抑菌活性相对较好(54.5%~63.6%),优于triadimefon和chlorantraniliprole;部分化合物如N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)-3,3-二甲基丁酰胺80和N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)-4-氟苯甲酰胺(8h)对苹果轮纹病菌具有中等抑菌活性.值得注意的是,化合物8e的杀粘虫活性和对油菜菌核病菌的抑菌活性都较为突出,可用作新农药创制研究的新型参考结构.     

Synthesis and plant-growth regulatory activities of novel imine derivatives containing 1H-1,2,4-triazole and thiazole rings

<正>Eleven new imine derivatives 6 containing 1H-1,2,4-triazole and thiazole rings were synthesized by the condensation of 5-((1H- 1,2,4-triazol-1-yl)methyl)-4-tert-butylthiazol-2-amine with various substituted benzaldehydes.The structures of the title compounds were characterized by ~1H NMR,MS and elemental analysis.The plant-growth regulatory activities of these compounds were evaluated.The primary bioassay results indicated that these target compounds exhibited promising plant-growth regulatory activities.     

The first (ferrocenylmethyl)imidazolium and (ferrocenylmethyl)triazolium room temperature ionic liquids

N-(Ferrocenylmethyl)imidazole (3a), 1-(ferrocenylmethyl)-1,2,4-triazole (3b), 1,1'-bis[(1H-imidazol-1-yl)methyl]ferrocene (8a), 1,1'-bis([1H-(2-methyl)imidazol-1-yl]methyl]ferrocene (8b), and 1,1'-bis[(1H-1,2,4-triazol-1-yl)methyl]ferrocene (8c) were synthesized in moderate yields. These compounds were quaternized with methyl iodide to form 1-(ferrocenylmethyl)-3-methylimidazolium iodide (4a), 1-(ferrocenylmethyl)-4-methyl-1,2,4-triazolium iodide (4b), 1,1'-bis([1-(2,3-dimethyl)imidazolium]methyl)ferrocene diiodide (9b), and 1,1'-bis([1-(4-methyl)-1,2,4-triazolium]methyl)ferrocene diiodide (9c), respectively, in excellent yields. Compounds 4a, 4b, 9b, and 9c were metathesized with bis(trifluoromethanesulfonyl)amide to give high yields of 5a, 5b, 10b, and 10c. With potassium hexafluorophosphate, 9b forms 10d. Salts 5a, 5b, and 10c are the first room-temperature ionic liquids with cations containing an organometallic moiety that exhibit T(g) values well below room temperature, i.e., -32, -16, and -11 degrees C. The compounds were characterized by (1)H, (19)F, and (13)C NMR, MS, and elemental analyses. T(g) values and melting points were determined by DSC. T(d) values (5% weight loss temperature) were recorded by TGA. X-ray single-crystal structures show that 9c and 10d crystallize in the triclinic space group P.     

新型苯并咪唑衍生物的合成及其抗凝血活性

以3-［(3-氨基-4-甲基氨基苯甲酰)吡啶-2-基氨基］丙酸乙酯为原料,与4-氰基-3-氟苯取代基乙酸经环化反应制得3-【【2-｛［(4-氰基-3-氟苯取代基）甲基］-1-甲基-1-H-苯并咪唑-5-基｝羰基】吡啶-2-基】氨基丙酸乙酯（3a, 3e）; 3经水解和酰胺化反应制得3-【【【2-｛［(4-氰基-3-氟苯基)取代基］甲基｝-1-甲基-1H-苯并咪唑-5-基】羰基】吡啶-2-基氨基】丙酰取代胺基（6a~6h）;6与乙酰氧肟酸经环合反应合成了8个新型的苯并咪唑衍生物（7a~7h）,其结构经1H NMR和HR-ESI-MS表征。抗凝血活性结果表明： 7a和7c的抗凝血活性最好,其aPTT值分别为(83.1±4.2) s和(80.7±2.9) s,优于阳性对照药达比加群酯(75.3±2.1)s。     

Design and synthesis of novel quinoline derivatives bearing oxadiazole,isoxazoline, triazolothiadiazole,triazolothiadiazine, and piperazine moieties

A new series of 2,3-disubstituted quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2-chloroquinoline-3-carbaldehyde 1 , which was transformed to 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 by reaction with 4-phenylpiperazine in DMF-containing anhydrous K₂CO₃; then, compound 2 was oxidized by iodine in methanol, and methyl 2-(4-phenylpiperazin-1-yl)quinoline-3-carboxylate 3 was synthesized. The key intermediate 4 , 4-amino-5-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 6a-c , respectively. Moreover, compound 2 condensed with o-phenylenediamine to give 2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimidazole 7 . Interaction of 7 and 2-chloromethyl-5-aryl-1,3,4-oxadiazoles in the presence of K₂CO₃ led to the title compounds 8a-c . Furthermore, 4,5-dihydroisoxazoline derivatives 9a-c were obtained by the reaction of readily accessible starting materials including 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 , 1-phenyl-2-(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et₃N. The hydrazone intermediates 10a-c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3-acetyl-5-aryl-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazoles 11a-c . Structures of these compounds were established by their elemental analysis, IR, ¹H NMR, and mass spectral data.