Discovery and structure-activity relationship studies of novel tetrahydro-β-carboline derivatives as apoptosis initiators for treating bacterial infections

Developing and excavating new agrochemicals with highly active and safe is an important tactic for protecting crop health and food safety.In this paper,to discover the new bactericide candidates,we designed,prepared a new type of1,2,3,4-tetrahydro-β-carboline(THC)derivatives and evaluated the in vitro and in vivo bioactivities against the Xanthomonas oryzae pv.oryzae(Xoo),Xanthomonas axonopodis pv.citri(Xac),and Pseudomonas syringae pv.actinidiae(Psa).The in vitro bioassay results exhibited that most title molecules possessed good activity toward the three plant pathogenic bacteria,the compound A17 showed the most active against Xoo and Xac with EC50 values of 7.27 and 4.89 mg mL^(-1)respectively,and compound A8 exhibited the best inhibitory activity against Psa with EC50value of 4.87 mg mL^(-1).Pot experiments showed that compound A17 exhibited excellent in vivo antibacterial activities to manage rice bacterial leaf blight and citrus bacterial canker,with protective efficiencies of 52.67 and 79.79%at 200 mgmL^(-1),respectively.Meanwhile,compound A8 showed good control efficiency(84.31%)against kiwifruit bacterial canker at 200 mg mL^(-1).Antibacterial mechanism suggested that these compounds could interfere with the balance of the redox system,damage the cell membrane,and induce the apoptosis of Xoo cells.Taken together,our study revealed that tetrahydro-β-carboline derivatives could be a promising candidate model for novel broadspectrum bactericides.

Chiral Ligands from Abrine.4. Heterocycle-Containing 1,2,3,4-Tetrahydro-β-Carboline Methyl Ester Used for Catalysis of Enantioselective Addition of Diethylzinc to Benzaldehyde

Four 1, 2,3,4-tetrahydro - β - c arboline amino acid esters with a heterocycle at the C- 1position were used as chiral ligands in the enantioselective addition reactions. The differentpositions of the heteroatoms gave different effects, and medium but opposite enantioselectivitywas recorded.

A New β-Carboline Alkaloid and a New Derivate of Isoferulic Acid from Anemone altaica

A new β-carboline alkaloid, 4-（9H-β-carbolin-1-yl）-4-oxobutyric acid and a new derivate of isoferulic acid, （E）-3-（3-hydroxy-4-methoxyphenyl）acrylic acid carboxymethyl ester, were isolated from the roots of Anemone altaica. Their structures were determined on the basis of spectral data.

β-Carboline alkaloids from Trigonostemon filipes and Trigonostemon lii

Sixβ-carboline alkaloids including three new ones,trifilines A-C(1-3)were isolated from Trigonostemon filipes,along with a newβ-carboline alkaloid,trigonoine C(7)isolated from Trigonostemon lii.Their structures were elucidated by extensive spectroscopic techniques.Trifilines A(1)and B(2)showed weak anti-HIV-1 activity with EC50 values of 54.61μg/mL and 9.75μg/mL,along with TI(Therapeutic index)values of 1.52 and 1.42,respectively.This is the first time to report the chemical constituents of Trigonostemon filipes.

Solid Phase Synthesis of β-Carbolines

Synthesis of β-carbolines on solid phase using TCCA as the key reagent is developed.

Synthesis, Characterization and X-ray Crystal Structure of 2-Benzyl-7-butoxyl-9-isobutyl-1-methyl-β-carboline Bromide

2-Benzyl-7-butoxyl-9-isobutyl-1-methyl-β-carboline bromide（H-2-65） was synthesized by the reaction of Harmine with 1-iodobutane via N9-alkylation, demethyl and N2-quaternarization to obtain the new compound. The results demonstrate that H-2-65 has more remarkable anticancer activities in vitro. The results of 1H NMR, 13 C NMR, DEPT, g COSY, g HSQC, g HMBC, MS, single-crystal X-ray diffraction and elemental analysis showed that the title compound crystallizes in the triclinic system, space group P1 with a = 9.545（5）, b = 11.724（5）, c = 11.839（6） , α = 77.530（6）, β = 87.169（6）, γ = 72.823（5）o, Z = 2, V = 1235.8（10）3, Dc = 1.294 g·cm-3, F（000） = 504, the final R = 0.0453, wR = 0.1262 and S = 1.044.

β-Carboline alkaloids from the roots of Peganum harmala L.

This study reports the isolation of four newβ-carboline alkaloids(1−4)and six previously identified alkaloids(5−10)from the roots of Peganum harmala L.Among these compounds,1 and 2 were characterized as rareβ-carboline-quinazoline dimers exhibiting axial chirality.Compound 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring,and compound 4 was a novel annomontineβ-carboline.The structures of these compounds were elucidated by spectroscopic data and quantum mechanical calculations.The biosynthetic pathways of 1−3 were proposed.Additionally,the cytotoxicity of some isolates against four cancer cell lines(HL-60,A549,MDA-MB-231,and DU145)was evaluated.Notably,compound 4 exhibited significant cytotoxicity against HL-60,A549,and DU145 cells with IC_(50) values of 12.39,12.80,and 30.65μmol·L^(−1),respectively.Furthermore,compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC_(50) value of 17.32μmol·L^(−1).

基于AB型单体聚醚酰亚胺共聚物的合成与性能

将AB型单体3-氨基-5,6,9,10-四氢-[5]螺旋烯-7,8-二羰基-二甲酸酐(ATHDA)与4,4’-(4,4’-异亚丙基二苯氧基)双(邻苯二甲酸酐)(BPADA)和4,4’-二氨基二苯醚(ODA)通过高温一步法共聚,制备了一系列ATHDA含量不同的聚醚酰亚胺PEI-AB_(x)(x为ATHDA用量,以BPADA和ODA的总质量计,下同)。采用FTIR、~1HNMR、DSC、DMA、TGA对聚合物进行了表征,对其力学性能和溶解性进行了测试。结果表明,PEI-AB_(x)特性黏数在0.60~0.87 dL/g之间,均具有良好的成膜性,且该系列聚合物在常见的有机溶剂N,N-二甲基乙酰胺、N-甲基吡咯烷酮中均具有优异的溶解性;由DMA测得的玻璃化转变温度(T_(g))在228~256℃之间,N_(2)气氛下5%热失重温度(T_(5%))为505~536℃,表明PEI-AB_(x)具有优异的热稳定性;聚合物薄膜的拉伸强度、杨氏模量和断裂伸长率分别在41.7~88.1 MPa、1.7~2.7 GPa和3.3%~4.8%之间,具有良好的力学性能。另外,聚合物分子链中的四氢-[5]螺旋烯结构可脱氢芳构化,与PEI-AB_(20)相比,芳构化后PEI-AB_(20)的T_(g)从256℃提高至283℃,T_(5%)从531℃提升至557℃,表明芳构化后聚合物耐热性得到进一步提升。

Antibacterial Activity of 9-Octadecanoic Acid-Hexadecanoic Acid-Tetrahydrofuran-3,4-Diyl Ester from Neem Oil

The 9-octadecanoic acid-hexadecanoic acid-tetrahydrofuran-3,4-diyl ester from neem oil was investigated for antibacterial activity against three bacterial strains viz., Staphylococcus aureus ATCC No. 25923, Escherichia coli ATCC No. 44102 and Salmonella sp. ATCC No. 50 041 in vitro. The minimum inhibitory concentration （MIC） and minimum bactericidal concentration （MBC） values of the 9-octadecanoic acid-hexadecanoic acid-tetrahydrofuran-3,4-diyl ester were determined by using the broth microdilution dilution （BMD） method at different concentrations ranging from 20 to 0.625 mg mL-1. Its time-inhibition curve against E. coli was also tested and showed that the MIC values for the bacterial strains S. aureus, E. coli and Salmonella sp. were 20, 5 and 10 mg mL-1, respectively. Its MBC values were 20, 20 and 10 mg mL-1, respectively. The antibacterial activity of 9-octadecanoic acid-hexadecanoic acid-tetrahydrofuran-3,4-diyl ester against three strain tested showed the relationship with time and concentration.

Green Chemistry Approach to Fast and Highly Efficient One-Pot Synthesis of Bis-Isoxazolyl-1,2,5,6-Tetrahydro Pyridine-3-Carboxylates

The synthesis of the bis-isoxazolyl-1,2,5,6-tetrahydro pyridine-3-carboxylates is achieved in high yield without the production of toxic waste products by using room temperature ionic liquid (RTILs) triethyl ammonium acetate (TEAA). The RTIL TEAA played the dual role of efficient green solvent as well as recyclable catalyst.

Efficient Synthesis of 3,5,6,8-Tetrahydro-4H-thiopyrano[4′,3′:4,5]· thieno[2,3-d]pyrimidin-4-ones via an Iminophosphorane

3,5,6,8-Tetrahydro-4H-thiopyrano[4＇,3＇：4,5]thieno[2,3-d]pyrimidin-4-ones（7） were synthesized via the base catalytic reactions of amines or phenols with carbodiimides（5）, which were obtained from the aza-Wittig reac tions of iminophosphoranes（4） with aromatic isocyanates.

Design, Synthesis and Antifungal Activity of 6-Fluoro-3,3a,4,5-tetrahydro-2H-pyrazolo[4,3-c]-quinoline-2-carboxamide Derivatives

A series of 6-fluoro-3,3a,4,5-tetrahydro-2H-pyrazolo[4,3-c]quinoline-2-carboxamide derivatives was designed based on the bioisosterism and combination principle in drug design. The target compounds were synthesized from substituted aniline through Michael addition, cyclization, Mannich reaction and condensation with 4-substituted semicarbazides, and the structures were confirmed by mass spectrometry（MS） and 1H NMR. The antifungal assay was carried out in vitro by two-fold dilution. The result shows that all the compounds are of antifungal activities against the tested fungi at different levels.

Synthesis and Molecular Structure of Acetic Acid-3,5-diacetoxy-2-acetoxymethyl-6-(4-quinoxalin-2-yl-phenoxy)-tetrahydro-pyran-4-yl-ester

The title compound, acetic acid-3,5-diacetoxy-2-acetoxymethyl-6-（4-quinoxalin- 2-yl-phenoxy）-tetrahydro-pyran-4-yl-ester 8 （C28H28N2O10, Mr = 552.54）, has been synthesized and its crystal structure was determined by X-ray diffraction analysis. It crystallizes in monoclinic, space group P21, a = 10.060（8）, b = 5.648（4）, c = 24.11（2）A, β = 91.078（10）°, Z = 2, V= 1369.9（19）A^3, Dc = 1.339 g/cm^3,μ（MoKa） = 1.03 cm^-1, F（000） = 580.00, T =. 193.1 Kx-9 θmax = 25.03, （△/σ）max = 0.0000, Flack = -0.0（24）, the final R = 0.0680 and wR = 0.140 （w = 1/[0.0016Fo^2 ＋ 1.00000（Fo^2）]/（4Fo^2）） for 3126 observed reflections （1 〉 20（/））. The pyranoid ring adopts chair conformation in the sugar moiety, and all of the acetyl groups are in the e bond of the pyranoid ring, so the sugar moiety is very stable.

Crystal Structure of 1, 1-Dichloro-la, 3-diphenyl-1, la, 2, 3-tetrahydro-azirino [2, 1-d ] [1, 5]benzothiazepine(C_(22),H_(17)Cl_2NS )

The crystal structure of 1, l-dichloro-la, 3-diphenyl-l, la, 2, 3-te-trahydro-azirino[2, l-d ] [l, 5]benzothizeapine (C22H17Cl2NS, Mr= 398. 35) has beendetermined. The title compound crystallizes in orthorhombic space group Pbca with celldimensions a= 11. 579(3), b= 15. 14O(4), c=2l. 534(5) A, V= 3775. 04(5) A 3, Z= 8, D. = 1' 402g. cm-3, MoKa(λ= 0. 7l073 A ), F (000) = lO64, μ= O. 245mm-1. The structure was solved by using direct methods and refined by full-matrixleast-Squares method, and the final crystallographic discrepancy factor is 0. 046 for4l94 observed rcflections. The molecular backbone is a tricyclic system with the centralseven-membered l, 5-thiazepine ring in twisted boat-like conformation and cis-fused toboth azirine ring and benzene ring.

利用改进的Pictet-Spengler反应合成多取代β-咔啉

β-咔啉结构广泛存在于生物活性分子之中,为探索非酸性反应条件下合成β-咔啉衍生物的方法,以色胺类化合物和醛类为原料,以改进的Pictet-Spengler反应为关键步骤,再经氧化脱氢合成4个多取代β-咔啉化合物(2a~2d),其结构经1 H NMR和MS(ESI)确证。经过对Pictet-Spengler反应步骤中物料比、溶剂、反应温度与时间进行考察后发现:在色胺类化合物为2.0 mmol,醛为3.0 mmol,六氟异丙醇钙为0.4 mmol,二氯甲烷为20.0 mL,室温反应24 h的最优条件下,四氢-β-咔啉化合物中间体(1a~1d)的收率为75%~89%,反应存在取代基效应,含芳香性基团底物收率较高。

元胡止痛口服液药材、中间体及制剂的定量指纹图谱方法研究

建立了适用于元胡止痛口服液原料药材、中间体及制剂中若干生物碱类成分的定量指纹图谱方法。采用DIKMA Diamonsil Plus C18-A色谱柱(4.6 mm×250 mm,5μm),以0.04%乙酸铵溶液(冰醋酸调至pH4.0,A)-乙腈(B)为流动相进行梯度洗脱,在280 nm下进行检测。指纹图谱中含共有峰7个,其精密度、重复性、稳定性的相对标准偏差(RSD)均小于5.0%。对延胡索乙素、去氢延胡索甲素进行定量分析,其分别在6.15~123μg/mL和10.15~203μg/mL范围内线性关系良好,相关系数(r^(2))> 0.999,进样精密度、方法重复性的RSD均小于5.0%,供试品溶液在24 h内稳定。延胡索乙素、去氢延胡索甲素在低、中、高3个加标水平下的平均回收率为89.6%~107%,RSD小于3.0%。所建立的分析方法稳定、准确、可靠,能够对药材、中间体及制剂中的中等极性成分进行检测,可用于考察工业生产中元胡成分的量值传递情况,从而为改进元胡止痛口服液制药过程控制水平提供技术支持。

3-三氟甲基-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐的合成工艺研究

以三氟乙酰肼和乙酰氯为起始原料,经5步反应合成了西他列汀的关键中间体3-三氟甲基-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐,并对反应条件进行了优化,优化条件下总收率超过55.0%,纯度高于99.5%,所有单一杂质含量控制在0.1%以内。

不对称Pictet-Spengler反应中有机催化研究进展

手性四氢-β-咔啉骨架广泛存在于天然产物和药物分子中,是其活性的关键结构.不对称Pictet-Spengler反应是高效构建四氢-β-咔啉化合物的直接途径.根据有机催化剂种类,我们从手性磷酸、手性方酰胺和其他催化剂3个方面,综述了近5年来有机催化不对称Pictet-Spengler反应的研究进展.

Mannich反应合成噻虫胺与噻虫嗪中间体的应用研究

为提高第2代新烟碱类杀虫剂噻虫胺与噻虫嗪的产品纯度,降低其在工业生产中的废水排放量,对噻虫胺中间体1,5-二甲基-2-硝基亚胺基-全氢-1,3,5-三嗪和噻虫嗪中间体3-甲基-4-硝基亚胺四氢-1,3,5-噁二嗪的反应机理进行研究。发现噻虫胺中间体1,5-二甲基-2-硝基亚胺基-全氢-1,3,5-三嗪的合成在碱性条件下进行,而噻虫嗪中间体3-甲基-4-硝基亚胺四氢-1,3,5-噁二嗪的合成既可在酸性也可在碱性条件下进行,酸性条件下产品收率更高,且都符合Mannich反应机理。Mannich反应在有机化学合成,特别是在药物合成方面具有非常重要的地位,展望了其在农药合成领域的发展趋势。

对称性硫脲的绿色合成工艺

以乙二胺、CS_(2)为原料、水为溶剂,一锅合成了亚乙基硫脲(ETU),收率和HPLC纯度均达到99%以上。利用NMR、FTIR对产物结构进行了确证。考察了CS_(2)滴加温度、乙二胺与CS_(2)物质的量比、回流反应温度、回流反应升温速率及NaOH反应段NaOH用量对ETU收率、HPLC纯度的影响。结果表明,ETU的最佳合成工艺条件为CS_(2)滴加温度25~30℃、n(乙二胺)∶n(CS_(2))=1∶1.20、回流反应温度65~70℃、回流反应升温速率0.17℃/min、NaOH反应段NaOH用量为乙二胺质量的3.0%。以此工艺为模板,合成了1,3-二乙基硫脲(DETU)和四氢-2(1H)-嘧啶硫酮(PUR)。中试实验表明,该工艺稳定可靠,产品收率、HPLC纯度均达到99%以上,母液可循环套用。