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中文题名：

 1, 3, 9-多取代β-咔啉衍生物的合成及其生物活性研究    

姓名：

 霍新玉    

学号：

 20162007004    

学科代码：

 081704    

学科名称：

 应用化学    

学生类型：

 硕士    

院系：

 化学化工学院    

专业：

 化学工程与技术    

研究方向：

 天然产物开发与利用    

第一导师姓名：

 代斌    

第一导师单位：

 石河子大学    

第二导师姓名：

 张洁    

完成日期：

 2019-06-03    

外文题名：

 Synthesis and fungicidal evaluation of 1,3,9-multiple substituted-carboline derivatives    

中文关键词：

  &beta ; -咔啉 ; 合成 ; 结构修饰 ; 抑菌活性    

外文关键词：

  &beta ; -carbazoline ; syntheses ; structural modification ; antibacterial activity      

中文摘要：

β-咔啉类生物碱是一类具有广泛生物活性的重要天然产物，其高效的抗菌、抗肿瘤、抗病毒、抗疟等活性引发了人们的关注。众多研究表明β-咔啉类生物碱具有较为突出的抗肿瘤活性，但因其自身毒性未能应用于临床，因此我们另辟蹊径，着重研究这类生物碱的抗菌能力，进而开发出结构新颖、低毒副作用、且拥有自主知识产权的杀菌剂。

基于课题组前期工作，以及大量的文献查阅，本论文按照活性亚结构拼接原理进行化合物的设计，旨在对β-咔啉母环进行合成与进一步结构修饰，并对获得的目标化合物进行体外抗菌活性的初步评价，期望在一系列β-咔啉衍生物中筛选出抗菌活性高的化合物，为新型杀菌剂的开发奠定基础。

第二章，以L-色氨酸和Harmine为原料，经多步反应设计合成了两个系列的1,2,3-三氮唑-β-咔啉衍生物；第三章，以L-色氨酸为原料，再经过经典的Pictet-Spengler反应、芳构化、烷基化、氧化等多步反应合成两个系列苯并咪唑-β-咔啉衍生物；第四章，以上一章合成的关键中间体为原料，与邻氨基苯硫酚反应，合成两个系列的苯并噻唑-β-咔啉衍生物；以上三章所合成的目标产物均为新化合物，所有结构经由1H NMR、13C NMR、HRMS以及熔点确证，并采用菌丝生长速率法初步测定了它们对棉花枯萎病原菌（Fusarium oxysporum）、棉花立枯丝核菌（Rhizoctorzia Solani）、葡萄灰霉病原菌（Botrytis cinereal Pers.）、向日葵菌核病原菌（Sunflower sclerotinia rot）以及油菜菌核病原菌（Rape sclerotinia rot）的抑菌活性。

本研究共合成了60个目标化合物，活性测试结果显示，大部分化合物对向日葵菌核病原菌表现出较高的抑制活性，其中化合物X7r的抗菌能力优于对照药品carbendazim和azoxystrobin；在β-咔啉的1位引入苯并咪（噻）唑基团有益于对棉花立枯丝核菌和油菜菌核病原菌的抑制，而在β-咔啉的3位引入苯并咪（噻）唑基团更适合抑制棉花枯萎病原菌以及葡萄灰霉病原菌，其中Y2g抗菌活性突出，在浓度为50 μg/mL时，对葡萄灰霉病原菌的抑制率达到100%；在所有化合物中，H9b和Y2c对受试菌种表现出广谱抗性。

综上所述，本研究通过在β-咔啉母环上引入1,2,3-三氮唑、苯并咪唑以及苯并噻唑基团，得到了多个抗菌活性优异的化合物，丰富了抗菌化合物数据库，为新型杀菌剂的研发奠定了基础。

 

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外文摘要：

β-carboline alkaloids are a kind of important natural products with a wide range of biological activities, and it has been a focus due to their high efficiency in antibacterial, anti-tumor, anti-virus, anti-malaria and other activities. Quantities of research have shown that β-carboline alkaloids have outstanding antitumor activity, but because of their own toxicity, they have not been applied in clinical until now. Therefore, we have developed a new way to study the antibacterial ability of this kind of alkaloids and developed a series of novel fungicides with independent intellectual property rights, low toxic and side effects.

This study based on our previous work as well as a large of literature reviews and designed the compounds according to the combination principles, aimed to synthesize and modify the framework of β-carbazoline and evaluate the antibacterial activity of the target compounds in vitro. It is expected to provide canditate compounds for new fungicides with high antibacterial activity, screened out from the series of β-carbazoline derivatives we designed.

In the second chapter, two series of 1,2,3-triazole-β-carboline derivatives were synthesized from L-tryptophan and Harmine via multi-step reaction. In chapter three, two series of benzimidazole-β-carbazoline derivatives were synthesized by Pictet-Spengler reaction, aromatization, alkylation and oxidation from L-tryptophan. In the fourth chapter, the key intermediate, from the above chapter, are raw materials, and reacted with o-aminothiophenal to obtain two series of benzothiazole-β-carbazoline. The target products synthesized in the above three chapters are all new compounds, which was identified by 1H NMR, 13C NMR, HRMS and melting piont, respectively. Using mycelium growth rate method, all the compounds were tested on the antibacterial activities in vitro against the five fungus: Fusarium oxysporum, Rhizoctorzia Solani, Botrytis cinereal Pers, Sunflower sclerotinia rot, Rape sclerotinia rot.

A total of 60 compounds were synthesized in this study and the preliminary results showed that most compounds exhibit high inhibiting effect against Sunflower sclerotinia rot, especially X7r, better than that of the control drugs carbendazim and azoxystrobin. 1-substituted-β-carboline derivatives are benefical for inhibition of Rhizoctorzia Solani and Rape sclerotinia rot, while 3- substituted-β-carboline derivatives are more suitable for Fusarium oxysporum and Botrytis cinereal Pers. It’s worth mentioning that compound Y2g has shown outstanding antibacterial activity, the inhibition rate is 100% at 50 μg/mL, against Botrytis cinereal Pers. Specifically, compound H9b and Y2c exhibited broad-spectrum fungicidal activity against most of the tested fungi.

In conclusion, a number of novel compounds with excellent antibacterial activity were obtained by introducing 1,2,3-triazole, benzimidazole and benzothiazole groups into the skeleton of β-carboline, which enriched the database of antimicrobial drugs and laid a foundation for the development of new fungicides.

 

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参考文献：

  1. Smirnova O B, Golovko T V, Granik V G. Carbolines. Part 2: comparison of some of the properties of α-, γ-, and δ-carbolines (Review)[J]. Pharmaceutical Chemistry Journal, 2011 45(7): 389-400.

  2. Cao R, Chen, Q, Hou, X, et al. Synthesis, acute toxicities, and antitumor effects of novel 9-substituted β-carboline derivatives[J]. Bioorganic & Medicinal Chemistry, 2004, 12(17): 4613-4623

  3. Konda M, Shioiri T, Yamada S. Amino acids and peptides. XVII. A biogenetic-type, asymmetric synthesis of (S)-laudanosine from L-3-(3,4-dihydroxyphenyl) alanine by 1,3-transfer of asymmetry[J]. Chemical & Pharmaceutical Bulletin. 1975, 23(5): 1063-1076.

  4. Sathish M, Kavitha B, Nayak V L, et al. Synthesis of podophyllotoxin linked β-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors[J]. European Journal of Medicinal Chemistry, 2018, 144: 557-571.

  5. Bailey P D, Clingan P D, Mills T J, et al. Total Synthesis of (-)-Raumacline[J]. Chemical Communications, 2003, 35(22): 2800-2801.

  6. 马养民, 李延超, 闫倩茹, 等. 一种合成四氢-β-咔啉二酮哌嗪化合的新方法[J]. 化学世界, 2012, 3: 165-168.

  7. Ikeda R, Iwaki T, Okabayashiet T, et al. 3-Benzylamino-β-carboline derivatives induce apoptosis through G2/M arrest in human carcinoma cells HeLa S-3 [J]. European Journal of Medicinal Chemistry, 2011, 46: 636-646.

  8. Ramu M, Mohd N M, Sharif M M, et al. Copper-catalyzed protodecarboxylation and aromatization of tetrahydro-β-carboline-3-carboxylic acids[J]. Synlett, 2014, 25(01): 120-122.

  9. Huang W, Li J, Lihua O. Facile synthesis of isoquinolines, β-carbolines, and 3-deazapurines[J]. Synthetic Communications, 2007, 37: 2137-2143.

  10. Cox E D, Cook J M. The Pictet-Spengler condensation: a new direction for an old reaction[J]. Chemical Reviews, 1995: 1797-1842.

  11. Hagen T J, Skolnick P, Cook J M. Synthesis of 6-substituted β-carbolines that behave as benzodiazepine receptor antagonists or inverse agonists[J]. Journal of Medicinal Chemistry, 1987, 30: 750-753.

  12. Cao R, Chen H, Peng W, et al. Design, synthesis and in vitro and in vivo antitumor activities of novel β-carboline derivatives[J]. Journal of Medicinal Chemistry, 2005, 40(10): 991-1001.

  13. Li Y, Prakash S R. Synthesis of C-14-labeled novel IKK inhibitor: 2-[14C]-N-(6-chloro-9H-pyrido [3,4-b]indol-8-yl)-3-pyridinecarboxamide [J]. Journal of Labelled Compounds & Radiopharmaceuticals, 2005, 48(5): 323-330.

  14. Ramu S, Srinath S, kumar A A, et al. Metal free one pot synthesis of β-carbolines via a domino Pictet-Spengler reaction and aromatization[J]. Molecular Catalysis, 2019, 468: 86–93.

  15. Huang W J, Singh O V, Chen C H, et al. Synthesis of (±)-glaucine and (±)-neospirodienone via an one-pot Bischler-Napieralski reaction and oxidative coupling by a hypervalent iodine reagent[J]. Helvetica Chimica Acta, 2004, 87: 167-174.

  16. Heravi M M, Khaghaninejad S, Nazari N. Bischler-Napieralski Reaction in the Syntheses of Isoquinolines[J]. Advances in Heterocyclic Chemistry, 2014, 112: 183-234.

  17. Itoh N, Sugasawa S. Phosphorous pentoxide-pyridine: a new combination for Bischler-Napieralski reaction[J]. Tetrahedron, 1957, 1(1-2): 45-48.

  18. Snyder H R, Werber F X. Polyphosphoric acid as a dehydrating agent. I. The cyclodehydration of some α-acylamino-β-arylpropionic acids[J]. Journal of the American Chemical Society, 1950, 72(7): 2962-2965.

  19. Kende A S, Ebetino F H, Battista R, et al. New tactics in heterocyclis syntheses[J]. Heterocycles, 1984, 21, 91-106.

  20. Jiang W, Wen R, Laronze J. Y. β-Carbolines. synthesis of several new bis-β-carboline compounds[J]. Journal of Chinese Pharmaceutical Sciences, 1999, 8(3): 177-179.

  21. Sanchez-Sancho F, Mann E, Herradon B. Efficient syntheses of polyannular heterocycles featuring m

    1. Smirnova O B, Golovko T V, Granik V G. Carbolines. Part 2: comparison of some of the properties of α-, γ-, and δ-carbolines (Review)[J]. Pharmaceutical Chemistry Journal, 2011 45(7): 389-400.

    2. Cao R, Chen, Q, Hou, X, et al. Synthesis, acute toxicities, and antitumor effects of novel 9-substituted β-carboline derivatives[J]. Bioorganic & Medicinal Chemistry, 2004, 12(17): 4613-4623

    3. Konda M, Shioiri T, Yamada S. Amino acids and peptides. XVII. A biogenetic-type, asymmetric synthesis of (S)-laudanosine from L-3-(3,4-dihydroxyphenyl) alanine by 1,3-transfer of asymmetry[J]. Chemical & Pharmaceutical Bulletin. 1975, 23(5): 1063-1076.

    4. Sathish M, Kavitha B, Nayak V L, et al. Synthesis of podophyllotoxin linked β-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors[J]. European Journal of Medicinal Chemistry, 2018, 144: 557-571.

    5. Bailey P D, Clingan P D, Mills T J, et al. Total Synthesis of (-)-Raumacline[J]. Chemical Communications, 2003, 35(22): 2800-2801.

    6. 马养民, 李延超, 闫倩茹, 等. 一种合成四氢-β-咔啉二酮哌嗪化合的新方法[J]. 化学世界, 2012, 3: 165-168.

    7. Ikeda R, Iwaki T, Okabayashiet T, et al. 3-Benzylamino-β-carboline derivatives induce apoptosis through G2/M arrest in human carcinoma cells HeLa S-3 [J]. European Journal of Medicinal Chemistry, 2011, 46: 636-646.

    8. Ramu M, Mohd N M, Sharif M M, et al. Copper-catalyzed protodecarboxylation and aromatization of tetrahydro-β-carboline-3-carboxylic acids[J]. Synlett, 2014, 25(01): 120-122.

    9. Huang W, Li J, Lihua O. Facile synthesis of isoquinolines, β-carbolines, and 3-deazapurines[J]. Synthetic Communications, 2007, 37: 2137-2143.

    10. Cox E D, Cook J M. The Pictet-Spengler condensation: a new direction for an old reaction[J]. Chemical Reviews, 1995: 1797-1842.

    11. Hagen T J, Skolnick P, Cook J M. Synthesis of 6-substituted β-carbolines that behave as benzodiazepine receptor antagonists or inverse agonists[J]. Journal of Medicinal Chemistry, 1987, 30: 750-753.

    12. Cao R, Chen H, Peng W, et al. Design, synthesis and in vitro and in vivo antitumor activities of novel β-carboline derivatives[J]. Journal of Medicinal Chemistry, 2005, 40(10): 991-1001.

    13. Li Y, Prakash S R. Synthesis of C-14-labeled novel IKK inhibitor: 2-[14C]-N-(6-chloro-9H-pyrido [3,4-b]indol-8-yl)-3-pyridinecarboxamide [J]. Journal of Labelled Compounds & Radiopharmaceuticals, 2005, 48(5): 323-330.

    14. Ramu S, Srinath S, kumar A A, et al. Metal free one pot synthesis of β-carbolines via a domino Pictet-Spengler reaction and aromatization[J]. Molecular Catalysis, 2019, 468: 86–93.

    15. Huang W J, Singh O V, Chen C H, et al. Synthesis of (±)-glaucine and (±)-neospirodienone via an one-pot Bischler-Napieralski reaction and oxidative coupling by a hypervalent iodine reagent[J]. Helvetica Chimica Acta, 2004, 87: 167-174.

    16. Heravi M M, Khaghaninejad S, Nazari N. Bischler-Napieralski Reaction in the Syntheses of Isoquinolines[J]. Advances in Heterocyclic Chemistry, 2014, 112: 183-234.

    17. Itoh N, Sugasawa S. Phosphorous pentoxide-pyridine: a new combination for Bischler-Napieralski reaction[J]. Tetrahedron, 1957, 1(1-2): 45-48.

    18. Snyder H R, Werber F X. Polyphosphoric acid as a dehydrating agent. I. The cyclodehydration of some α-acylamino-β-arylpropionic acids[J]. Journal of the American Chemical Society, 1950, 72(7): 2962-2965.

    19. Kende A S, Ebetino F H, Battista R, et al. New tactics in heterocyclis syntheses[J]. Heterocycles, 1984, 21, 91-106.

    20. Jiang W, Wen R, Laronze J. Y. β-Carbolines. synthesis of several new bis-β-carboline compounds[J]. Journal of Chinese Pharmaceutical Sciences, 1999, 8(3): 177-179.

    21. Sanchez-Sancho F, Mann E, Herradon B. Efficient syntheses of polyannular heterocycles featuring microwave-accelerated Bischler-Napieralski reaction, stereoselective Heck cyclization, and Claisen rearrangement[J]. Synlett, 2000, 4: 509-513.

    22. Prati F, Spaggiari A, Davoli P, et al. (PhO)3P·Cl2-promoted Bischler-Napieralski-type cyclization: a mild access to β-carbolines[J]. Synlett, 2005, (4): 661-663.

    23. Movassaghi M, Hill M D. A versatile cyclodehydration reaction for the synthesis of isoquinoline and β-Carboline derivatives[J]. Organic Letters, 2008, 10(16): 3485-3488.

    24. Robinson B. Study on the Fischer indole synthesis[J]. Chemical Reviews, 1969, 69(2): 227-250.

    25. Trudell M L, Basile A S, Shannon H E, et al. Synthesis of 7, 2-dihydropyrido [3,4-b:5,4-b'] diindoles. A novel class of rigid, planar benzodiazepine receptor ligands[J]. Medicinal Chemistry, 1987, 30: 456-458.

    26. Suzuki H, Tsukakoshi Y, Tachikawa T, et al. A new synthesis of 4-oxygenated β-carboline derivatives by Fischer indolization[J]. Tetrahedron Letters, 2005, 46(22): 3831-3834.

    27. Kusurkar R S, Goswami S K. Efficient one-pot synthesis of anti-HIV and anti-tumour β-carbolines [J]. Tetrahedron, 2004, 60(25): 5315-5318.

    28. Too P C, Chua S H, Wong S H, et al. Synthesis of Azaheterocycles from aryl ketone o-acetyl oximes and internal alkynes by Cu-Rh bimetallic relay catalysts[J]. Journal of Organic Chemistry, 2011, 76(15): 6159-6168.

    29. Yan Q, Gin E, Banwell M G, et al. A unified approach to the isomeric α-, β-, γ-, and δ-carbolines via their 6,7,8,9-tetrahydro counterparts[J]. Journal of Organic Chemistry, 2017, 82(8): 4328-4335.

    30. Ling Y, Feng J, Luo L, et al. Design and synthesis of C3-substituted β-carboline-based histone deacetylase inhibitors with potent antitumor activities[J]. Chemmedchem, 2017, 12(9): 646-651.

    31. Lou L L, Liu S, Yan Z Y, et al. Tetrahydro-β-carboline alkaloids from carthamus tinctorius L. with tyrosinase inhibitory activity[J]. Phytochemistry Letters, 2017, 22: 107-112.

    32. Kumar S, Singh A, Kumar K, et al. Recent insights into synthetic β-carbolines with anti-cancer activities[J]. European Journal of Medicinal Chemistry, 2017, 142: 48-73.

    33. Kovvuri J, Nagaraju B, Nayak V L, et al. Design, synthesis and biological evaluation of new β-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors[J]. European Journal of Medicinal Chemistry, 2018, 143: 1563-1577.

    34. Sathish M, Kavitha B, Nayak V L, et al. Synthesis of podophyllotoxin linked β-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors[J]. European Journal of Medicinal Chemistry, 2018, 144: 557-571.

    35. Adesanya S A, Chbani M, Païs M, et al. Brominated β-carbolines from the marine tunicate Eudistoma album[J]. Journal of Natural Products, 1992, 55(4): 525–527.

    36. Zhang P Y, Wang J L, Wan S B, et al. First total synthesis of eudistalbin A[J]. Chinese Chemical Letters, 2010, 21(8): 889–891.

    37. Ikeda R, Iwaki T, Iida T, et al. 3-Benzylamino-β-carboline derivatives induce apoptosis through G2/M arrest in human carcinoma cells HeLa S-3[J]. European Journal of Medicinal Chemistry, 2011, 46(2): 636-646.

    38. Ikeda R, Kimura T, Tsutsumi T, et al. Structure-activity relationship in the antitumor activity of 6-, 8- or 6,8-substituted 3-benzylamino-β-carboline derivatives[J]. Bioorganic Medicinal Chemistry Letters, 2012, 22(10): 3506-3515.

    39. Guo L, Fan W X, Chen X M, et al. Synthesis and antitumor activities of β-carboline derivatives[J]. Chinese Journal of Organic Chemistry, 2013, 33: 332-338.

    40. Chen Y F, Lin Y C, Chen J P, et al. Synthesis and biological evaluation of novel 3,9-substituted β-carboline derivatives as anticancer agents[J]. Bioorganic & Medicinal Chemistry Letters, 2015, 25(18): 3873–3877.

    41. Spindler A, Stefan K, Wiese M. Synthesis and investigation of tetrahydro-β-carboline derivatives as inhibitors of the breast cancer resistance protein (ABCG2)[J]. Journal of Medicinal Chemistry, 2016, 59(13): 6121-6135.

    42. Kawato Y, Aonuma M, Hirota Y, et al. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11[J]. Cancer Research, 1991, 51: 4187-4191.

    43. Dai J, Dan W, Schneider U, et al. β-Carboline alkaloid monomers and dimers: Occurrence, structural diversity, and biological activities[J]. European Journal of Medicinal Chemistry, 2018, 157: 622-656.

    44. Rinehart K L, Kobayashi J, Harbour G C, et al. Udistomins A-Q, β-carboline from the antiviral Caribbean tunicate Eudistoma olivaceum[J]. Journal of the American Chemical Society, 1987, 109(11): 3378-3387.

    45. Schuup P, Poehner T, Edrada R, et al. Eudistomins W and X, two new β-carbolines from the Micronesian Tunicate Eudistoma sp[J]. Journal of Natural Products, 2003, 66(2): 272-275.

    46. O’Donnell G, Gibbons S. Antibacterial activity of two canthin-6-one alkaloids from Allium neapolitanum[J]. Phytotherapy Research, 2007, 21(7), 653-657.

    47. Ferreira M E, Nakayama H, de Arias A R, et al. Effects of canthin-6-one alkaloids from Zanthoxylum chiloperone on Trypanosoma cruzi-infected mice[J]. Journal of Ethnopharmacology, 2007, 109(2): 258-263.

    48. Till M, Prinsep M R. 5-Bromo-8-methoxy-1-methyl-β-carboline, an Alkaloid from the New Zealand Marine Bryozoan Pterocella vesiculosa[J]. Journal of Natural Products, 2009, 72(4): 796-798.

    49. Nenaah, G. Antibacterial and antifungal activities of (beta)-carboline alkaloids of Peganum harmala (L) seeds and their combination effects[J]. Fitoterapia, 2010, 81(7): 779-782.

    50. Hou Z, Zhu L, Yu X, Sun M, Miao F, Zhou L. Design, Synthesis, and Structure-Activity Relationship of New 2-Aryl-3,4-dihydro-β-carbolin-2-ium Salts as Antifungal Agents[J]. Journal of Agricultural and Food Chemistry. 2016, 64(14): 2847-2854.

    51. Kim C K, Riswanto R, Won T H, et al. Manzamine alkaloids from an Acanthostrongylophora sp. sponge[J]. Journal of Natural Products. 2017, 80(5): 1575-1583.

    52. Zhang Z J, Jiang Z, Zhu Q, et al. Discovery of β-carboline oxadiazole derivatives as fungicidal agents against rice sheath blight[J]. Journal of Agricultural and Food Chemistry, 2018, 66: 9598-9607.

    53. Wang Y H, Tang J G, Wang R R, et al. Flazinamide, a novel β-carboline compound with anti-HIV actions[J]. Biochemical and Biophysical Research Communications, 2007, 355(4): 1091-1095.

    54. Ashok P, Sharma H, Lathiya H, et al. In-silico design and study of novel piperazinyl β-carbolines as inhibitor of HIV-1 reverse transcriptase[J]. Medicinal Chemistry Research, 2015, 24(2): 513-522.

    55. Liu Y, Song H, Huang Y, et al. Design, Synthesis, and Antiviral, Fungicidal, and Insecticidal Activities of Tetrahydro-β-carboline-3-carbohydrazide Derivatives[J]. Journal of Agricultural and Food Chemistry, 2014, 62(41):9987-9999.

    56. Song H J, Liu Y X, Liu Y X, et al. Design, synthesis, anti-TMV, fungicidal, and insecticidal activity evaluation of 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid derivatives based on virus inhibitors of plant sources[J]. Bioorganic & Medicinal Chemistry Letters, 2014, 24(22): 5228-5233.

    57. Song H, Liu Y, Liu Y, et al. Synthesis and antiviral and fungicidal activity evaluation of β-carboline, dihydro-β-carboline, tetrahydro-β-carboline alkaloids, and their derivatives[J]. Journal of Agricultural & Food Chemistry, 2014, 62(5): 1010-1018.

    58. Huang Y, Guo Z, Song H, et al. Design, Synthesis, and Biological Activity of β-Carboline Analogues Containing Hydantoin, Thiohydantoin, and Urea Moieties[J]. Journal of Agricultural and Food Chemistry, 2018, 66(31): 8253-8261.

    59. Davis R A, Duffy S, Avery V M, et al. (+)-7-Bromotrypargine: an antimalarial β-carboline from the Australia marine sponge Ancorina sp[J]. Tetrahedron Letters, 2010, 51: 583-585.

    60. Kuo P C, Shi L S, Damu A G, et al. Cytotoxic and Antimalarial β-Carboline Alkaloids from the Roots of Eurycoma longifolia[J]. Journal of Natural Products, 2003, 66(10):1324-1327.

    61. Baelen G V, Hostyn S, Dhooghe L, et al. Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues[J]. Bioorganic & Medicinal Chemistry, 2009, 17(20):7209-7217.

    62. Pedroso R B, Tonin L T D, Ueda-Nakamura T, et al. Beta-carboline-3-carboxamide derivatives as promising antileishmanial agents[J]. Ann Trop Med Parasitol, 2011, 105(8): 549-557.

    63. Ashok P, Chander S, Ana Tejería, et al. Synthesis and anti-leishmanial evaluation of 1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline derivatives against Leishmania infantum[J]. European Journal of Medicinal Chemistry, 2016, 123:814-821.

    64. Ashok P, Chander S, Smith T K, et al. Design, synthesis and biological evaluation of piperazinyl-β-carbolinederivatives as anti-leishmanial agents[J]. European Journal of Medicinal Chemistry, 2018, 150:559.

    65. Dayan F E, Cantrell C L, Duke S O. Natural products in crop protection[J]. Bioorganic & Medicinal Chemistry, 2009, 17: 4022-4034.

    66. Rosell G, Quero C, Coll J, et al. Biorational insecticides in pest management[J]. Journal of Pesticide Science, 2008, 33: 103-121.

    67. Petroski R J, Stanley D W. Natural compounds for pest and weed control[J]. Journal of Agricultural and Food Chemistry, 2009, 57, 8171-8179.

    68. Crombie L. Natural product chemistry and its part in the defence against insects and fungi in agriculture[J]. Pesticide Science, 1999, 55, 761-774.

    69. Zhang S, Xu Z, Gao C, et al. Triazole derivatives and their anti-tubercular activity[J]. European Journal of Medicinal Chemistry, 2017, 138: 501-513.

    70. Dheer D, Singh V, Shankar R. Medicinal attributes of 1,2,3-triazoles: Current developments[J]. Bioorganic Chemistry, 2017, 71: 30-54.

    71. Fan Y L, Ke X, Li M. Coumarin-triazole hybrids and their biological activities[J]. Journal of Heterocyclic Chemistry, 2018, 55: 791-802.

    72. Gao F, Zhang X, Wang T, et al. Quinolone hybrids and their anti-cancer activities: An overview[J]. European Journal of Medicinal Chemistry, 2019, 165: 59-79.

    73. Valdez J, Cedillo R, Hernandez-Campos A, et al. Synthesis and antiparasitic activity of 1H-benzimidazole derivatives[J]. Bioorganic & Medicinal Chemistry Letters, 2002, 12: 2221-2224.

    74. Fonseca T, Gigante B, Gilchrist T L. A short synthesis of phenanthro[2,3-d]imidazoles from dehydroabietic acid. Application of the methodology as a convenient route to benzimidazoles[J]. Tetrahedron, 2001, 57: 1793-1799.

    75. Pabba C, Wang H J, Mulligan S R, et al. Microwave-assisted synthesis of 1-aryl-1H-indazoles via one-pot two-step Cu-catalyzed intramolecular N-arylation of arylhydrazones[J]. Tetrahedron Lett, 2005, 46: 7553-7557.

    76. Denny W A, Rewcastle G W, Baguley B C. Potential antitumor agents. 59. structure-activity relationships for 2-phenylbenzimidazole-4-carboxamidesa, new class of "minimal" DNA-Intercalating agents which may not act via topoisomerase II[J]. Journal of Medicinal Chemistry, 1990, 33:814-819.

    77. Jordan A D, Luo C, Reitz A B. Efficient conversion of substituted aryl thioureas to 2-aminobenzothiazoles using benzyltrimethylammonium tribromide[J]. Journal of Organic Chemistry, 2003, 68(22): 8693-8696.

    78. Beaulieu C, Wang Z, Denis D, et al. Benzimidazoles as new potent and selective DP antagonists for the treatment of allergic rhinitis[J]. Bioorganic & Medicinal Chemistry Letters, 2004, 14(12): 3195-3199.

    79. Gomaa M S, Armstrong J L, Bobillon B, et al. Novel azolyl-(phenylmethyl)]aryl /heteroarylamines: potent CYP26 inhibitors and enhancers of all-trans retinoic acid activity in neuroblastoma cells[J]. Bioorganic & Medicinal Chemistry, 2008, 16(17):8301-8313.

    80. Bondock S, Fadaly W, Metwally M A. Synthesis and antimicrobial activity of some new thiazole, thiophene and pyrazole derivatives containing benzothiazole moiety[J]. Cheminform, 2010, 45(9):3692-3701.

    81. Ruddarraju R R, Murugulla A C, Kotla R, et al. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives[J]. European Journal of Medicinal Chemistry, 2016, 123: 379-396.

    82. Kant R, Kumar D, Agarwal D, et al. Synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities[J]. European Journal of Medicinal Chemistry, 2016, 113: 34-49.

    83. Huo J P, Hu H W, Zhang M, et al. A mini review of the synthesis of poly-1,2,3-triazole-based functional materials[J]. RSC Advances, 2017, 7(4): 2281-2287.

    84. Floros M C, Bortolatto J F, Oliveira J O B, et al. Antimicrobial activity of amphiphilic triazole-linked polymers derived from renewable sources[J]. ACS Biomaterials Science & Engineering, 2016, 2(3): 336-343.

    85. Vatmurge N S, Hazra B G, Pore V S, et al. Synthesis and antimicrobial activity of β-lactam-bile acid conjugates linked via triazole[J]. Bioorganic & Medicinal Chemistry Letters, 2008, 18(6): 2043-2047.

    86. Jagasia R, Holub J M, Bollinger M, et al. Peptide Cyclization and Cyclodimerization by CuI-Mediated Azide-Alkyne Cycloaddition[J]. Journal of Organic Chemistry, 2009, 74,(8): 2964-2974.

    87. Huber D, Hübner H, Gmeiner P. 1,1’-Disubstituted Ferrocenes as Molecular Hinges in Mono- and Bivalent Dopamine Receptor Ligands[J]. Journal of Medicinal Chemistry, 2009, 52(21): 6860-6870.

    88. Huo X Y, Guo L, Wei Y T, et al. Synthesis and Fungicidal Activity of Novel β-Carboline Derivatives[J]. Agrochemicals. 2018, 57: 3-6.

    89. (a) Lippke K P, Schunack W G, Wenning W, et al. β-Carbolines as benzodiazepine receptor ligands. 1. Synthesis and benzodiazepine receptor interaction of esters of β-carboline-3-carboxylic acid[J]. Journal of Medicinal Chemistry, 1983, 26(4): 499-503.(b) Brossi A, Focella A, Teitel S. Alkaloids in mammalian tissues. 3. Condensation of L-tryptophan and L-5-hydroxytryptophan with formaldehyde and acetaldehyde[J]. Journal of Medicinal Chemistry, 1973, 16(4): 418-420.

    90. Xinjiang Huashidan Pharmaceutical Research Co., Ltd. EP 1634881 A1, 2006.

    91. Cao R H, Chen Q, Hou X R, et al. Synthesis, acute toxicities and antitumor effects of novel 9-substituted β-carboline derivatives[J]. Bioorganic & Medicinal Chemistry, 2004, 12(17): 4613-4623.

    92. Cao R H, Guan X D, Shi B X, et al. Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents[J]. European Journal of Medicinal Chemistry, 2010, 45(6): 2503-2515.

    93. Yuan X Y, Zhang L, Han X Q, et al. Synthesis and fungicidal activity of the strobilurins containing 1,3,4-thiodiazole ring[J]. Chinese Journal of Organic Chemistry, 2014, 34(1), 170-177.

    94. Pesticides guidelines for laboratory bioactivity tests: part 2: petri plate test for determining fungicide inhibition of mycelial growth: NY/T 1156.2-2006. Beijing: China Agriculture Press, 2006.(农药室内生物测定试验准则杀菌剂第2部分: 抑制病原真菌菌丝生长试验平皿法: NY/T 1156.2-2006. 北京: 中国农业出版社, 2006.)

    95. Ruddarraju R R, Murugulla A C, Kotla R, et al. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives[J]. European Journal of Medicinal Chemistry, 2016, 123: 379-396.

    96. Dubovis M V, Rudakov G F, Kulagin A S, et al. A new method of synthesis of substituted 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles and their fungicidal activity[J]. Tetrahedron, 2018, 74: 672-683.

    97. Zheng X C, Wan Y J, Ling F, et al. Copper-Catalyzed Tandem Reaction of Terminal Alkynes and Sulfonyl Azides for the Assembly of Substituted Aminotriazoles[J]. Organic Letters, 2017, 19: 3859-3862.

    98. Hao C B, Zhou C J, Xie J W, et al. An efficient copper-catalyzed one-pot synthesis of 1-aryl-1,2,3-triazoles from arylboronic acids in water under mild conditions[J]. Chinese Journal of Chemistry, 2016, 33(11): 1317-1320.

    99. Zhou C J, Zhang J, Liu P, et al. 2-Pyrrolecarbaldiminato–Cu(II) complex catalyzed three-component 1,3-dipolar cycloaddition for 1,4-disubstituted 1,2,3-triazoles synthesis in water at room temperature[J]. RSC Advances, 2015, 5:6661–6665.

    100. 刘长令, 翟煜翥, 张运晓, 等. 防治灰霉病用杀菌剂的开发[J]. 农药, 2000, 39(3): 1-6.

    101. Liu H B, Gao W W, Tangadanchu V K R, et al. Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation[J]. European Journal of Medicinal Chemistry, 2017, 143: 66-84.

    102. Zhang H Z, Damu G L V, Cai G X, et al. Design, synthesis and antimicrobial evaluation of novel benzimidazole type of Fluconazole analogues and their synergistic effects with Chloromycin, Norfloxacin and Fluconazole[J]. European Journal of Medicinal Chemistry, 2013, 64: 329-344.

    103. Wu Q F, Cao R H, Feng M X, et al. Synthesis and in vitro cytotoxic evaluation of novel 3,4,5-trimethoxyphenyl substituted β-carboline derivatives[J]. European Journal of Medicinal Chemistry, 2009; 44: 533-540.

    104. Cao R H, Peng W L, Chen H S, et al. Synthesis and in vitro cytotoxic evaluation of 1,3-bisubstituted and 1,3,9-trisubstituted β-carboline derivatives[J]. European Journal of Medicinal Chemistry, 2005, 40: 249-257.

    105. Guo L, Xie J W, Fan W X, et al. Synthesis and antitumor activities of novel bivalent 1-heterocyclic-β-carbolines linked by alkylamino spacer[J]. Chinese Journal of Organic Chemistry, 2017, 37(7): 1741-1747.

    106. Chen W, Zhang G X, Guo L, et al. Synthesis and biological evaluation of novel alkyl diamine linked bivalent beta-carbolines as angiogenesis inhibitors[J]. European Journal of Medicinal Chemistry, 2016, 124: 249-261.

    107. Guo L, Fan W X, Chen X M, et al. Synthesis and antitumor activities of β-carboline derivatives[J]. Chinese Journal of Organic Chemistry, 2013, 33(2): 332-338.

    108. Chen Q, Chen W, Fan W X, et al. Design, synthesis and biological evaluation of novel alkyl diamine linked bivalent β-carbolines as angiogenesis inhibitors. Bioorganic Medicinal Chemistry Letters, 2016, 26(20): 5065-5068.

    109. Guo L, Chen W, Fan

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 2019-06-03    

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