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研究生： 華 生
Jayakumar, Srinivasan
論文名稱： 利用新型骨牌式反應合成喹啉并喹啉暨研發可抑制71型腸病毒之絞合芳香族化合物
Syntheses of Quinolinoquinolines by a New Domino Reaction and Hinged Aromatic Compounds against Enterovirus 71
指導教授： 胡紀如
Hwu, Jih Ru
口試委員: 鄭建鴻
Cheng, Chien-Hong
彭之皓
PENG, CHI-HOW
許銘華
HSU, MING-HUA
蔡淑貞
TSAY, SHWU-CHEN
謝發坤
Shieh, Fa-Kuen
學位類別： 博士
Doctor
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2020
畢業學年度： 108
語文別： 英文
論文頁數： 165
中文關鍵詞： 細胞成像 、苯炔 、骨牌式反應 、抗病毒 、腸病毒71型
外文關鍵詞： cell imaging, Benzyne, Domino reaction, Antiviral, Enterovirus 71
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    • 本論文討論了兩個主題。 首先，本人成功開發一種新型骨牌式反應，應用此反應，可有效合成喹啉并喹啉。 該等化合物可應用做為檢測癌細胞之螢光探針。 其次，本人成功合成一系列具抑制71型腸病毒活性之鉸合芳香族化合物，所得之構效關係將可幫助腸病毒藥物之研發.
    螢光探針活體細胞成像是醫學診斷及生物學研究之重要工具。這些信息對於理解並分析生物系統之功能有極大幫助。這些螢光探針具高靈敏度且用途廣泛。由於近紅外光（NIR）光能穿透生物組織，近紅外光（NIR）螢光探針之發射峰出現在「生物光學窗口」（650900 nm）中。文獻中多數螢光團之發射波長為紫外線（UV）或低於600 nm之可見光範圍。因此，我們開發了一種新型骨牌式反應，該反應涉及使用氮-雜芳烴，芳烴，及炔烴，並以高收率（〜85％）得到喹啉并喹啉化合物。該骨牌式反應具有3個關鍵步驟，即1,2消除，氮-芳基化反應，及[4 + 2]環加成反應。共成功合成15個產物，其中兩個產物顯示出更長之發射波長（λmax = 674 nm和604 nm）。在此遠紅/近紅外波長區間，達到了最小之光毒性及最大之生物組織穿透力。另外並利用MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物）測定法研究了該等化合物之細胞毒性。螢光實驗中之CT-26癌細胞細胞質中顯示為紅色發射，故所合成出之化合物可應用於活細胞成像。
    另外我們並設計合成了鉸合芳香化合物，根據生物活性測試，其具抑制71型腸病毒(EV71)活性。腸病毒屬於單鏈核糖核酸(RNA)病毒，與幾種人類和哺乳動物疾病相關。 如今沒有任何可用於治療腸病毒的藥物，故研發新的抗腸道病毒藥物刻不容緩。我成功合成了一系列鉸合芳族化合物並針對EV71進行生物活性測試。 在這些綴合物中，共有三個化合物在人惡性胚胎横纹肌瘤细胞(RD)中，表現出對EV71病毒之極佳抑制活性。 經由我所建立之構效關係，發現化合物具嗎啉和三氟苯環基團時，可得最佳抗病毒活性。

    Two major research themes are studied in this dissertation. First, a new domino reaction was developed with success for the synthesis of quinolinoquinolines efficiently. These compounds can be used as a flourescent probe for the detection of cancer cells. Second, hinged aromatic compounds were synthesized to act as agents against enterovirus 71.
    Live-cell imaging with fluorescent probes is an essential tool for medical diagnostics and biological studies. This information helps to understand the way in which biological system function. These fluorescent probes are highly sensitive and versatile. Near-infrared (NIR) fluorescent probes, of which emission peaks appear in the “biological window” (650900 nm), are of interest due to deep tissue penetration of NIR light. Most of the fluorophores in the literature have emission wavelength in the ultraviolet (UV) or visible range below 600 nm. Therefore, I synthesized quinolinoquinoline compounds which had the emission wavelength above 600 nm.
    Quinolinoquinoline compounds were synthesized through a new domino reaction that involved the use of N-heteroarenes, aryne and alkyne in good yields (~ 85%). This domino reaction had 3-steps in it namely 1,2-elimination, N-arylation, and [4 + 2] cycloaddition. Among the 15 molecules synthesized, two molecules showed longer emission wavelengths (λmax = 674 nm and 604 nm). At these far red/near-infrared wavelengths light achieves minimum phototoxicity and maximal tissue penetration. The in vitro toxicity of these compounds using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay were investigated and cell viability was found to be 96% (6.0 h interaction time, 10 ppm concentration). The acquired images showed red emission in the cytoplasm of the CT-26 cancer cells. These compounds can be utilized for live-cell imaging. Identification of the disease in vitro was accomplished by this fluorescent probe.
    Next, I turned my focus on curing the disease. Towards this goal, I designed and synthesized hinged aromatic compounds to act as agents against enterovirus 71. Enterovirus belongs to a group of single-stranded RNA viruses associated with several human and mammalian diseases. Nowadays, there are no available drugs for the treatment of enteroviruses (EV). Upon the urgent quest of new anti-enterovirus drugs, a series of hinged aromatic compounds were synthesized and tested against EV71. Among these conjugates, three new agents exhibited inhibitory activity towards EV71 virus in RD cells. The morpholine and trifluorobenzene rings showed the greatest antiviral activity based on their structureactivity relationship.
     

    Content Abstract (in English)………………………………….………………………………...i Abstract (in Chinese)………………………………………...………………………..iii Acknowledgement....………………………………………………………………….v Content………………………………………………………………………………..vi List of Figures……………………………………………….……………………….xix List of Table………………………………………………………………………….xxi List of Schemes……………………………………………………………………….xxi 1. Introduction…………………………………………………………………………1 2. Results...……………………………………………………………………………26 2.1 Synthesis of quinolinoquinolines from silylaryl triflates, alkynes, and N- heteroarenes....…………………………………………………………26 2.2 Optimization of reaction condition for the syntheses of quinoline derivatives ………………….………………………………………….27 2.3 Synthesis of various quinoline derivatives………………………….…32 2.4 Spectroscopic analysis for the structure identification of 8a...………...32 2.5 Intracellular uptake experiments of quinolinoquinoline derivatives using confocal microscopy...………………………………………………....34 2.6 Cell viability assay……………………………………………………..35 2.7 Intracellular uptake of 8d and 8f using confocal microscopy..………..36 2.8 Chemical Synthesis by the Method 1: Direct Meerwin Arylation of Heteroarenes...…………………………………………………………37 2.9 Chemical Synthesis by the Method 2: Palladium-catalyzed Cross-coupling Reaction Involving CH Activation……………………...….39 2.10 Structural identification of new conjugated compounds..………..……41 2.11 Measurement of Lipophilicity……………………………..…………..42 2.12 Test of Antiviral Activity against EV-A71…..……………..…………42 3. Discussion………………………………………………………………………….44 3.1 Plausible mechanism for the synthesis of isoquinolinoquinoline 8a..…44 3.2 Structure Activity Relationship comparsion of quinolinoquinolines….45 3.3 In vitro cellular uptake of the CT-26 cells internalized with 8d and 8f monitored using confocal laser scanning optical microscopy...……….49 3.4 Chemical Synthesis and Physical Properties…………………...……...49 3.5 Determination of log P values…………………………………………51 3.6 Lipophilicity………………………………………………………..….51 3.5 Structure–Activity Relationship……………………………………….52 4. Conclusion……………...………………………………………………………….57 5. Experimental……………………………………………………………..………..59 Standard Procedure 1 for the Syntheses of Quinoline Derivatives…………...…61 Dimethyl 4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6a)…..……………61 Dimethyl 7-bromo-4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6b)....……62 Dimethyl 6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7a)….………….63 Dimethyl 10-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7b).64 Dimethyl 12-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7c)..65 Dimethyl 7-bromo-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7d).......66 Dimethyl 8-methyl-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7e).......67 Dimethyl 8aH-benzo[g]quinolino[1,2-a]quinoline-7,8-dicarboxylate (7f)….…68 Dimethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8a).……..69 Dimethyl 9-bromo-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate(8b)………………………………………………………………70 Dimethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8c)...…71 Dimethyl 2,3-Difluoro-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8d)…………………………………………………………………………….72 Diethyl 11bH-Isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8e)……….73 Diethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8f)……..74 Di-tert-butyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8g).75 Ethyl 5-(3-Formylphenyl)furan-2-carboxylate (11)…………………………...76 Ethyl 5-(3-[5-(Trimethylsilyl)-1H-pyrazol-3-yl]phenyl)furan-2-carboxylate (13)………………………………………………………………………….….77 Ethyl 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylate (14)………………...78 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylic acid (15)…………………..79 Standard Procedure 2 for the Synthesis of Polycycle Derivatives 17ac, 19 a, b, 20, and 21…………………………………………..…………………………..80 (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)(pyrrolidin-1-yl)methanone (17a)...80 Piperidin-1-yl (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17b)….81 Azepan-1-yl(5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17c)…….82 N-(4-Fluorophenyl)5-[3-(1H-pyrazol-3-yl)phenyl]furan-2-carboxamide (19a)83 N-(4-Methoxyphenyl)5-[3-(1H-pyrazol-3-yl)phenyl]-furan-2-carboxamide (19b) …………………………………………………………………………..84 N-Cyclopropyl-5-[3-(1H-pyrazol-3-yl)phenyl]Furan-2-carboxamide (20)…...85 N-(2-Methoxyethyl)5-[3-(1H-pyrazol-3-yl)phenyl]thiophene-2-carboxamide (21)……………………………………………………………………………..86 3-[1-Methyl-5-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]benzaldehyde (25c)...87 Morpholino-(5-[3-(1H-Pyrazol-3-yl)phenyl]-1-methyl-1H-pyrrol-2-yl)methanone (28j)…………………………………………………..…………88 6. References………………………………………………………………………….90 7. Spectra…………………………………………………………………………….100 1H NMR spectrum of Dimethyl 4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6a)……………………………………………………………………………101 13C NMR spectrum of Dimethyl 4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6a) ...………………………………………………………………………... 101 IRspectrum of Dimethyl 4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6a).102 HRMS spectrum of Dimethyl 4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6a)……………………………………………………………………………102 1H NMR spectrum of Dimethyl 7-bromo-4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6b).……………………………………………………………103 13C NMR spectrum of Dimethyl 7-bromo-4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6b).………………………………………………………….. 103 IR spectrum of Dimethyl 7-bromo-4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6b).……………………………………………………………104 HRMS spectrum of Dimethyl 7-bromo-4aH-pyrido[1,2-a]quinoline-5,6-dicarboxylate (6b).……………………………………………………………104 1H NMR spectrum of Dimethyl 6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7a).……………………………………………………………105 13C NMR spectrum of Dimethyl 6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7a).……………………………………………………………105 IR spectrum of Dimethyl 6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7a).…………………………………………………………………………...106 HRMS spectrum of Dimethyl 6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7a).…………………………………………………………………………...106 1H NMR spectrum of Dimethyl 10-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7b)…………………………………………………………….107 13C NMR spectrum of Dimethyl 10-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7b)………………………………………………………...107 IR spectrum of Dimethyl 10-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7b)…………………………………………………………….108 HRMS spectrum of Dimethyl 10-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7b)…………………………………………………………….108 1H NMR spectrum of Dimethyl 12-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7c)……………………………………………………….........109 13C NMR spectrum of Dimethyl 12-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7c)………………………………………………………...109 IR spectrum of Dimethyl 12-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7c)………………………………………………………….…110 HRMS spectrum of Dimethyl 12-methoxy-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7c)………………………………………………………….…110 1H NMR spectrum of Dimethyl 7-bromo-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7d).............................................................................................111 13C NMR spectrum of Dimethyl 7-bromo-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7d).............................................................................................111 IR spectrum of Dimethyl 7-bromo-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7d).............................................................................................112 HRMS spectrum of Dimethyl 7-bromo-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7d).............................................................................................112 1H NMR spectrum of Dimethyl 8-methyl-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7e).............................................................................................113 13C NMR spectrum of Dimethyl 8-methyl-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7e).............................................................................................113 IR spectrum of Dimethyl 8-methyl-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7e).............................................................................................114 HRMS spectrum of Dimethyl 8-methyl-6aH-quinolino[1,2-a]quinoline-5,6-dicarboxylate (7e).............................................................................................114 1H NMR spectrum of Dimethyl 8aH-benzo[g]quinolino[1,2-a]quinoline-7,8-dicarboxylate (7f)…………………………………………………………..…115 13C NMR spectrum of Dimethyl 8aH-benzo[g]quinolino[1,2-a]quinoline-7,8-dicarboxylate (7f)…………………………………………………………..…115 IR spectrum of Dimethyl 8aH-benzo[g]quinolino[1,2-a]quinoline-7,8-dicarboxylate (7f)……………………………………………………………..116 HRMS spectrum of Dimethyl 8aH-benzo[g]quinolino[1,2-a]quinoline-7,8-dicarboxylate (7f)……………………………………………………………..116 1H NMR spectrum of Dimethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8a)………………………………………………………...…..117 13C NMR spectrum of Dimethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8a)………………………………………………………...…..117 IR spectrum of Dimethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8a)……………………………………………………...……..118 HRMS spectrum of Dimethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8a)………………………………………………………...…..118 1H NMR spectrum of Dimethyl 9-bromo-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8b)…………………………………………………...…119 13C NMR spectrum of Dimethyl 9-bromo-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8b) …………………………………………………..…119 IR spectrum of Dimethyl 9-bromo-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8b)………………………………….........................................120 HRMS spectrum of Dimethyl 9-bromo-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8b) …………………………………………………..…120 1H NMR spectrum of Dimethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8c)………………………………………………………….…121 13C NMR spectrum of Dimethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8c) ……………………………………………………………121 IR spectrum of Dimethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8c) ……………………………………………………………122 HRMS spectrum of Dimethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8c)…………………………………………………………….122 1H NMR spectrum of Dimethyl 2,3-Difluoro-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8d)………………………………………...123 13C NMR spectrum of Dimethyl 2,3-Difluoro-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8d)………………………………………...123 IR spectrum of Dimethyl 2,3-Difluoro-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8d)……………………………………………………..124 HRMS spectrum of Dimethyl 2,3-Difluoro-11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8d)……………………………………………………..124 1H NMR spectrum of Diethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8e)…………………………………………………………….125 13C NMR spectrum of Diethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8e)…………………………………………………………….125 IR spectrum of Diethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8e)…………………………………………………………………………....126 HRMS spectrum of Diethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8e)…………………………………………………………….126 1H NMR spectrum of Diethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8f)……………………………………………………………..127 13C NMR spectrum of Diethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8f)..............................................................................................127 IR spectrum of Diethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8f)……………………………………………………………..128 HRMS spectrum of Diethyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8f)……………………………………………………………..128 1H NMR spectrum of Di-tert-butyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8g)………………………………………………………….…129 13C NMR spectrum of Di-tert-butyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8g)………………………………………………………….…129 IR spectrum of Di-tert-butyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8g)………………………………………………………….…130 HRMS spectrum of Di-tert-butyl 13bH-Quinolino[1,2-f]phenanthridine-14,15-dicarboxylate (8g)…………………………………………………………….130 1H NMR spectrum of Ethyl 5-(3-Formylphenyl)furan-2-carboxylate (11)…...131 13C NMR spectrum of Ethyl 5-(3-Formylphenyl)furan-2-carboxylate (11)…..131 IR spectrum of Ethyl 5-(3-Formylphenyl)furan-2-carboxylate (11)…………..132 HRMS spectrum of Ethyl 5-(3-Formylphenyl)furan-2-carboxylate (11)……..132 1H NMR spectrum of Ethyl 5-(3-[5-(Trimethylsilyl)-1H-pyrazol-3-yl]phenyl)furan-2-carboxylate (13)………………………………………..…133 13C NMR spectrum of Ethyl 5-(3-[5-(Trimethylsilyl)-1H-pyrazol-3-yl]phenyl)furan-2-carboxylate (13)………………………………………..…133 IR spectrum of Ethyl 5-(3-[5-(Trimethylsilyl)-1H-pyrazol-3-yl]phenyl)furan-2-carboxylate (13)………………………………………………………………134 HRMS spectrum of Ethyl 5-(3-[5-(Trimethylsilyl)-1H-pyrazol-3-yl]phenyl)furan-2-carboxylate (13)…………………………………………..134 1H NMR spectrum of Ethyl 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylate (14)……………………………………………………………………………135 13C NMR spectrum of Ethyl 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylate (14)…………………………………………………………………………....135 IR spectrum of Ethyl 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylate (14)…………………………………………………………………………....136 HRMS spectrum of Ethyl 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylate (14)…………………………………………………………………………....136 1H NMR spectrum of 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylic acid (15)…………………………………………………………………………....137 13C NMR spectrum of 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylic acid (15)……………………………………………………………………………137 IR spectrum of 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylic acid (15)....138 HRMS spectrum of 5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-carboxylic acid (15)…………………………………………………………………………....138 1H NMR spectrum of (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)(pyrrolidin-1-yl)methanone (17a)…………………………………………………………...139 13C NMR spectrum of (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)(pyrrolidin-1-yl)methanone (17a)…………………………………………………………...139 IR spectrum of (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)(pyrrolidin-1-yl)methanone (17a)…………………………………………………………...140 HRMS spectrum of (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)(pyrrolidin-1-yl)methanone (17a)…………………………………………………………...140 1H NMR spectrum of Piperidin-1-yl (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17b)…………………………………………………………..141 13C NMR spectrum of Piperidin-1-yl (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17b)…………………………………………………………..141 IR spectrum of Piperidin-1-yl (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17b)…………………………………………………………..142 HRMS spectrum of Piperidin-1-yl (5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17b)…………………………………………………………..142 1H NMR spectrum of Azepan-1-yl(5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17c)…………………………………………………………...143 13C NMR spectrum of Azepan-1-yl(5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17c)…………………………………………………………...143 IR spectrum Azepan-1-yl(5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17c)…………………………………………………………………………..144 HRMS spectrum Azepan-1-yl(5-[3-(1H-Pyrazol-3-yl)phenyl]furan-2-yl)methanone (17c)…………………………………………………………...144 1H NMR spectrum of N-(4-Fluorophenyl)5-[3-(1H-pyrazol-3-yl)phenyl]furan-2-carboxamide (19a)…………………………………………………………....145 13C NMR spectrum of N-(4-Fluorophenyl)5-[3-(1H-pyrazol-3-yl)phenyl]furan-2-carboxamide (19a)……………………………………………………….…145 IR spectrum of N-(4-Fluorophenyl)5-[3-(1H-pyrazol-3-yl)phenyl]furan-2-carboxamide (19a)……………………………………………………………146 HRMS spectrum of N-(4-Fluorophenyl)5-[3-(1H-pyrazol-3-yl)phenyl]furan-2-carboxamide (19a)……………………………………………………………146 1H NMR spectrum of N-(4-Methoxyphenyl)5-[3-(1H-pyrazol-3-yl)phenyl]-furan-2-carboxamide (19b)…………………………………………………...147 13C NMR spectrum of N-(4-Methoxyphenyl)5-[3-(1H-pyrazol-3-yl)phenyl]-furan-2-carboxamide (19b)…………………………………………………...147 IR spectrum of N-(4-Methoxyphenyl)5-[3-(1H-pyrazol-3-yl)phenyl]-furan-2-carboxamide (19b)……………………………………………………………148 HRMS spectrum of N-(4-Methoxyphenyl)5-[3-(1H-pyrazol-3-yl)phenyl]-furan-2-carboxamide (19b)………………………………………………………....148 1H NMR spectrum of N-Cyclopropyl-5-[3-(1H-pyrazol-3-yl)phenyl]Furan-2-carboxamide (20)……………………………………………………………..149 13C NMR spectrum of N-Cyclopropyl-5-[3-(1H-pyrazol-3-yl)phenyl]Furan-2-carboxamide (20)…………………………………………………………..…149 IR spectrum of N-Cyclopropyl-5-[3-(1H-pyrazol-3-yl)phenyl]Furan-2-carboxamide (20)……………………………………………………………..150 HRMS spectrum of N-Cyclopropyl-5-[3-(1H-pyrazol-3-yl)phenyl]Furan-2-carboxamide (20)……………………………………………………………..150 1H NMR spectrum of N-(2-Methoxyethyl)5-[3-(1H-pyrazol-3-yl)phenyl]thiophene-2-carboxamide (21)………………………………….....151 13C NMR spectrum of N-(2-Methoxyethyl)5-[3-(1H-pyrazol-3-yl)phenyl]thiophene-2-carboxamide (21)…………………………………….151 IR spectrum of N-(2-Methoxyethyl)5-[3-(1H-pyrazol-3-yl)phenyl]thiophene-2-carboxamide (21)……………………………………………………………..152 HRMS spectrum of N-(2-Methoxyethyl)5-[3-(1H-pyrazol-3-yl)phenyl]thiophene-2-carboxamide (21)………………………………….…152 1H NMR spectrum of 3-[1-Methyl-5-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]benzaldehyde (25c)………………………………………………………...153 13C NMR spectrum of 3-[1-Methyl-5-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]benzaldehyde (25c)………………………………………………………...153 IR spectrum of 3-[1-Methyl-5-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]benzaldehyde (25c)………………………………………………………...154 HRMS spectrum of 3-[1-Methyl-5-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]benzaldehyde (25c)………………………………………………………...154 1H NMR spectrum of Morpholino-(5-[3-(1H-Pyrazol-3-yl)phenyl]-1-methyl-1H-pyrrol-2-yl)methanone (28j)……………………………………………...155 13C NMR spectrum of Morpholino-(5-[3-(1H-Pyrazol-3-yl)phenyl]-1-methyl-1H-pyrrol-2-yl)methanone (28j)……………………………………………...155 IR spectrum of Morpholino-(5-[3-(1H-Pyrazol-3-yl)phenyl]-1-methyl-1H-pyrrol-2-yl)methanone (28j)………………………………………………….156 HRMS spectrum of Morpholino-(5-[3-(1H-Pyrazol-3-yl)phenyl]-1-methyl-1H-pyrrol-2-yl)methanone (28j)……………………………………………….…156 8. Crystallographic data…………………………………………………………....157 X-ray Crystal Data of Dimethyl 11bH-isoquinolino[2,1-a]quinoline-12,13-dicarboxylate (8a) ……………………………………………………………158 List of Figures Figure 1. A mechanical domino process……………………………………………….1 Figure 2. Typical quinoline-containing fused N-heterocyclic bioactive molecules….10 Figure 3. Representative examples of bioactive octahydroindolo[2,3-a]quinolizine systems……………………………………………………………………..11 Figure 4. Representation of biological window……………………………………....12 Figure 5. Categorization of NIR BODIPY backbones……………………………….12 Figure 6. Representative example of NIR rhodamine backbone……………………..13 Figure 7. Structure of Enterovirus 71…………………………………………………….14 Figure 8. Structure of Capsid-binding inhibitors………………………………………...15 Figure 9. Viral capsid structure and location of canyon……………………………...15 Figure 10. Replication of picornavirus……………………………………………….16 Figure 11. Mechanisms for the induction of apoptosis……………………………….17 Figure 12. Biphenylimidazopyridines………………………………………………...22 Figure 13. Benzimidazole-coumarin-ribofuranosides hybrids………………………..23 Figure 14. Structure of the initial lead compound with antiviral properties………….23 Figure 15. Overview of all new compounds active against DENV or YFV…………24 Figure 16 Design of our Hinged Framework…………………………………………..25 Figure 17 ORTEP diagram of compound 8a, obtained by X-ray analysis……………..34 Figure 18 Emission spectra of pyridino/quinolino/isoquinolino/phenanthridino quinolines of the newly developed annulation reaction…………………...35 Figure 19 Effect of different concentrations of 8d, 8f on CT-26 cell viability after 24 h incubation…………………………………………………………………36 Figure 20 In vitro cellular uptake of the CT-26 cells internalized with 8d and 8f monitored using confocal laser scanning optical microscopy………….37 Figure 21 ORTEP diagram of compound 28g (on the left side) obtained by X-ray analysis……………………………………………………………………. 43 List of Tables Table 1. Recent Hinged compounds with anti-viral activity (20192017)…………..21 Table 2. Optimization of Yield for Reaction 1a + 2a + 4a 7a in Scheme 11 by Use of Various Solvents, Fluorides, Temperatures, and Reaction Times……29 Table 3. Structures of reactants 15 and products quinoline derivatives 68 as well as the isolated yields of newly developed domino reaction…………………...30 Table 4. According to the EC50, CC50, SI, and log P values of all compounds listed in Table 4, the following SAR guidelines are deduced for their activity against EV-71……………………………………………………………………….54 List of Schemes Scheme 1. Intramolecular domino reactions occur to generate steroids………………...2 Scheme 2. Reaction of -silylphenyl triflates with allenylsilanes to generate (-phenanthrenyl)vinylsilanes…………………………………………………3 Scheme 3. Mechanism for the autoxidative annulation to form phenanthrenes……….4 Scheme 4. Arynes formation and its application in multi-component reactions……....6 Scheme 5. MCR involving Quinoline, Aryne, and alkyne………………………….....6 Scheme 6. Three-component coupling reaction in the synthesis of an isoquinuclidine through a [4 + 2] DielsAlder cycloaddition………………………………7 Scheme 7. Syntheses of spirooxazino isoquinoline (left) and (pyridinyl)indolin-2-one (right) derivatives from the reactions of benzyne with different N-heteroarenes……………………………………………………………….7 Scheme 8. Pyridine-initiated multi-component coupling reaction in the synthesis of an indoline-2-one derivatives………………………………………………….7 Scheme 9. Benzye-induced multi-component synthesis of oxazinoquinolines………..7 Scheme 10. Synthesis of benzopyrano[3,4,-a] quinolizines and vinyl chromenes……..9 Scheme 11. Divergent synthetic route toward indoloquinolizine ……………….……..9 Scheme 12. Synthesis of radiometric probe……………………………………….….11 Scheme 13. N-Heterocycle Triggered Multicomponent Reactions of Arynes with Alkynes……………………………………………………………………27 Scheme 14. Reaction of arynes, quinoline and nitrile.…………………………….….28 Scheme 15. Benzye-induced synthesis of N-heteroarenes in the presence of alkynes..29 Scheme 16. Direct Meerwin Arylation of Heteroarenes……………………………....37 Scheme 17. Palladium-catalyzed Cross-coupling Reaction Involving CH Activation………………………………………………………………..39 Scheme 18. A plausible mechanism for the synthesis of isoquinolinoquinoline 8a…..44 Scheme 19. Various approaches to form the strategic bond…………………………..50

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