臺灣博碩士論文加值系統

含氟喹啉酮類抗菌劑，如norfloxacin, ofloxacin, ciprofloxacin, 及temafloxacin曾被用作為結核分枝桿菌(Mycobacterium tuberculosis)感染的化學治療藥劑。由於結核桿菌的脂質外鞘具有明顯的脂溶性，使其成為細胞內物質交流的阻隔。含氟喹啉酮類試劑因具脂溶性，使之能穿透進入結核桿菌的細胞外鞘，而達到高濃度產生抑制生長的活性。
在我們的研究論文裡試著去合成新的抗結核試劑，例如以含氟喹啉酮帶有5-取代-吡喃-4-酮(5-substiuted-pyran-4-one)，3-取代-吡啶-4-酮(3-substiuted-pyridin- 4-one)及芳香基(aryl-)或雜環芳香基-腙(heteroaryl-hydrazone)並評估其抗結核菌的活性。氟喹啉酮的篩選是由Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF)進行試驗，在藥物濃度6.25μg/mL時進行抗H37Rv菌株的篩選，以N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethoxy)- fluoroquinolones 14a-d之化合物顯示大於50%的抑制活性，其餘的化合物則沒有活性或只有微弱的活性。

Abstract
Several of the fluoroquinolone antibacterial agents, such as norfloxacin, ofloxacin, ciprofloxacin, and temafloxacin, have been examined as potential chemotherapeutics for Mycobacterium tuberculosis infection. These fluoroquinolones show good penetration into macrophages where they are both concentrated and retain a high degree of activity. This property is particularly important since it is well-known that surface-associated lipids of mycobacteria form a transport barrier when compared to the cell wall of true bacteria.
In our studies to discover new anti-TB agents, numerous fluoroquinolones, bearing 5-substiuted-pyran-4-one, 3-substiuted-pyridin- 4-one, and aryl- or heteroaryl-hydrazone, were synthesized and evaluated for anti-TB activities. Among the fluoroquinolones were screened against H37Rv at a sample concentration of 6.25μg/mL by the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF). Among the N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethoxy)-fluoroquinolones 14a-d demonstrated >50% inhibitory activity and the remaining test compounds were inactive or weakly active.

目錄
中文摘要 ---------------------------------------1
英文摘要 ---------------------------------------2
壹、緒言
一、前言 -----------------------------------3
二、研究動機 -------------------------------5
貳、合成方法 -----------------------------------13
一、pyranone與pyridinone的合成 -------------14
二、含氟喹啉酮的合成 -----------------------15
參、藥理活性測試實驗方法與活性結果討論
一、實驗方式 -------------------------------25
二、活性結果與討論 -------------------------27
肆、實驗部分
一、溶劑及處理過程 -------------------------30
二、儀器及試藥 -----------------------------30
三、各化合物的製備 -------------------------34
伍、參考文獻 -----------------------------------72
附錄

伍、參考資料
1. Maddry, J. A.; Bansal, N.; Bermudez, L. E.; Comber, R. N.; Orme, I. M.; Suling, W. J.; Wilson, L. N.; Reynolds, R. C. Homologated Aza Analogs of Arabinose as Antimycobacterial Agents. Bioorganic & Medicinal Chemistry Letters. 1998, 8, 237-242.
2. Bottari, B.; Maccari, R.; Monforte, F.; Ottana, R.; Rotondo, E.; Vigorita, M. G. Isoniazid-Related Copper(II) and Nickel(II) Complexes with Antimycobacterial In Vitro Activity. Bioorganic & Medicinal Chemistry Letters. 2000, 10, 657-660.
3. Artico, M.; Mai, A.; Sbardella, G.; Massa, S.; Lampis, G.; Deidda, D.; Pompei, R. N-[4-(1,1’-Biphenyl)Methyl]-4-(4-Thiomorpholinylmethyl) Benzenamines as Non-oxazolidinone Analogues of Antimycobacterial U-100480. Bioorganic & Medicinal Chemistry Letters. 1998, 8, 1493-1498.
4. Ayers, J. D.; Lowary, T. L.; Morehouse, C. B.; Besra, G. S. Synthetic Arabinofuranosyl Oligosaccharides as Mycobacterial Arabinosyltransferase Substrates. Bioorganic & Medicinal Chemistry Letters. 1998, 8, 437-442.
5. Berning, S. E. The Role of Fluoroquinolones in Tuberculosis Today . Drugs. 2001, 61, 9-18
6. Jacobs, M. R. Activity of Quinolones Against Mycobacteria. Drugs. 1999, 58, 19-22
7. Tzeng, C. C.; Chen, Y. L. Recent Developments in Antibacterial 4-Quinolones-3-carboxylic. The Chinese Pharmaceutical Journal. 2002, 54, 229-243.
8. Champe, P. C.; Harvey, R.A. Steps in Prokaryotic DNA Synthesis. Lippincott’s Illustrated Reviews: Biochemistry 2nd Edition
9. Thomas M. Devlin Types of DNA Structure. Biochemistry 3th Edition
10. Sakagami, K.; Iwamatsu, K.; Atsumi, K.; Hatanka, M. Synthetic Cephalosporins. VI. Synthesis and Antibacterial Activity of 7-[(Z)-2- (2-Aminothiazol-4-yl)-(1-carboxy-1-methyl)ethoxyiminoacetamido]-3-(3-hydroxy-4-pyridon-1-yl)methyl-3-cephem-4-carboxylic Acid and Related Compounds. Chem. Pharm. Bull. 1990, 38, 2271-2273.
11. Sakagami, K.; Iwamatsu, K.; Atsumi, K.; Hatanka, M. Synthetic Cephalosporins. VII. Synthesis and Antibacterial Activity of 7-[(Z)-2- (2-Aminothiazol-4-yl)-2-(3-(3-hydroxy-4-pyridon-1-yl)-3-carboxypropoxyimino)acetamido]-3-(1,2,3-thiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic Acid and Its Related Compounds. Chem. Pharm. Bull. 1990, 38, 3476-3479.
12. Choi, K. I.; Cha, J. H.; Pae, A. N.; Cho, Y. S.; Koh, H. Y.; Chang, M.
H.; Kang, H. Y.; Chung, B. Y. Synthesis and Structure-activity Relationships of Cephalosporins Having a Pyridone Moiety at the C-7 Position. The Journal of Antibiotics. 1997, 50, 279-282.
13. Setti, E. L.; Fiakpui, C.; Phillips, O. A.; Czajkowski, D. P.; Atchison, K.; Micetich, R. G.; Maiti, S. N. Chemical Modification of Tazobactam Synthesis of 2β-[(4-Substitued)-1,2,3-triazol-1-yl]methyl Penicillanic Acid Sulfone Derivatives. The Journal of Antibiotics. 1995, 48, 1320-1329.
14. Chang, M. H.; Choi, K. I.; Cha, J. H.; Pae, A. N.; Cho, Y. S.; Kang, H. Y.; Koh, H.Y. Studies on New Catechol Containing Cephalosporins II. Synthesis and Structure-activity Relationships of Cephalosporins Having a Catechol Moiety at the C-7 Position. The Journal of Antibiotics. 1995, 48, 1375-1377.
15. Bottari, B.; Maccari, R.; Monforte, F.; Ottana, R.; Rotondo, E. Isoniazid-Related Copper(II) and Nickel(II) Complexes with Antimycobacterial In Vitro Activity. Part 9. Bioorganic & Medicinal Chemistry Letters. 2000, 10, 657-660.
16. Savini, l.; Chiasserini, C.; Gaeta, A.; Pellerano, C. Synthesis and Anti-tubercular Evaluation of 4-Quinolyhydrazones. Bioorganic & Medicinal Chemistry Letters. 2002, 10, 2193-2198.
17. Kalyanam, N.; Likhate, M. A.; Fuhrer, H. Synthesis and Stereochemistry of a 4,5-dihydroxy-tetrahydropyran-2-carboxylic acid. Indian J. Chem. Sect. B. 1991, 30, 358.
18. Teitei, T. Chemistry of Kojic Acid : One-step Synthesis of Benzothiazoles and Other Fused Heterocycles from Kojic Acid Derivatives. Aust. J. Chem. 1983, 36, 2307-2315.
19. Gould, G. and Jacobs, W. A. Synthesis of 4-Hydroxyquinolines from Anilines and Diethyl Ethoxymalonate via Cyclization of the Intermediate Anilinomethylenemalonate Followed by Hydrolysis and Decarboxylation. J. Am. Chem. Soc. 1939, 61, 2890.
20. Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Trikura, T. Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubstitued 1-Alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids. J. Med. Chem. 1980, 23, 1358-1363.
21. Chu, D. T. W. and Maleczka, Jr. R. E. Synthesis of 4-Oxo-4H- quino[2,3,4-I,j][1,4]-benoxazine-5-carboxylic Acid Derivatives.
J. Heterocyclic Chem. 1987, 24, 453-456.
22. Kondo, H.; Sakamoto, F.; Kodera, Y.; Tsukamoto, G. Studies on Prodrugs. 5. Synthesis and Autimicrobital Activity of N-(Oxoalkyl)norfloxacin Derivatives. J. Med. Chem. 1986, 29, 2020-2024.
23. Ziegler, Jr. C. B.; Kuck, N. A.; Harris, S. M.; Lin, Y. Synthesis and In Vitro Biological Activity of Some 7-[Hydrazino], -[Hydrazoly] quinolone-3-carboxylic Acids. J. Heterocyclic Chem. 1988, 25, 1543-1546.
24. Collins, L. A. and Eranzblau, S. G. Microplate Alamar Blue Assay versus BACTEC 460 System for High-Throughput Screening of Compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrobial Agents and Chemotherapy. 1997, 41, 1004-1009.
25. Leysen, D. C.; Haemers, A.; Pattyn, S. R. Mycobacteria and the New Quinolones. Antimicrobial Agents and Chemotherapy. 1989, 33, 1-5.
伍、參考資料
1. Maddry, J. A.; Bansal, N.; Bermudez, L. E.; Comber, R. N.; Orme, I. M.; Suling, W. J.; Wilson, L. N.; Reynolds, R. C. Homologated Aza Analogs of Arabinose as Antimycobacterial Agents. Bioorganic & Medicinal Chemistry Letters. 1998, 8, 237-242.
2. Bottari, B.; Maccari, R.; Monforte, F.; Ottana, R.; Rotondo, E.; Vigorita, M. G. Isoniazid-Related Copper(II) and Nickel(II) Complexes with Antimycobacterial In Vitro Activity. Bioorganic & Medicinal Chemistry Letters. 2000, 10, 657-660.
3. Artico, M.; Mai, A.; Sbardella, G.; Massa, S.; Lampis, G.; Deidda, D.; Pompei, R. N-[4-(1,1’-Biphenyl)Methyl]-4-(4-Thiomorpholinylmethyl) Benzenamines as Non-oxazolidinone Analogues of Antimycobacterial U-100480. Bioorganic & Medicinal Chemistry Letters. 1998, 8, 1493-1498.
4. Ayers, J. D.; Lowary, T. L.; Morehouse, C. B.; Besra, G. S. Synthetic Arabinofuranosyl Oligosaccharides as Mycobacterial Arabinosyltransferase Substrates. Bioorganic & Medicinal Chemistry Letters. 1998, 8, 437-442.
5. Berning, S. E. The Role of Fluoroquinolones in Tuberculosis Today . Drugs. 2001, 61, 9-18
6. Jacobs, M. R. Activity of Quinolones Against Mycobacteria. Drugs. 1999, 58, 19-22
7. Tzeng, C. C.; Chen, Y. L. Recent Developments in Antibacterial 4-Quinolones-3-carboxylic. The Chinese Pharmaceutical Journal. 2002, 54, 229-243.
8. Champe, P. C.; Harvey, R.A. Steps in Prokaryotic DNA Synthesis. Lippincott’s Illustrated Reviews: Biochemistry 2nd Edition
9. Thomas M. Devlin Types of DNA Structure. Biochemistry 3th Edition
10. Sakagami, K.; Iwamatsu, K.; Atsumi, K.; Hatanka, M. Synthetic Cephalosporins. VI. Synthesis and Antibacterial Activity of 7-[(Z)-2- (2-Aminothiazol-4-yl)-(1-carboxy-1-methyl)ethoxyiminoacetamido]-3-(3-hydroxy-4-pyridon-1-yl)methyl-3-cephem-4-carboxylic Acid and Related Compounds. Chem. Pharm. Bull. 1990, 38, 2271-2273.
11. Sakagami, K.; Iwamatsu, K.; Atsumi, K.; Hatanka, M. Synthetic Cephalosporins. VII. Synthesis and Antibacterial Activity of 7-[(Z)-2- (2-Aminothiazol-4-yl)-2-(3-(3-hydroxy-4-pyridon-1-yl)-3-carboxypropoxyimino)acetamido]-3-(1,2,3-thiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic Acid and Its Related Compounds. Chem. Pharm. Bull. 1990, 38, 3476-3479.
12. Choi, K. I.; Cha, J. H.; Pae, A. N.; Cho, Y. S.; Koh, H. Y.; Chang, M.
H.; Kang, H. Y.; Chung, B. Y. Synthesis and Structure-activity Relationships of Cephalosporins Having a Pyridone Moiety at the C-7 Position. The Journal of Antibiotics. 1997, 50, 279-282.
13. Setti, E. L.; Fiakpui, C.; Phillips, O. A.; Czajkowski, D. P.; Atchison, K.; Micetich, R. G.; Maiti, S. N. Chemical Modification of Tazobactam Synthesis of 2β-[(4-Substitued)-1,2,3-triazol-1-yl]methyl Penicillanic Acid Sulfone Derivatives. The Journal of Antibiotics. 1995, 48, 1320-1329.
14. Chang, M. H.; Choi, K. I.; Cha, J. H.; Pae, A. N.; Cho, Y. S.; Kang, H. Y.; Koh, H.Y. Studies on New Catechol Containing Cephalosporins II. Synthesis and Structure-activity Relationships of Cephalosporins Having a Catechol Moiety at the C-7 Position. The Journal of Antibiotics. 1995, 48, 1375-1377.
15. Bottari, B.; Maccari, R.; Monforte, F.; Ottana, R.; Rotondo, E. Isoniazid-Related Copper(II) and Nickel(II) Complexes with Antimycobacterial In Vitro Activity. Part 9. Bioorganic & Medicinal Chemistry Letters. 2000, 10, 657-660.
16. Savini, l.; Chiasserini, C.; Gaeta, A.; Pellerano, C. Synthesis and Anti-tubercular Evaluation of 4-Quinolyhydrazones. Bioorganic & Medicinal Chemistry Letters. 2002, 10, 2193-2198.
17. Kalyanam, N.; Likhate, M. A.; Fuhrer, H. Synthesis and Stereochemistry of a 4,5-dihydroxy-tetrahydropyran-2-carboxylic acid. Indian J. Chem. Sect. B. 1991, 30, 358.
18. Teitei, T. Chemistry of Kojic Acid : One-step Synthesis of Benzothiazoles and Other Fused Heterocycles from Kojic Acid Derivatives. Aust. J. Chem. 1983, 36, 2307-2315.
19. Gould, G. and Jacobs, W. A. Synthesis of 4-Hydroxyquinolines from Anilines and Diethyl Ethoxymalonate via Cyclization of the Intermediate Anilinomethylenemalonate Followed by Hydrolysis and Decarboxylation. J. Am. Chem. Soc. 1939, 61, 2890.
20. Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Trikura, T. Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubstitued 1-Alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids. J. Med. Chem. 1980, 23, 1358-1363.
21. Chu, D. T. W. and Maleczka, Jr. R. E. Synthesis of 4-Oxo-4H- quino[2,3,4-I,j][1,4]-benoxazine-5-carboxylic Acid Derivatives.
J. Heterocyclic Chem. 1987, 24, 453-456.
22. Kondo, H.; Sakamoto, F.; Kodera, Y.; Tsukamoto, G. Studies on Prodrugs. 5. Synthesis and Autimicrobital Activity of N-(Oxoalkyl)norfloxacin Derivatives. J. Med. Chem. 1986, 29, 2020-2024.
23. Ziegler, Jr. C. B.; Kuck, N. A.; Harris, S. M.; Lin, Y. Synthesis and In Vitro Biological Activity of Some 7-[Hydrazino], -[Hydrazoly] quinolone-3-carboxylic Acids. J. Heterocyclic Chem. 1988, 25, 1543-1546.
24. Collins, L. A. and Eranzblau, S. G. Microplate Alamar Blue Assay versus BACTEC 460 System for High-Throughput Screening of Compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrobial Agents and Chemotherapy. 1997, 41, 1004-1009.
25. Leysen, D. C.; Haemers, A.; Pattyn, S. R. Mycobacteria and the New Quinolones. Antimicrobial Agents and Chemotherapy. 1989, 33, 1-5.