臺灣博碩士論文加值系統

多融合雜環芳香化合物具有一個平面結構具有抗癌、抗菌、抗濾過性病毒等生物活性，因此本論文主要設計合成出一系列11-alkoxylated和11-aminated苯并呋喃[2,3-b]喹啉衍生物並探討其抗肺結核及細胞毒活性。
將化合物anthranilic acid與2-coumaranone在POCl3中加熱迴流，進行環化與氯化反應後可得已知化合物11-氯苯并呋喃[2,3-b]喹啉 (11-chlorobenzofuro[2,3-b]quinoline) (62)，在C-11位置上進行含有酚、苯胺及脂肪胺類化合物的取代反應，合成出一系列衍生物並評估其抗肺結核及細胞毒活性。
從抗結核菌活性結果，我們發現苯并呋喃[2,3-b]喹啉類衍生物在C-11導入苯胺類取代基比酚類取代基更有活性。而其中化合物11-methylamino- benzofuro[2,3-b]quinoline (75b)、11-dimethylaminobenzofuro[2,3-b]quinoline (75j)和11-methoxybenzofuro[2,3-b]quinoline (79a)都有很強的抗結核桿菌活性(MIC < 0.20 μg/mL)；另外在正常細胞VERO中，其IC50分別為5.55、 > 30.00和11.77 μg/mL，以化合物75j具有低細胞毒活性。在選擇指標(selective index; SI = IC50/MIC)方面，以化合物75j、79a和75b有明顯的選擇性，其SI值分別為大於150、58.85與27.75。

Planar polyfused heteroaromatic compounds have various biological activities such as anticancer, antibacterial and antiviral effects. A series of 11-alkoxylated and 11-aminated benzofuro[2,3-b]quinoline derivatives were designed, synthesized, and evaluated for their anti-TB and cytotoxic activities.

The known 11-chlorobenzofuro[2,3-b]quinoline (62) was synthesized in situ from anthranilic acid and 2-coumaranone in phosphorus oxychloride in 51% yield for the first time. Treatment of 62 with alcohols and amines gave 11-alkoxylated and 11-aminated benzofuro[2,3-b]quinoline derivatives respectively, which were evaluated for their anti-TB and cytotoxic activities.

Our results indicated that 11-arylaminated derivatives were more active than their respective 11-aryloxylated analogues against Mycobacterium tuberculosis. Among the tested compounds, 11-methylamino- benzofuro[2,3-b]quinoline (75b), 11-dimethylaminobenzofuro[2,3-b]quinoline (75j) and 11-methoxybenzofuro[2,3-b]quinoline (79a) exhibited significant activities against the growth of M. tuberculosis (MIC values of < 0.20 μg/mL) and low cytotoxicities against VERO cell with IC50 values of 5.55, > 30.00 and 11.77 μg/mL respectively. The selectivity index (SI = IC50/MIC) for 79a, 75b, and 75j was greater than 58.85, 27.75, and 150 respectively.

目錄
正文目錄------------------------------------------------------------------------------------- I

表目錄---------------------------------------------------------------------------------------- II

圖目錄---------------------------------------------------------------------------------------- IV


正文目錄
中文摘要------------------------------------------------------------------------------------- 1
英文摘要------------------------------------------------------------------------------------- 2
壹、緒論--------------------------------------------------------------------------------------- 3
貳、研究背景及目的------------------------------------------------------------------------ 15
參、合成方法、結果與討論-------------------------------------------------------------- 30
一、苯并呋喃[2,3-b]喹啉類衍生物之逆合成分析-1--------------------------- 30
二、苯并呋喃[2,3-b]喹啉類衍生物之逆合成分析-2--------------------------- 33
三、苯并呋喃[3,2-b]喹啉類衍生物之逆合成分析------------------------------ 37
四、實驗結果與討論----------------------------------------------------------------- 38
肆、藥理活性結果與討論------------------------------------------------------------------ 50
一、體外抗癌活性測試-------------------------------------------------------------- 50
二、抗結核桿菌測試----------------------------------------------------------------- 60
伍、結論--------------------------------------------------------------------------------------- 69
陸、合成實驗部份--------------------------------------------------------------------------- 72
一、溶劑及處理過程------------------------------------------------------------------------ 72
二、儀器及試藥------------------------------------------------------------------------------ 72
三、各化合物的製備------------------------------------------------------------------------ 78
柒、藥理活性測試方法--------------------------------------------------------------------- 141
一、體外抗癌活性測試-------------------------------------------------------------- 141
二、抗結核桿菌測試:---------------------------------------------------------------- 143
捌、參考文獻--------------------------------------------------------------------------------- 146
玖、研究成果目錄--------------------------------------------------------------------------- 158
一、投稿論文--------------------------------------------------------------------------------- 158
二、學會壁報論文發表--------------------------------------------------------------------- 158
表目錄
表一、臨床上抗結核病藥物的分類------------------------------------------------------ 7
表二、Cryptolepine衍生物體外抗細胞增生及抗菌之活性------------------------- 19
表三、Quindoline 衍生物體外抗細胞增生及抗菌之活性-------------------------- 20
表四、化合物46-50體外抗結核菌之活性--------------------------------------------- 21
表五、Camptothecin 衍生物體外肺癌細胞株之抑制活性(IC50, μM)-------------- 22
表六、茚[1,2-c]喹啉衍生物體外抗腫瘤細胞增生之抑制活性(IC50, μM)--------- 23
表七、E、Z form結構的13C-NMR光譜的化學位移值-------------------------------- 42
表八、化合物77a-d、80c-f的13C-NMR(100 MHz) 光譜的化學位移值-------- 43
表九、化合物84a-i、85a-d之1H-NMR (400 MHz)光譜的化學位移值---------- 49
表十、苯并呋喃[2,3-b]喹啉類衍生物體外抗癌細胞之活性-1---------------------- 51
表十一、苯并呋喃[2,3-b]喹啉類衍生物體外抗癌細胞之活性-2------------------- 52
表十二、苯并呋喃[2,3-b]喹啉類衍生物體外抗癌細胞之活性-3------------------- 53
表十三、苯并呋喃[2,3-b]喹啉類衍生物體外抗癌細胞之活性-4------------------- 54
表十四、苯并呋喃[2,3-b]喹啉類衍生物體外抗癌細胞之活性-5------------------- 55
表十五、苯并呋喃[2,3-b]喹啉類衍生物體外抗癌細胞之活性-6------------------- 56
表十六、苯并呋喃[2,3-b]喹啉類衍生物體外抗癌細胞之活性-7------------------- 58
表十七、苯并呋喃[2,3-b]喹啉類衍生物體外抗結核菌之活性-1------------------- 61
表十八、苯并呋喃[2,3-b]喹啉類衍生物體外抗結核菌之活性-2------------------- 62
表十九、苯并呋喃[2,3-b]喹啉類衍生物體外抗結核菌之活性-3------------------- 63
表二十、苯并呋喃[2,3-b]喹啉類衍生物體外抗結核菌之活性-4------------------- 64
表二十一、苯并呋喃[2,3-b]喹啉類衍生物體外抗結核菌之活性-5---------------- 65
表二十二、苯并呋喃[2,3-b]喹啉類衍生物體外抗結核菌之活性-6---------------- 66
表二十三、苯并呋喃[2,3-b]喹啉類衍生物體外抗結核菌及正常細胞之活性--- 67
表二十四、抗結核藥物及化合物75b、75j和79a體外抗結核菌之活性----------- 70
圖目錄
圖一、第一線抗結核藥物與第二線抗結核藥物--------------------------------------- 8
圖二、臨床前試驗開發階段之抗結核化合物------------------------------------------ 11
圖三、正在進行臨床試驗之抗結核化合物--------------------------------------------- 13
圖四、具有2-phenylnaphthalene-type類似骨架之平面化合物---------------------- 16
圖五、具有2-phenylnaphthalene類似骨架之線形與角形化合物------------------- 17
圖六、化合物36-38----------------------------------------------------------------------- 17
圖七、Fluoroquinolone類之化合物45------------------------------------------------ 20
圖八、Erythromycin和clarithromycin及其oxime之衍生物---------------------- 24
圖九、苯并呋喃[2,3-b]喹啉類衍生物------------------------------------------------- 25
圖十、Proposed mechanism for the formation of 11-chlorobenzofuro[2,3-b]-
-quinoline (62)---------------------------------------------------------------------- 31
圖十一、Proposed mechanism for the formation of 11-methylbenzofuro[2,3-b]-
-quinoline (66)------------------------------------------------------------------- 34
圖十二、Proposed mechanism for the formation of benzofuro[2,3-b]quinoline-
-11-carbaldehyde (67)---------------------------------------------------------- 34

1.WHO: World Health Organization. Global tuberculosis control 2009. epidemiology, strategy, financing; 2009.
2.Cobrett, E. L.; Watt, C. J.; Walker, N. Maher, D.; Williams, B. G.; Raviglione, M. C.; Dye C. The growing burden of tuberculosis global trends and interactions with the HIV epidemic. Arch. Intern. Med. 2003, 163, 1009-1021.
3.Small, P. M.; Fujiwara, P. I. Management of tuberculosis in the United States. N. Engl. J. Med. 2001, 345, 189-200.
4.Cummins, S. L. Tuberculosis in primitive tribes and its bearing on the tuberculosis of civilized communities. Int. J. Public Health. 1920, 1, 137-171.
5.Kaufmann, S. H. E. Robert Koch, the Nobel Prize, and the ongoing threat of tuberculosis. N. Engl. J. Med. 2005, 353, 2423-2426.
6.Young, D. B.; Perkins, M. D.; Duncan, K.; Barry, C. E. Confronting the scientific obstacles to global control of tuberculosis. J. Clin. Invest. 2008, 118, 1255-1265.
7.American thoracic society. Diagnostic standards and classification of tuberculosis in adults and children. Am. J. Respir. Crit. Care Med. 2000, 161, 1376-1395.
8.Palmer, C. E.; Jablon, S.; Edwards, P. Q. Tuberculosis morbidity of young men in relation to tuberculin sensitivity and body build. Am. Rev. Tuberc. 1957, 76, 517-539.
9.Edward, L. B.; Acquaviva, F. A.; Palmer, C. E. Height, weight, tuberculosis infection, and tuberculosis disease. Arch. Environ. Health. 1971, 22, 106-112.
10.McNeil, M. R.; Brennan, P. J. Structure, function and biogenesis of the cell envelope of mycobacteria in relation to bacterial physiology, pathogenesis and drug resistance; some thoughts and possibilities arising from recent structural information. Res. Microbiol. 1991, 142, 451-463.
11.Ebert, R. H. Treatment of tuberculosis. Dis. Mon. 1956, 2, 1-39.
12.Tam, C. M. Development of new antituberculosis drugs: its relevance worldwide and in the Asia-Pacific region. Respirology. 2008, 13, S125-S131.
13.Chen, P. L.; Lee, H. C.; Shan, Y. S.; Ko, Lee, N. Y.; Chang, C. M.; Wu, C. J.; Lee, C. C.; Ko, W. C. Respiratory failure and acalculous cholecystitis in a patient with AIDS and disseminated tuberculosis: masking effect of fluoroquinolone monotherapy and immune restoration syndrome. Int. J. Infect. Dis. 2009, 13, e165-e168.
14.Laurenzi, M.; Ginsberg, A.; Spigelman, M. Challenges associated with current and future TB treatment. Infect. Disord. Drug Targets. 2007, 7, 105-119.
15.Hinshaw, H. C.; Pyle, M. M.; Feldman, W. H. Streptomycin in tuberculosis. Am. J. Med. 1947, 2, 429-435.
16.Gyselen, A.; Verbist, L.; Prignot, J.; Cosemans, J. Capreomycin in the re-treatment of patients with pulmonary tuberculosis. Tubercle. 1965, 46, 243-249.
17.McClatchy, J. K.; Kanes, W.; Davidson, P. T.; Moulding, T. S. Cross-resistance in M. tuberculosis to kanamycin, capreomycin and viomycin. Tubercle. 1977, 58, 29-34.

18.Hanessian, S.; Kornienko, A.; Swayze, E. E. Probing the functional requirements of the L-haba side-chain of amikacin-synthesis, 16S A-site rRNA binding, and antibacterial activity. Tetrahedron. 2003, 59, 995-1007.
19.Sanders W. E.; Hartwig, J. C. Schnieder, N.; Cacciatore, R.; Valdez, H. Activity of amikacin against mycobacteria in vitro and in murine tuberculosis. Tubercle. 1982, 63, 201-208.
20.Dean, G. S.; Rhodes, S. G.; Coad, M.; Whelan, A. O.; Wheeler, P. Villareal-Ramos, B.; Mead, E.; Johnson, L.; Clifford, D. J.; Hewinson, R. G.; Vordermeier, H. M. Isoniazid treatment of Mycobacterium bovis in cattle as a model for human tuberculosis. Tuberculosis. 2008, 88, 586-594.
21.Kikugawa, K.; Hayatsu, H.; Ukita, T. On the reaction of nucleic acids with isoniazid. Chem. Biol. Interact. 1970, 1, 247-256.
22.Sarasin, F. P.; Perrier, A.; Rochat. T. Isoniazid preventive therapy for pulmonary tuberculosis sequelae: Which patients up to which age? Tuber. Lung Dis. 1995, 76, 394-400.
23.Kahana, L. M. Ethambutol in tuberculosis . Biomed. Pharmacother. 1990, 44, 85-89.
24.Schiavano, G. F.; Celeste, A. G.; Salvaggio, L.; Sisti, M.; Brandi, G.. Efficacy of macrolides used in combination with ethambutol, with or without other drugs, against Mycobacterium avium within human macrophages. Int. J. Antimicrob. Agents. 2001, 18, 525-530.
25.Lefford, M. J.; Mitchison. D. A. Comparison of methods for testing the sensitivity of mycobacterium tuberculosis to ethionamide. Tubercle. 1966, 47, 250-262.
26.Viswanathan, R.; Gupta, N. P.; Rao, P. U.; Roy, D.C. A trial on cycloserine in salvage cases of pulmonary tuberculosis. Tubercle. 1963, 44, 351-354.
27.Goff, D. C.; Corinne, C.; Gottlieb, J. D.; Evins, A. E.; Walsh, J.; Raeke, L.; Otto, M. W.; Schoenfeld, D.; Green, M. F. Once-weekly d-cycloserine effects on negative symptoms and cognition in schizophrenia: An exploratory study. Schizophr. Res. 2008, 106, 320-327.
28.Van Deun, A.; Barrera, L.; Bastian, I.; Fattorini, L.; Hoffmann, H.; Kam, K. M.; Rigouts, L.; Rüsch-Gerdes, S.; Wright, A. Mycobacterium tuberculosis strains with highly discordant rifampin susceptibility test results. J Clin Microbiol. 2009, 47, 3501-3506.
29.Gasymov, O. K.; Abduragimov, A. R.; Gasimov, E. O.; Yusifov, T. N.; Dooley, A. N.; Glasgow, B. J. Tear lipocalin: potential for selective delivery of rifampin. Biochim. Biophys. Acta. 2004, 1688, 102-111.
30.Sato, K.; Tomioka, H.; Akaki, T.; Kawahara, S. Antimicrobial activities of levofloxacin, clarithromycin, and KRM-1648 against Mycobacterium tuberculosis and Mycobacterium avium complex replicating within Mono Mac 6 human macrophage and A-549 type II alveolar cell lines. Int. J. Antimicrob. Agents. 2000, 16, 25-29.
31.Wimer, S. M.; Schoonover, L.; Garrison, M. W. Levofloxacin: a therapeutic review. Clin. Ther. 1998, 20, 1049-1070.
32.Trivedi, S. S.; Desai, S. G. Pyrazinamidase activity of Mycobacterium tuberculosis—A test of sensitivity to pyrazinamide. Tubercle. 1987, 68, 221-224.
33.Tripathy, S. P.; Mitchison, D. A.; Nair, N. G. K.; Radhakrishna, S.; Subbammal S. A comparison of various measures of sensitivity of M. tuberculosis to pyrazinamide. Tubercle. 1970, 51, 375-388.
34.Dempsey, T. G.; Logg, M. H. para-Aminosalicylic acid in tuberculosis. J. Lancet. 1948, 251, 119.
35.Wadee, A. A. A 25-kDa fraction from Mycobacteria tuberculosis that inhibits leukocyte bactericidal activity: Reversal by gamma interferon and clofazimine. Res. Microbiol. 1990, 141, 249-252.
36.Das, R. K.; Roy, B. Evaluation of genotoxicity of clofazimine, an antileprosy drug, in mice in vivo. I. Chromosome analysis in bone marrow and spermatocytes. Mutat. Res. 1990, 241, 161-168.
37.Arbiser, J. L.; Moschella, S. L. Clofazimine: A review of its medical uses and mechanisms of action. J. Am. Acad. Dermatol. 1995, 32, 241-247.
38.Koga, T.; Fukuoka, T.; Doi, N.; Harasaki, T.; Inoue, H.; Hotoda, H.; Kakuta, M.; Muramatsu, Y.; Yamamura, N.; Hoshi, M.; Hirota, T. Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium intracellulare in vitro and in vivo. J. Antimicrob. Chemother. 2004, 54, 755-760.
39.Sood, R.; Bhadauriya, T.; Rao, M.; Gautam, R.; Malhotra, S.; Barman, T. K.; Upadhyay, D. J.; Rattan, A. Antimycobacterial activities of oxazolidinones: a review. Infect. Disord. Drug Targets. 2006, 6, 343-354.
40.Parrish, N. M.; Houston, T.; Jones, P. B.; Townsend, C.; Dick, J. D. In vitro activity of a novel antimycobacterial compound, N-octanesulfonylacetamide, and its effects on lipid and mycolic acid synthesis. Antimicrob. Agents Chemother. 2001, 45, 1143-1150.
41.Protopopova, M.; Hanrahan, C.; Nikonenko, B.; Samala, R.; Chen, P.; Gearhart, J.; Einck, L.; Nacy, C. A. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J. Antimicrob. Chemother. 2005, 56, 968-974.
42.Arora, S. K.; Sinha, N.; Jain, S.; Upadhayaya, R. S.; Jana, G.; Ajay, S.; Sinha, R. K. Preparation of pyrrole derivatives as antimycobacterial compounds. Patent No. WO 2004026828, 2004.
43.Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D. N.; Kreiswirth, B. N.; Barry, C. E.; Baker, W. R. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature. 2000, 405, 962-966.
44.Matsumoto, M; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, Y. OPC-67683, a nitro-dihydroimidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med. 2006, 3, 2131-2144.
45.Andries, K.; Verhasselt, P.; Guillemont, J.; Göhlmann, H. W. H.; Neefs, J. M.; Winkler, H.; Van Gestel, J. ; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. A. Diarylquinoline drug active on the ATP synthase of mycobacterium tuberculosis. Science. 2005, 307, 223-227.
46.Cortázar, T. M.; Coombs, G. H.; Walker, J. Leishmania panamensis: Comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine. Exp. Parasitol. 2007, 116, 475-482.
47.Nunn, P.; Reid, A.; De Cock, K. M. Tuberculosis and HIV infection: the global setting. J. Infect. Dis. 2007, 196, S5-S14.
48.Chen, C. C.; Liu, D. F.; Chou, T. C. Design of antineoplastic agents on the basis of the “2-phenylnaphthalene-tpe” structural pattern. I. synthesis of substitutrd 3-phenylquinazolones, benzoxazolo[2,3-b]-quinazolones and benzothiazolo[2,3-b]quinazolones. Heterocycles. 1993, 35, 775-789.
49.Harding, M. M.; Long, G. V.; Brown, C. L. Solution conformation of the antitumor drug streptonigrin. J. Med. Chem. 1993, 36, 3056-3060.
50.Czoch, W. P.; Pognan, F.; Kaczmarek, L.; Boratynski, J. Synthesis and structure-activity relationship of methyl-substituted indolo[2,3-b]quinolines: novel cytotoxic, DNA topoisomerase II inhibitors. J. Med. Chem. 1994, 37, 3503-3510.
51.Cheng, C. C.; Dong, Q.; Liu, D. F.; Luo, Y. L.; Liu, L. F.; Chen, A. Y.; Yu, C.; Savaraj, N.; Chou, T. C. Design of antineoplastic agents on the basis of the “2-phenylnaphthalene-type” structural pattern. 2. synthesis and biological activity studies of benzo[b]naphtha-[2,3-d]furan-6,11-dione derivatives. J. Med. Chem. 1993, 36, 4108-4112.
52.Cirrincione, G.; Almerico, A. M.; Barraja, P.; Diana, P.; Lauria, A.; Passannanti, A.; Musiu, C.; Pani, A.; Murtas, P.; Minnei, C.; Marongiu, M. E.; La Colla, P. Derivatives of the new ring system indolo[1,2-c]benzo[1,2,3]-triazine with potent antitumor and antimicrobial activity. J. Med. Chem. 1999, 42, 2561-2568.
53.He, L.; Chang, H. X.; Chou, T. C.; Savaraj, N.; Cheng, C. C. Design of antineoplastic agents based on the “2-phenylnaphthalene-type” structural pattern-synthesis and biological activity studies of 11H-indolo[3,2-c]-
-quinoline derivatives. Eur. J. Med. Chem. 2003, 38, 101-107.
54.Zhou, J. L.; Lu, Y. J.; Ou, T. M.; Zhou, J. M.; Huang, Z. S.; Zhu, X. F.; Du, C. J.; Bu, X. Z.; Ma, L.; Gu, L. Q.; Li, Y. M.; Chan, A. S. Synthesis and evaluation of quindoline derivatives as G-quadruplex inducing and stabilizing ligands and potential inhibitors of telomerase. J. Med. Chem. 2005, 48, 7315-7321.
55.Chen, Y. L.; Huang, H. Y.; Lu, C. M.; Li, K. C.; Tzeng, C. C. Synthesis and anticancer evaluation of certain indolo[2,3-b]quinoline derivatives. Bioorg. Med. Chem. 2004, 12, 6539-6546.
56.Chen, Y. L.; Chung, C. H.; Chen, I. L.; Chen, P. H.; Jeng, H. Y. Synthesis and cytotoxic activity evaluation of indolo-, pyrrolo-, and benzofuro-quinolin-2(1H)-ones and 6-anilinoindoloquinoline derivatives. Bioorg. Med. Chem. 2002, 10, 2705-2712.
57.Arzel, E.; Rocca, P.; Grellier, P.; Labaeïd, M.; Frappier, F.; Guéritte, F.; Gaspard, C.; Marsais, F.; Godard, A.; Quéguiner, G. New synthesis of benzo-δ-carbolines, cryptolepines, and their salts: in vitro cytotoxic, antiplasmodial, and antitrypanosomal activities of δ-carbolines, benzo-δ-carbolines, cryptolepines, and cryptolepines. J. Med. Chem. 2001, 44, 949-960.
58.Alajarin, M.; Molina, P.; Vidal, A. Formal total synthesis of the alkaloid cryptotackieine (neocryptolepine). J. Nat. Prod. 1997, 60, 747-748.
59.Cimanga, K.; De Bruyne, T.; Pieters, L.; Vlietinck, A. J.; Turger, C. A. In vitro and in vivo antiplasmodial activity of cryptolepine and related alkaloids from Cryptolepis sanguinolenta. J. Nat. Prod. 1997, 60, 688-691.
60.Luo, J.; Fort, D. M.; Carlson, T. J.; Noamesi, B. K.; nii-Amon-Kotei, D.; King, S. R.; Tsai, J.; Quan, J.; Hobensack, C.; Lapresca, P.; Waldeck, N.; Mendez, C. D.; Joland, S. D.; Bierer, D. E.; Reaven, G. M. Cryptolepis sanguinolenta: an ethnobotanical approach to drug discovery and the isolation of a potentially useful new antihyperglycaemic agent. Diabet Med. 1998, 15, 367-374.


61.Paulo, A.; Gomes, E. T.; Steele, J.; Warhurst, D. C.; Houghton, P. J. Antiplasmodial activity of cryptolepis sanguinolenta alkaloids from leaves and roots. Planta Med. 2000, 66, 30-34.
62.Wright, C. W.; Addae-Kyereme, J.; Breen, A. G.; Brown, J. E.; Cox, M. F.; Croft, S. L.; Gökçek, Y.; Kendrick, H.; Phillips, R. M.; Pollet, P. L. Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents. J. Med. Chem. 2001, 44, 3187-3194.
63.Gibbons, S.; Fallah, F.; Wright, C. W. Cryptolepine hydrochloride: a potent antimycobacterial alkaloid derived from Cryptolepis sanguinolenta. Phytother. Res. 2003, 17 , 434-436.
64.Lavrado, J.; Paulo, A.; Gut, J.; Rosenthal, P. J.; Moreira, R. Cryptolepine analogues containing basic aminoalkyl side-chains at C-11: synthesis, antiplasmodial activity, and cytotoxicity. Bioorg. Med. Chem. Lett. 2008, 18, 1378-1381.
65.Sheu, J. Y.; Chen, Y. L.; Fang, K. C.; Wang, T. C.; Peng, C. F.; Tzeng, C. C. Synthesis and antibacterial activity of 1-(substituted-benzyl)-6-fluoro-
-1,4-dihydro-4-oxoquinoline-3-carboxylic acids and their 6,8-difluoro
analogs. J. Heterocyclic Chem. 1998, 35, 955-964.
66.Sheu, J. Y.; Chen, Y. L.; Tzeng, C. C.; Hsu, S. L.; Fang, K. C.; Wang, T. C. Synthesis, and antimycobacterial and cytotoxic evaluation of certain fluoroquinolone derivatives. Helv. Chim. Acta. 2003, 86, 2481-2489.
67.Zhao, Y. L.; Chen, Y. L.; Sheu, J. Y.; Chen, I. L.; Wang, T. C.; Tzeng, C. C. Synthesis and anti-inflammatory evaluation of 9-phenoxyacridine and 4-phenoxyfuro[2,3-b]quinoline derivatives. part 2. Bioorg. Med. Chem. 2005, 13, 3921-3927.

68.Chen, Y. L.; Huang, H. Y.; Chen, Y. W.; Huang, Z. Y.; Tzeng, C. C.; Liu, C. L.; Yao, C. W. Synthesis and antimycobacterial evaluation of pyranone and pyridinone metal-chelator bearing fluoroquinolones. Chin. Pharm. J. 2005, 57, 57-70.
69.Copp, B. R.; Christiansen, H. C.; Lindsay, B. S.; G Franzblau, S. Identification of heteroarylenamines as a new class of antituberculosis lead molecules. Bioorg. Med. Chem. Lett. 2005, 15, 4097-4099.
70.Dallavalle, S.; Ferrari, A.; Biasotti, B.; Merlini, L.; Penco, S.; Gallo, G.; Marzi, M.; Tinti, M. O.; Martinelli, R.; Pisano, C.; Carminati, P.; Carenini, N.; Beretta, G.; Perego, P.; De Cesare, M.; Pratesi, G.; Zunino, F. Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity. J. Med. Chem. 2001, 44, 3264-3274.
71.Tseng, C. H.; Chen, Y. L.; Lu, P. J.; Yang, C. N.; Tzeng, C. C. Synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives. Bioorg. Med. Chem. 2008, 16, 3153-3162.
72.Zhu, Z. J.; Krasnykh, O.; Pan, D.; Petukhova, V.; Yu, G.; Liu, Y.; Liu, H.; Hong, S.; Wang, Y.; Wan, B.; Liang, W.; Franzblau, S. G. Structure-activity relationships of macrolides against Mycobacterium tuberculosis. Tuberculosis. 2008, 88, S49-S63.
73.Grosset, J. H. Newer drugs in leprosy. Int. J. Lepr. Other Mycobact. Dis. 2001, 69, S14–S18.
74.Kinoshita, Y.; Ajisawa, Y.; Ikeguchi, S.; Ujiie, S.; Tsutsumi, N. Remedy for osteoporosis. Patent No. JP 63297324. 1988.
75.Xiao, Z.; Waters, N. C.; Woodard, C. L.; Li, Z.; Li, P. K. Design and synthesis of Pfmrk inhibitors as potential antimalarial agents. Bioorg. Med. Chem. Lett. 2001, 11, 2875-2878.
76.Hazeldine, S. T.; Polin, L.; Kushner, J.; White, K,; Corbett, T. H.; Horwitz, J. P. Synthesis and biological evaluation of conformationally constrained analogs of the antitumor agents XK469 and SH80. Part 5. Bioorg. Med. Chem. 2006, 14, 2462-2467.
77.Kawase, Y.; Yamaguchi, S.; Maeda, O.; Hayashi, A.; Hayashi, I.; Tabata, K.; Kondo, M. The synthesis of benzofuroqinolines. I. some benzofuro[2,3-b]quinoline and benzofuro[3,2-c]quinoline derivatives. J. Heterocyclic Chem. 1979, 16, 487-491.
78.Kawase, Y.; Yamaguchi, S.; Morita, M.; Uesugi, T. The synthesis of benzofuroquinolines. II. two benzofuroquinolinones and some benzofuroquinoline derivatives. Bull. Chem. Soc. Jpn. 1980, 53, 1057-1060.
79.Rampa, A.; Bisi, A.; Belluti, F.; Gobbi, S.; Valenti, P.; Andrisano, V.; Cavrini, V.; Cavalli, A.; Recanatini, M. Acetylcholinesterase inhibitors for potential use in Alzheimer''s disease: molecular modeling, synthesis and kinetic evaluation of 11H-indeno-[1,2-b]-quinolin-10-ylamine derivatives. Bioorg. Med. Chem. 2000, 8, 497-506.
80.Cerri, A.; Almirante, N.; Barassi, P.; Benicchio, A.; Fedrizzi, G.; Ferrari, P.; Micheletti, R.; Quadri, L.; Ragg, E.; Rossi, R.; Santagostino, M.; Schiavone, A.; Serra, F.; Zappavigna, M. P.; Melloni, P. 17β-O-aminoalkyloximes of 5β-androstane-3β,14β-diol with digitalis-like activity: synthesis, cardiotonic activity, structure-activity relationships, and molecular modeling of the Na+,K+-ATPase receptor. J. Med. Chem. 2000, 43, 2332-2349.
81.Silverstein, R. M.; Webster, F. X.; Kiemle, D. J., Spectrometric indentification of organic compounds. 6th ed. New York: Wiley, p227-228.
82.Pejkovic´-Tadic´, I.; Hanisavljevic´-Jakovljevic´, M.; Nesic´, S.; Pascual, C.; Simon, W. Protonenresonanzspektren von oximenaromatischer aldehyde. Helv. Chim. Acta. 1965, 48, 1157-1160.
83.National Institute of Allergy and Infectious Diseases, Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF), http://www.taacf.org.
84.Orme, I. Search for new drugs for treatment tuberculosis. Antimicrob. Agents Chemother. 2001, 45, 1943-1946.
85.Yamaguchi, S.; Tsuzuki, K.; Sannomiya, Y.; Oh-hira, Y.; Kawase, Y. The synthesis of benzofuroquinolines. V. Some benzofuro[3,2-b]quinoline derivatives. J. Heterocyclic. Chem. 1989, 26, 285-287.
86.Goodwin, C. J.; Holt, S. J.; Downes, S.; Marshall, N. J. Microculture tetrazolium assays: a comparison between two new tetrazolium salts, XTT and MTS. J. Immunol. Methods. 1995, 179, 95-103.
87.Collins, L. A.; Franzblau, S. G., Microplate Alamar Blue Assay versus BACTEC 460 System for High-Throughput Screening of Compounds against Mycobacterium tuberculosus and Mycobacterium avium, Antimicrobial Agents and Chemotherapy. 1997, 41, 1004-1009.