嚴重呼吸道症候群 (Severe Acute Respiratory Syndrome，SARS)是由感染性SARS冠狀病毒所引起的事件，在瞭解SARS冠狀病毒蛋白酶在生物體內的作用機制，期待能發展出SARS冠狀病毒蛋白酶的抑制劑。本論文使用Passerini反應為中心反應，快速地合成五個不同的SARS-CoV Mpro抑制劑核心結構，接著合成衍生出800個分子，利用這樣的分子庫，進行SARS抑制劑活性的篩選，試圖找出效果佳的抑制劑。在本合成的5個系列中，發現數個抑制活性IC50小於10 μΜ的分子，其中在系列4中，化合物35-B8及35-B5的IC50值分別為0.9、1.4，為分子庫中最佳的兩個可能抑制分子，希望利用這兩個分子作為核心結構，在C端衍生出不同的分子進行篩選，發展出更有效的抑制劑。

SARS (Severe Acute Respiratory Syndrome) is an infectious disease caused by a novel human coronavirus. SARS-CoV Mpro is a crucial protease in the virus’s replication cycle. By a understanding of SARS-CoV Mpro catalysis and a full substrate specificity spectrum for SARS-CoV Mpro, we hope to design and synthesize inhibitors against SARS. We applied the Passerini reaction to form five α-hydroxyl amide core structures and followed by formation of another amide bond to generate five α-hydroxyl amide libraries. Eight hundred compounds were synthesized and their activities against SARS-CoV Mpro were screened. Few compounds of the library members show their IC50 less than 10 μΜ. In the fourth series, we’ve found that compounds 35-B8 and 35-B5 showed strong inhibition (IC50 = 0.9、1.4μΜ) for SARS main protease. Then use compounds 35-B8 and 35-B5 as cores, its C-terminal can be further modified by amide or ester bond formation to yield new libraries. By means of this approach, the best SARS-CoV Mpro inhibitors were screened and obtained.

﹝ ﹞http://www.who.int/en/
﹝ ﹞(a) Drosten, C.; Gunther, S.; Preiser, W.; van der, W. S.; Brodt, H. R.; Becker, S.; Rabenau, H.; Panning, M.; Kolesnikova, L.; Fouchier, R. A.; Berger, A.; Burguiere, A. M.; Cinatl, J.; Eickmann, M.; Escriou, N.; Grywna, K.; Kramme, S.; Manuguerra, J. C.; Muller, S.; Rickerts, V.; Sturmer, M.; Vieth, S.; Klenk, H. D.; Osterhaus, A. D.; Schmitz, H.; Doerr, H. W. N. Engl. J. Med. 2003, 348, 1967. (b) Ksiazek, T. G.; Erdman, D.; Goldsmith, C. S.; Zaki, S. R.; Peret, T.; Emery, S.; Tong, S.; Urbani, C.; Comer, J. A.; Lim, W.; Rollin, P. E.; Dowell, S. F.; Ling, A. E.; Humphrey, C. D.; Shieh, W. J.; Guarner, J.; Paddock, C. D.; Rota, P.; Fields, B.; DeRisi, J.; Yang, J. Y.; Cox, N.; Hughes, J. M.; LeDuc, J. W.; Bellini, W. J.; Anderson, L. J. N. Engl. J. Med. 2003, 348, 1953.
﹝ ﹞(a) Rota, P. A.; Oberste, M. S.; Monroe, S. S.; Nix, W. A.; Campagnoli, R.; Icenogle, J. P.; Penaranda, S.; Bankamp, B.; Maher, K.; Chen, M. H.; Tong, S.; Tamin, A.; Lowe, L.; Frace, M.; DeRisi, J. L.; Chen, Q.; Wang, D.; Erdman, D. D.; Peret, T. C.; Burns, C., Ksiazek, T. G.; Rollin, P. E.; Sanchez, A.; Liffick, S.; Holloway, B.; Limor, J.; McCaustland, K.; Olsen-Rasmussen, M.; Fouchier, R.; Gunther, S.; Osterhaus, A. D.; Drosten, C.; Pallansch, M. A.; Anderson, L. J.; Bellini, W. J. Science 2003, 300, 1394. (b) Marra, M. A.; Jones, S. J.; Astell, C. R.; Holt, R. A.; Brooks-Wilson, A.; Butterfield, Y. S.; Khattra, J.; Asano, J. K.; Barber, S. A.; Chan, S. Y.; Cloutier, A.; Coughlin, S. M.; Freeman, D.; Girn, N.; Griffith, O. L.; Leach, S. R.; Mayo, M.; McDonald, H.; Montgomery, S. B.; Pandoh, P. K.; Petrescu, A. S.; Robertson, A. G.; Schein, J. E.; Siddiqui, A.; Smailus, D. E.; Stott, J. M.; Yang, G. S.; Plummer, F.; Andonov, A.; Artsob, H.; Bastien, N.; Bernard, K.; Booth, T. F.; Bowness, D.; Czub, M., Drebot M.; Fernando, L.; Flick, R.; Garbutt, M.; Gray, M.; Grolla, A.; Jones, S.; Feldmann, H.; Meyers, A.; Kabani, A.; Li, Y.; Normand, S.; Stroher, U.; Tipples, G. A.; Tyler, S.; Vogrig R.; Ward, D.; Watson, B.; Brunham, R. C.; Krajden, M.; Petric, M.; Skowronski, D. M.; Upton, C.; Roper, R. L. Science 2003, 300, 1399.
﹝4﹞Anand, K.; Ziebuhr, J.; Wadhwani, P.; Mesters, J. R.; Hilgenfeld, R. Science 2003, 300, 1763.
﹝ ﹞Stadler, K.; Masignani, V.; Eickmann, M.; Becker, S.; Abrignani, S.; Klenk, H.-D.; Rappuoli, R. Nature Reviews Microbiology 2003, 1, 209.
﹝ ﹞Holmes, K. V.; Enjuanes, L. Science 2003, 300, 1377
﹝ ﹞Flint, S. J.; Enquist, L. W.; Racaniello, V. R.; Skalka, A. M. Principles of Virology 2nd Ed. AMERICAN SOCIETY FOR MICROBIOLOGY, Washington, 2004, pp. 835-837
﹝ ﹞Yang, H.; Yang, M.; Ding, Y.; Liu, Y.; Lou, Z.; Zhou, Z.; Sun, L.; Mo, L.; Ye, S.; Pang, H.; Gao, G. F.; Anand K.; Bartlam, M.; Hilgenfeld, R.; Rao, Z. Proc. Natl. Acad. Sci. 2003, 100, 13190.
﹝ ﹞Bacha, U.; Barrila, J.; Velazquez-Campoy, A.; Leavitt, S. A.; Freire, E. Biochemistry 2004, 43, 4906.
﹝ ﹞(a) Matthews, D. A.; Smith, W. W.; Ferre, R. A.; Condon, B.; Budahazi, G.; Sisson, W.; Villafranca, J. E.; Janson, C. A.; McElroy, H. E.; Gribskov, C. L.; Worland, S. Cell 1994, 77, 761. (b) Seipelt, J.; Guarne, A.; Bergmann, E.; James, M.; Sommergruber, W.; Fita, I.; Skern, T. Virus Res. 1999, 62, 159.
﹝ ﹞Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359.
﹝ ﹞Hegyi, A.; Ziebuhr, J. J. Gen. Virol. 2002, 83, 595.
﹝ ﹞Fan, K.; Wei, P.; Feng, Q.; Chen, S.; Huang, C.; Ma, L.; Lai, B.; Pei, J.; Liu, Y.; Chen, J.; Lai, L. J. Biol. Chem. 2004, 279 , 1637.
﹝ ﹞Nelson, D. L.;Cox, M. M. Lehninger Principles of Biochemistry 3rd Ed. WORTH
﹝ ﹞Fersht, A. R.; Kirby A. J. Chem. Br. 1980, 16, 136.
﹝ ﹞Li, J. J. Name Reactions: A Collection of Detailed Reaction Mechanisms Spinger-Verlag, Berlin Heidelberg, 2002, pp. 269
﹝ ﹞Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
﹝ ﹞Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
﹝ ﹞Ugi, I.; Werner B.; Dömling, A. Molecules 2003, 8, 53.
﹝ ﹞Hoppe, D. Angew. Chem. Int. Ed. 1974, 13, 789.
﹝ ﹞Hoppe, D.; Schöllkopf, U. Liebigs Ann. Chem. 1972, 763, 1.
﹝ ﹞Kobayashi, Y.; Fukuyama, T J. Heterocycl. Chem. 1998, 35, 1043.
﹝ ﹞Leung, D.; Abbenante, G.; Fairlie D. P. J. Med. Chem. 2000, 43, 3.