請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91613完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 梁博煌 | zh_TW |
| dc.contributor.advisor | Po-Huang Liang | en |
| dc.contributor.author | 許寧 | zh_TW |
| dc.contributor.author | Srinivasa Rao Palla | en |
| dc.date.accessioned | 2024-02-20T16:12:28Z | - |
| dc.date.available | 2024-02-21 | - |
| dc.date.copyright | 2024-02-20 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-01-31 | - |
| dc.identifier.citation | References
1. Alaaeldin, R., Mustafa, M., Abuo-Rahma, G.E.-D.A., Fathy, M., 2022. In vitro inhibition and molecular docking of a new ciprofloxacin-chalcone against SARS-CoV-2 main protease. Fundam Clin. Pharmacol. 36, 160–170. doi: 10.1111/fcp.12708. 2. Bestle, D., Heindl, M.R., Limburg, H., Van Lam van, T., Pilgram, O., Moulton, H., Stein, D.A., Hardes, K., Eickmann, M., Dolnik, O., Rohde, C., Klenk, H.D., Garten, W., Steinmetzer, T., Böttcher-Friebertshäuser, E., 2020. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Sci. Alliance 3, e202000786. doi: 10.26508/lsa.202000786. 3. Bojadzic, D., Alcazar, O., Chen, J., Chuang, S.T., Condor Capcha, J.M., Shehadeh, L.A., Buchwald, P., 2021. Small-molecule inhibitors of the coronavirus Spike: ACE2 protein-protein interaction as blockers of viral attachment and entry for SARS-CoV-2. ACS Infect. Dis. 7, 1519–1534. doi: 10.1021/acsinfecdis.1c00070. 4. Cao, Y., Yisimayi, A., Jian, F., Song, W., Xiao, T., Wang, L., Du, S., Wang, J., Li, Q., Chen, X., Yu, Y., Wang, P., Zhang, Z., Liu, P., An, R., Hao, X., Wang, Y., Wang, J., Feng, R., Sun, H., Zhao, L., Zhang, W., Zhao, D., Zheng, J., Yu, L,, Li, C., Zhang, N., Wang, R., Niu, X., Yang, S., Song, X., Chai, Y., Hu, Y., Shi, Y., Zheng, L., Li, Z., Gu, Q., Shao, F., Huang, W., Jin, R., Shen, Z., Wang, Y., Wang, X., Xiao, J., Xie, X.S., 2022. BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection. Nature. 608, 593–602. doi: 10.1038/s41586-022-04980-y. 5. Cheng, Y.W., Chao, T.L., Li, C.L., Chiu, M.F., Kao, H.C., Wang, S.H., Pang, Y.H., Lin, C.H., Tsai, Y.M., Lee, W.H., Tao, M.H., Ho, T.C., Wu, P.Y., Jang, L.T., Chen, P.J., Chang, S.Y., Yeh, S.H. 2020. Furin inhibitors block SARS-CoV-2 Spike protein cleavage to suppress virus production and cytopathic effects. Cell Rep. 33, 108254. doi: 10.1016/j.celrep.2020.108254. 6. Dai, W., Zhang, B., Jiang, X.M., Su, H., Li, J., Zhao, Y., Xie, X., Jin, Z., Peng, J., Liu, F., Li, C., Li, Y., Bai, F., Wang, H., Cheng, X., Cen, X., Hu, S., Yang, X., Wang, J., Liu, X., Xiao, G., Jiang, H., Rao, Z., Zhang, L.K., Xu, Y., Yang, H., Liu, H., 2020. Structure-based design of antiviral drug candidates targeting SARS-CoV-2 main protease. Science 368, 1331–1335. doi: 10.1126/science.abb4489. 7. de Wit, E., van Doremalen, N., Falzarano, D., Munster, V.J., 2016. SARS and MERS: recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 14, 523–34. doi: 10.1038/nrmicro.2016.81. 8. Duran, N., Polat, M.F., Aktas, D.A., Alagoz, M.A., Ay, E., Cimen, F., Tek, E., Anil, B., Burmaoglu, S., Algul, O., 2021. New chalcone derivatives as effective against SARS-CoV-2 Agent. Int. J. Clin. Pract. 75, e14846. doi: 10.1111/ijcp.14846. 9. Essalmani, R., Jain, J., Susan-Resiga, D., Andréo, U., Evagelidis, A., Derbali, R.M., Huynh, D.N., Dallaire, F., Laporte, M., Delpal, A., Sutto-Ortiz, P., Coutard, B., Mapa, C., Wilcoxen, K., Decroly, E., Nq Pham, T., Cohen, É.A., Seidah, N.G. 2022. Distinctive roles of Furin and TMPRSS2 in SARS-CoV-2 infectivity. J. Virol. 96, e0012822. doi: 10.1128/jvi.00128-22. 10. Fraser, B.J., Beldar, S., Seitova, A., Hutchinson, A., Mannar, D., Li, Y., Kwon, D., Tan, R., Wilson, R.P., Leopold, K., Subramaniam, S., Halabelian, L., Arrowsmith, C.H., Bénard, F., 2022. Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation. Nat. Chem. Biol. 18, 963–971. doi: 10.1038/s41589-022-01059-7. 11. Ghosh, A.K., Raghavaiah, J., Shahabi, D., Yadav, M., Anson, B.J., Lendy, E.K., Hattori, S.I., Higashi-Kuwata, N., Mitsuya, H., Mesecar, A.D., 2021. Indole chloropyridinyl ester-derived SARS-CoV-2 3CLpro Inhibitors: Enzyme inhibition, antiviral Efficacy, structure-activity relationship, and X-ray structural studies. J. Med. Chem. 64, 14702–14714. doi: 10.1021/acs.jmedchem.1c01214. 12. Gobinath, P., Packialakshmi, P., Ali, D., Alarifi, S., Alotaibi, A., Idhayadhulla, A., Surendrakumar, R., 2021. Synthesis and cytotoxic activity of novel indole derivatives and their in Silico screening on Spike glycoprotein of SARS-CoV-2. Front. Mol. Biosci. 8, 637989. doi: 10.3389/fmolb.2021.637989. 13. Gordon, C.J., Tchesnokov, E.P., Woolner, E., Perry, J.K., Feng, J.Y., Porter, D.P., Götte, M., 2020. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from Severe Acute Respiratory Syndrome Coronavirus 2 with high potency. J. Biol. Chem. 295, 6785–6797. doi: 10.1074/jbc.RA120.013679. 14. Grein, J., Ohmagari, N., Shin, D., Diaz, G., Asperges, E., Castagna, A., Feldt, T., Green, G., Green, M.L., Lescure, F.X., Nicastri, E., Oda, R., Yo, K., Quiros-Roldan, E., Studemeister, A., Redinski, J., Ahmed, S., Bernett, J., Chelliah, D., Chen, D., Chihara, S., Cohen, S.H., Cunningham, J., D''Arminio Monforte, A., Ismail, S., Kato, H., Lapadula, G., L''Her, E., Maeno, T., Majumder, S., Massari, M., Mora-Rillo, M., Mutoh, Y., Nguyen, D., Verweij, E., Zoufaly, A., Osinusi, A.O., DeZure, A., Zhao, Y., Zhong, L., Chokkalingam, A., Elboudwarej, E., Telep, L., Timbs, L., Henne, I., Sellers, S., Cao, H., Tan, S.K., Winterbourne, L., Desai, P., Mera, R., Gaggar, A., Myers, R.P., Brainard, D.M., Childs, R., Flanigan, T., 2020. Compassionate use of Remdesivir for patients with severe Covid-19. N. Engl. J. Med. 382, 2327–2336. doi: 10.1056/NEJMoa2007016. 15. Hattori, S.I., Higashi-Kuwata, N., Hayashi, H., Allu, S.R., Raghavaiah, J., Bulut, H., Das, D., Anson, B.J., Lendy, E.K., Takamatsu, Y., Takamune, N., Kishimoto, N., Murayama, K., Hasegawa, K., Li, M., Davis, D.A., Kodama, E.N., Yarchoan, R., Wlodawer, A., Misumi, S., Mesecar, A.D., Ghosh, A.K., Mitsuya, H., 2021. A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication. Nat. Commun. 12, 668. doi: 10.1038/s41467-021-20900-6 16. Hoffman, R.L., Kania, R.S., Brothers, M.A., Davies, J.F., Ferre, R.A., Gajiwala, K.S., He, M., Hogan, R.J., Kozminski, K., Li, L.Y., Lockner, J.W., Lou, J., Marra, M.T., Mitchell, L.J. Jr, Murray, B.W., Nieman, J.A., Noell, S., Planken, S.P., Rowe, T., Ryan, K., Smith, G.J. 3rd, Solowiej, J.E., Steppan, C.M., Taggart, B., 2020. Discovery of ketone-based covalent inhibitors of Coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19. J. Med. Chem. 63, 12725–12747. doi: 10.1021/acs.jmedchem.0c01063. 17. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.H., Nitsche, A., Müller, M.A., Drosten, C., Pöhlmann, S., 2020a. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8. doi: 10.1016/j.cell.2020.02.052. 18. Hoffmann, M., Schroeder, S., Kleine-Weber, H., Müller, M.A., Drosten, C., Pöhlmann, S., 2020b. Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19. Antimicrob. Agents Chemother. 64, e00754–20. doi: 10.1128/AAC.00754-20. 19. Hoffmann, M., Sidarovich, A., Arora, P., Krüger, N., Nehlmeier, I., Kempf, A., Graichen, L., Winkler, M.S., Niemeyer, D., Goffinet, C., Drosten, C., Schulz, S., Jäck, H.M., Pöhlmann, S. 2022. Evidence for an ACE2-independent entry pathway that can protect from neutralization by an antibody used for COVID-19 therapy. mBio. 13, e0036422. doi: 10.1128/mbio.00364-22. 20. Hsu, M.F., Kuo, C.J., Chang, K.T., Chang, H.C., Chou, C.C., Ko, T.P., Shr, H.L., Chang, G.G., Wang, A.H., Liang, P.H., 2005. Mechanism of the maturation process of SARS-CoV 3CL protease. J. Biol. Chem. 280, 31257–31266. doi: 10.1074/jbc.M502577200. 21. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H., Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J., Cao, B., 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506. doi: 10.1016/S0140-6736(20)30183-5. 22. Imai, M., Iwatsuki-Horimoto, K., Hatta, M., Loeber, S., Halfmann, P.J., Nakajima, N., Watanabe, T., Ujie, M., Takahashi, K., Ito, M., Yamada, S., Fan, S., Chiba, S., Kuroda, M., Guan, L., Takada, K., Armbrust, T., Balogh, A., Furusawa, Y., Okuda, M., Ueki, H., Yasuhara, A., Sakai-Tagawa, Y., Lopes, T.J.S., Kiso, M., Yamayoshi, S., Kinoshita, N., Ohmagari, N., Hattori, S.I., Takeda, M., Mitsuya, H., Krammer, F., Suzuki, T., Kawaoka, Y., 2020. Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. Proc. Natl. Acad. Sci. USA. 117, 16587–16595. doi: 10.1073/pnas.2009799117. 23. Jackson, C.B., Farzan, M., Chen, B., Choe, H., 2022. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol. 23, 3−20. doi: 10.1038/s41580-021-00418-x. 24. Jayaram, B., Singh, T., Mukherjee, G., Mathur, A., Shekhar, S., Shekhar, V., 2012. A freely accessible web-server for target directed lead molecule discovery. BMC bioinformatics 13, 1−13. doi: 10.1186/1471-2105-13-S17-S7. 25. Jiang, L. 2014. Copper/N,N-dimethylglycine catalyzed Goldberg reactions between aryl bromides and amides, aryl iodides and secondary acyclic amides. Molecules 19, 13448−13460. doi: 10.3390/molecules190913448. 26. Jin, Z., Du, X., Xu, Y.. Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L.W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao, Z., Yang, H., 2020. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature 582, 289−293. doi: 10.1038/s41586-020-2223-y. 27. Kim, Y., Liu, H., Galasiti Kankanamalage, A.C., Weerasekara, S., Hua, D.H., Groutas, W.C., Chang, K.O., Pedersen, N.C., 2016. Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor. PLoS Pathog. 12, e1005531. doi: 10.1371/journal.ppat.1005531. 28. Kuo, C.J., Chao, T.L., Kao, H.C., Tsai, Y.M., Liu, Y.K., Wang, L.H., Hsieh, M.C., Chang, S.Y., Liang, P.H., 2021. Kinetic characterization and inhibitor screening for the proteases leading to identification of drugs against SARS-CoV-2. Antimicrob. Agents Chemother. 65, e02577-20. doi: 10.1128/AAC.02577-20. 29. Kuo, C.J., Liang, P.H., 2015. Characterization, inhibition, and engineering of the main protease of Severe Acute Respiratory Syndrome Coronavirus. ChemBioEng Rev. 2, 118–132. doi:10.1002/cben.201400031. 30. Kuo CJ, Liang PH., 2022. SARS-CoV-2 3CLpro displays faster self-maturation in vitro than SARS-CoV 3CLpro due to faster C-terminal cleavage. FEBS Lett. 596, 1214–1224. doi: 10.1002/1873-3468.14337. 31. Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., Zhang, Q., Shi, X., Wang, Q., Zhang, L., Wang, X. 2020. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581, 215–220. doi: 10.1038/s41586-020-2180-5. 32. Lee, J.Y., Kuo, C.J., Shin, J.S., Jung, E., Liang, P.H., Jung, Y.S., 2021. Identification of non-covalent 3C-like protease inhibitors against severe acute respiratory syndrome coronavirus-2 via virtual screening of a Korean compound library. Bioorg. Med. Chem. Lett. 42, 128067. doi: 10.1016/j.bmcl.2021.128067. 33. Lee, R.K., Li, T.N., Chang, S.Y., Chao, T.L., Kuo, C.H., Pan, M.Y., Chiou, Y.T., Liao, K.J., Yang, Y., Wu, Y.H., Huang, C.H., Juan, H.F., Hsieh, H.P., Wang, L.H. 2022. Identification of Entry Inhibitors against Delta and Omicron Variants of SARS-CoV-2. Int. J. Mol. Sci. 23, 4050. doi: 10.3390/ijms23074050. 34. Lipinski, C.A., 2004. Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov. Today Technol. 1, 337–341. doi: 10.1016/j.ddtec.2004.11.007. 35. Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., Bi, Y., Ma, X., Zhan, F., Wang, L., Hu, T., Zhou, H., Hu, Z., Zhou, W., Zhao, L., Chen, J., Meng, Y., Wang, J., Lin, Y., Yuan, J., Xie, Z., Ma, J., Liu, W.J., Wang, D., Xu, W., Holmes, E.C., Gao, G.F., Wu, G., Chen, W., Shi, W., Tan, W., 2020. Genomic characterisation and epidemiology of 2019 novel coronavirus: implication for virus origins and receptor binding. Lancet 395, 565–574. doi: 10.1016/S0140-6736(20)30251-8. 36. Mahoney, M., Damalanka, V.C., Tartellm, M.A., Chung, D.H., Lourenço, A.L., Pwee, D., Bridwell, A.E.M., Hoffmann, M., Voss, J., Karmakar, P., Azouz, N.P., Klingler, A.M., Rothlauf, P.W., Thompson, C.E., Lee, M., Klampfer, L., Stallings, C.L., Rothenberg, M.E., Pöhlmann, S., Whelan, S.P..J, O''Donoghue, A.J., Craik, C.S., Janetka, J.W., 2021. A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells. Proc. Natl. Acad. Sci. USA. 118, e2108728118. doi: 10.1073/pnas.2108728118. 37. Mondal, S., Chen, Y., Lockbaum, G.J., Sen, S., Chaudhuri, S., Reyes, A.C., Lee, J.M., Kaur, A.N., Sultana, N., Cameron, M.D., Shaffer, S.A., Schiffer, C.A., Fitzgerald, K.A., Thompson, P.R., 2022. Dual inhibitors of main protease (MPro) and cathepsin L as potent antivirals against SARS-CoV2. J. Am. Chem. Soc. 144, 21035–21045. doi: 10.1021/jacs.2c04626. 38. O''Boyle, N.M., Banck, M., James, C.A., Morley, C., Vandermeersch, T., Hutchison, G.R., 2011. Open Babel: An open chemical toolbox 2011. J. Cheminform. 3, 33. doi: 10.1186/1758-2946-3-33. 39. Ouyang, Y., Li, J., Chen, X., Fu, X., Sun, S., Wu, Q., 2021. Chalcone derivatives: Role in anticancer therapy. Biomolecules 11, 894. doi: 10.3390/biom11060894. 40. Özdemir, A., Altintop, M.D., Turan-Zitouni, G., Çiftçi, G.A., Ertorun, İ., Alataş, Ö., Kaplancikli, Z.A., 2015. Synthesis and evaluation of new indole-based chalcones as potential antiinflammatory agents. Eur. J. Med. Chem. 89, 304–309. doi: 10.1016/j.ejmech.2014.10.056. 41. Pires, D.E.V., Blundell, T.L., Ascher, D.B., 2015. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem. 58, 4066–4072. doi: 10.1021/acs.jmedchem.5b00104. 42. Ramesh, D., Joji, A., Vijayakumar, B.G., Sethumadhavan, A., Mani, M., Kannan, T., 2020. Indole chalcones: design, synthesis, in vitro and in silico evaluation against Mycobacterium tuberculosis. Eur. J. Med. Chem. 198, 112358. doi: 10.1016/j.ejmech.2020.112358. 43. Sheahan, T.P., Sims, A.C., Zhou, S., Graham, R.L., Pruijssers, A.J., Agostini, M.L., Leist, S.R., Schäfer, A., Dinnon, K.H. 3rd, Stevens, L.J., Chappell, J.D., Lu, X., Hughes, T.M,, George, A.S., Hill, C.S., Montgomery, S.A., Brown, A.J., Bluemling, G.R., Natchus, M.G., Saindane, M., Kolykhalov, A.A., Painter, G., Harcourt, J., Tamin, A., Thornburg, N.J., Swanstrom, R., Denison, M.R., Baric, R.S. , 2020. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 12, eabb5883. doi: 10.1126/scitranslmed.abb5883. 44. Shapira, T., Monreal, I.A., Dion, S.P., Buchholz, D.W., Imbiakha, B., Olmstead, A.D., Jager, M., Désilets, A., Gao, G., Martins, M., Vandal, T., Thompson, C.A.H., Chin, A., Rees, W.D., Steiner, T., Nabi, I.R., Marsault, E., Sahler, J., Diel, D.G., Van de Walle, G.R, August, A., Whittaker, G.R., Boudreault, P.L., Leduc, R., Aguilar, H.C., Jean, F., 2022. A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature 605, 340–348. doi: 10.1038/s41586-022-04661-w. 45. Sia, S.F., Yan, L.M., Chin, A.W.H., Fung, K., Choy, K.T., Wong, A.Y.L., Kaewpreedee, P., Perera, R.A.P.M., Poon, L.L.M., Nicholls, J.M., Peiris, M., Yen, H.L., 2020. Pathogenesis and transmission of SARS-CoV-2 in golden hamsters. Nature 583, 834–838. doi: 10.1038/s41586-020-2342-5. 46. Tang, W.F., Tsai, H.P., Chang, Y.H., Chang, T.Y., Hsieh, C.F., Lin, C.Y., Lin, G.H., Chen, Y.L., Jheng, J.R., Liu, P.C., Yang, C.M., Chin, Y.F., Chen, C.C., Kau, J.H., Hung, Y.J., Hsieh, P.S., Horng, J.T., 2021. Perilla (Perillafrutescens) leaf extract inhibits SARS CoV-2 via direct virus inactivation. Biomed. J. 44, 293–303. doi: 10.1016/j.bj.2021.01.005. 47. Vijayakumar, B.G., Ramesh, D., Joji, A., Prakasan, J.J., Kannan, T., 2020. In Silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur. J. Pharmacol. 886, 173448. doi: 10.1016/j.ejphar.2020.173448. 48. Voskiene, A., Mickevicius, V., Mikulskiene, G., 2007. Synthesis and structural characterization of products condensation 4-carboxy-1-(4-styrylcarbonylphenyl)-2-pyrrolidinones with hydrazines. Arkivoc 2007, 303–314. doi.org/10.3998/ark.5550190.0008.f29. 49. Vuong, W., Khan, M.B., Fischer, C., Arutyunova, E., Lamer, T., Shields, J., Saffran, H.A., McKay, R.T., van Belkum, M.J., Joyce, M.A., Young, H.S., Tyrrell, D.L., Vederas, J.C., Lemieux, M.J., 2020. Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication. Nat. Commun. 11, 4282. doi: 10.1038/s41467-020-18096-2. 50. Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., Xiao, G. 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30, 269–271. doi: 10.1038/s41422-020-0282-0. 51. Wu, F., Zhao, S., Yu, B., Chen, Y.M., Wang, W., Song, Z.G., Hu, Y., Tao, Z.W., Tian, J.H., Pei, Y.Y., Yuan, M.L., Zhang, Y.L., Dai, F.H., Liu, Y., Wang, Q.M., Zheng, J.J., Xu, L., Holmes, E.C., Zhang, Y.Z., 2020. A new coronavirus associated with human respiratory disease in China. Nature 579, 265−269. doi: 10.1038/s41586-020-2008-3. 52. Xu, M., Wu, P., Shen, F., Ji, J., Rakesh, .KP., 2019. Chalcone derivatives and their antibacterial activities: Current development. Bioorg. Chem. 91, 103133. doi: 10.1016/j.bioorg.2019.103133. 53. Yamamoto, M., Kiso, M., Sakai-Tagawa, Y., Iwatsuki-Horimoto, K., Imai, M., Takeda, M., Kinoshita, N., Ohmagari, N., Gohda, J., Semba, K., Matsuda, Z., Kawaguchi, Y., Kawaoka, Y., Inoue, J.I., 2020. The anticoagulant nafamostat potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and viral infection in vitro in a cell-type-dependent manner. Viruses 12, 629. doi: 10.3390/v12060629. 54. Yan, J. Chen, S. Zhang, J. Hu, L. Huang, X. Li, X., 2016. Synthesis, evaluation, and mechanism study of novel Indole-Chalcone derivatives exerting effective antitumor activity through microtubule destabilization in vitro and in vivo. J. Med. Chem. 59, 5264−5283. doi: 10.1021/acs.jmedchem.6b00021. 55. Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K., Hilgenfeld, R., 2020. X-ray structure of main protease of the novel coronavirus SARS-CoV-2 enables design of -ketoamide inhibitors. Science 368, 409–412. doi: 10.1126/science.abb3405. 56. Zhou, P., Yang, X.L., Wang, X.G., Hu, B., Zhang, L., Zhang, W., Si, H.R., Zhu, Y., Li, B., Huang, C.L., Chen, H.D., Chen, J., Luo, Y., Guo, H., Jiang, R.D., Liu, M.Q., Chen, Y., Shen, X.R., Wang, X., Zheng, X.S., Zhao, K., Chen, Q.J., Deng, F., Liu, L.L., Yan, B., Zhan, F.X., Wang, Y.Y., Xiao, G.F., Shi, Z.L., 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273. doi: 10.1038/s41586-020-2012-7. 57. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G., Gao, G.F., Tan, W., China Novel Coronavirus Investigating and Research Team., 2020. A novel coronavirus from patients with pneumonia in China, 2019. N. Eng. J. Med. 382, 727–733. doi: 10.1056/NEJMoa2001017. References (Part-II) 1. Levy, S. B.; Marshall, B. Antibacterial Resistance Worldwide: Causes, Challenges and Responses. Nat. Med. 2004, 10 (12 Suppl), S122–S129, DOI: 10.1038/nm1145 2. Ghosh, C.; Haldar, J. Membrane-Active Small Molecules: Designs Inspired by Antimicrobial Peptides. ChemMedChem. 2015, 10 (10), 1606–1624, DOI: 10.1002/cmdc.201500299 3. Lim, S. M.; Webb, S. A. R. Nosocomial Bacterial Infections in Intensive Care Units. I: Organisms and Mechanisms of Antibiotic Resistance. Anaesthesia 2005, 60 (9), 887–902, DOI: 10.1111/j.1365-2044.2005.04220.x 4. Fischbach, M. A.; Walsh. C. T. Antibiotics for Emerging Pathogen. Science 2009, 325 (5944), 1089–1093, DOI: 10.1126/science.1176667 5. Bulter, M. S.; Gigante V.; Sati, H.; Paulin, S.; Al-Sulaiman, L.; Rex, J. H.; Fernandes, P.; Arias, C. A.; Paul, M.; Thwaites, G. E.; Czaplewski, L.; Alm, R. A.; Lienhardt, C.; Spigelman, M.; Silver, L. L.; Ohmagari, N.; Kozlov, R.; Harbarth, S.; Beyer, P. Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is Needed. Antimicrob. Agents Chemother. 2022, 66 (3), e0199121, DOI: 10.1128/AAC.01991-21. 6. Grundmann, H.; Aires-de-Sousa, M.; Boyce, J.; Tiemersma, E. Emergence and Resurgence of Meticillin-Resistant Staphylococcus aureus as a Public-Health Threat. Lancet 2006, 368 (9538), 874–885, doi: 10.1016/S0140-6736(06)68853-3 7. Tacconelli, E.; Carrara, E.; Savoldi, A.; Harbarth, S.; Mendelson, M.; Monnet, D. L.; Pulcini, C.; Kahlmeter, G.; Kluytmans, J.; Carmeli, Y.; Ouellette, M.; Outterson, K.; Patel, J.; Cavaleri, M.; Cox, E. M.; Houchens, C. R.; Grayson, M. L.; Hansen, P.; Singh, N.; Theuretzbacher, U.; Magrini, N.; WHO Pathogens Priority List Working Group. Discovery, Research, and Development of New Antibiotics: the WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis. Lancet Infect. Dis. 2018, 18 (3), 318–327, DOI: 10.1016/S1473-3099(17)30753-3 8. Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A Privileged Structure in Medicinal Chemistry. Chem. Rev. 2017, 117 (12), 7762–7810, DOI: 10.1021/acs.chemrev.7b00020 9. Xu, M.; Wu, P.; Shen, F.; Ji, J.; Rakesh, K. P. Chalcone Derivatives and Their Antibacterial Activities: Current Development. Bioorg. Chem. 2019, 91, 103133, DOI: 10.1016/j.bioorg.2019.103133 10. Bhale, P. S.; Dongare, S. B.; Chanshetti, U. B. Synthesis and antimicrobial screening of chalcones containing imidazo[1,2-a] pyridine nucleus. Res. J. Chem. Sci. 2013, 3, 38–42. 11. Mohammad, F.; Rahaman, S. A.; Moinuddin, M. D. Synthesis and Antimicrobial Activity of 1-(2’,4’-Dichlorophenyl)-3-(Substituted aryl)-2-Propene-1-Ones. Int. J. Life Sci. Pharm. Res. 2009, 2, 82-87. 12. Asiri, A. M.; Khan, S. A. Synthesis, Characterization, and In Vitro Antibacterial Activities of Macromolecules Derived from Bis-Chalcone. J. Heter. Chem., 2012, 49 (6), 1434–1438, https://doi.org/10.1002/jhet.942 13. Asiri, A. M.; Khan, S. A. Green Synthesis, Characterization and Biological Evaluation of Novel Chalcones as Anti Bacterial Agents. Ara. J. Chem. 2017, 10 (2), S2890–S2895, DOI: 10.1016/j.arabjc.2013.11.018 14. Yadav, N.; Dixit, S. K..; Bhattacharya, A.; Mishra, L. C.; Sharma, M.; Awasthi, S. K.; Bhasin, V. K. Antimalarial Activity of Newly Synthesized Chalcone Derivatives in Vitro. Chem. Biol. Drug Des. 2012, 80 (2), 340–347, DOI: 10.1111/j.1747-0285.2012.01383.x 15. Insuasty, B.; Ramírez, J.; Becerra, D.; Echeverry, C.; Quiroga, J.; Abonia, R.; Robledo, S. M.; Velez, I. D.; Upegui, Y.; Munoz, J. A.; Ospina, V.; Nogueras, M.; Cobo, J. An Efficient Synthesis of New Caffeine-Based Chalcones, Pyrazolines and Pyrazolo[3,4-b][1,4]diazepines as Potential Antimalarial, Antitrypanosomal and Antileishmanial Agents. Eur. J. Med. Chem. 2015, 93, 401–413, DOI: 10.1016/j.ejmech.2015.02.040 16. Salum, L. B.; Altei, W. F.; Chiaradia, L. D.; Cordeiro, M. N. S.; Canevarolo, R. R.; Melo, C. P. S.; Winter, E.; Mattei, B.; Daghestani, H. N.; Santos-Silva, M. C.; Creczynski-Pasa, T. B.; Yunes, R. A.; Yunes, J. A.; Andricopulo, A. D.; Day, B. W.; Nunes, R. J.; Vogt, A. Cytotoxic 3,4,5-Trimethoxychalcones as Mitotic Arresters and Cell Migration Inhibitors. Eur. J. Med. Chem. 2013, 63, 501–510, DOI: 10.1016/j.ejmech.2013.02.037 17. Murthy, Y. L. N.; Suhasini, K. P.; Pathania, A. S.; Bhushan, S.; Sastry. Y. N. Synthesis, Structure Activity Relationship and Mode of Action of 3-Substitutedphenyl-1-(2,2,8,8-Tetramethyl-3,4,9,10-Tetrahydro-2H, 8H-Pyrano[2,3-f]chromen-6-yl)-Propenones as Novel Anticancer Agents in Human Leukaemia HL-60 Cells. Eur. J. Med. Chem. 2013, 62, 545–555, DOI: 10.1016/j.ejmech.2013.01.027 18. Liu, Z.; Tang, L.; Zou, P.; Zhang, Y.; Wang, Z.; Fang, Q.; Jiang, L.; Chen, G.; Xu, Z.; Zhang, H.; Liang, G. Synthesis and Biological Evaluation of Allylated and Prenylated Mono-Carbonyl Analogs of Curcumin as Anti-Inflammatory Agents. Eur. J. Med. Chem. 2014, 74, 671–682, DOI: 10.1016/j.ejmech.2013.10.061 19. Reichwald, C.; Shimony, O.; Dunkel, U.; Sacerdoti-Sierra, N.; Jaffe, C. L.; Kunick, C. 2-(3-Aryl-3-Oxopropen-1-yl)-9-Tert-Butyl-Paullones: a New Antileishmanial Chemotype. J. Med. Chem. 2008, 51 (3), 659–665, DOI: 10.1021/jm7012166 20. Carvalho, S. A.; Feitosa, L. O.; Soares, M.; Costa, T. E. M. M.; Henriques, M. G.; Salomao, K.; Castro, S. L. D.; Kaiser, M.; Brun, R.; Wardell, J. L.; Wardell, S. M. S. V.; Trossini, G. H. G.; Andricopulo, A. D.; Silva, E. F. D.; Fraga, C. A. M. Design and Synthesis of New (E)-Cinnamic N-Acylhydrazones as Potent Antitrypanosomal Agents. Eur. J. Med. Chem. 2012, 54, 512–521, DOI: 10.1016/j.ejmech.2012.05.041 21. Sharma, H.; Patil, S.; Sanchez, T. W.; Neamati, N.; Schinazi, R. F.; Buolamwini, J. K. Synthesis, Biological Evaluation and 3D-QSAR Studies of 3-Keto Salicylic Acid Chalcones and Related Amides as Novel HIV-1 Integrase Inhibitors. Bioorg. Med. Chem. 2011, 19 (6), 2030–2045, DOI: 10.1016/j.bmc.2011.01.047 22. Sivakumar, P. M.; Prabhakar, P. K.; Doble, M. Synthesis, Antioxidant Evaluation, and Quantitative Structure-Activity Relationship Studies of Chalcones. Med. Chem. Res. 2011, 20 (4), 482–492, DOI: 10.1007/s00044-010-9342-1 23. Sashidhara, K. V.; Avula, S. R.; Mishra, V.; Palnati, G. R.; Singh, L. R.; Singh, N.; Chhonker, Y. S.; Swami, P.; Bhatta, R. S.; Palit, G. Identification of Quinoline-Chalcone Hybrids as Potential Antiulcer Agents. Eur. J. Med. Chem. 2015, 89, 638–653, DOI: 10.1016/j.ejmech.2014.10.068 24. Greeff, J.; Joubert, J.; Malan, S. F.; Dyk, S. Antioxidant Properties of 4-Quinolones and Structurally Related Flavones. Bioorg. Med. Chem. 2012, 20 (2), 809–818, DOI: 10.1016/j.bmc.2011.11.068 25. Ghani, S. B. A.; Weaver, L.; Zidan, Z. H.; Ali, H. M.; Keevil, C. W.; Brown, R. Microwave Assisted Synthesis and Antimicrobial Activities of Flavonoid Derivatives. Bioorg. Med. Chem. Lett. 2008, 18 (2), 518–522, DOI: 10.1016/j.bmcl.2007.11.081 26. Yuan, Q.; Liu, Z.; Xiong, C.; Wu, L.; Wang, J.; Ruan, J. A Novel, Broad-Spectrum Antitumor Compound Containing the 1-Hydroxycyclohexa-2,5-Dien-4-One group: the Disclosure of a New Antitumor Pharmacophore in Protoapigenone 1. Bioorg. Med. Chem. Lett. 2011, 21 (11), 3427–3430, DOI: 10.1016/j.bmcl.2011.03.108 27. Auffret, G.; Labaied, M.; Frappier, F.; Rasoanaivo, P.; Grellier, P.; Lewin, G. Synthesis and Antimalarial Evaluation of a Series of Piperazinyl Flavones. Bioorg. Med. Chem. Lett. 2007, 17 (4), 959–963, DOI: 10.1016/j.bmcl.2006.11.051 28. Nakatsuka, T.; Tomimori, Y.; Fukuda, Y.; Nukaya, H. First Total Synthesis of Structurally Unique Flavonoids and Their Strong Anti-Inflammatory Effect. Bioorg. Med. Chem. Lett. 2004, 14 (12), 3201–3203, DOI: 10.1016/j.bmcl.2004.03.108 29. Ares, J. J.; Outt, P. E.; Randall, J. L.; Johnston, J. N.; Murray, P. D.; O'Brien, L. M.; Weisshaar, P. S.; Ems, B. L. Synthesis and Biological Evaluation of Flavonoids and Related Compounds as Gastroprotective Agents. Bioorg. Med. Chem. Lett., 1996, 6 (8), 995–998, DOI: 10.1016/0960-894X(96)00134-5 30. Harborne, J.B.; Williams, C. A. Advances in Flavonoid Research Since 1992. Phytochemistry 2000, 55 (6), 481–504, DOI: 10.1016/s0031-9422(00)00235-1 31. Casano, G.; Dumetre, A.; Pannecouque, C.; Hutter, S.; Azas, N.; Robin, M. Synthesis and Biological Evaluation of Pyrazole Derivatives Containing Thiourea Skeleton as Anticancer Agents. Bioorg. Med. Chem. 2010, 18 (16), 6012–6023, DOI: 10.1016/j.bmc.2010.06.067 32. Chu, W. C.; Baia, P. Y.; Yanga, Z. Q.; Cuia, D. Y.; Huaa, Y. G.; Yang, Y.; Yanga, Q. Q.; Zhanga, E.; Qina, S. Synthesis and Antibacterial Evaluation of Novel Cationic Chalcone Derivatives Possessing Broad Spectrum Antibacterial Activity. Eur. J. Med. Chem. 2018, 143, 905–921, DOI: 10.1016/j.ejmech.2017.12.009 33. Yin, B. T.; Yan, C. Y.; Peng, X. M.; Zhang, S. L.; Rasheed, S.; Geng, R. X.; Zhou, C. H. Synthesis and Biological Evaluation of α-Triazolyl Chalcones as a New Type of Potential Antimicrobial Agents and Their Interaction with Calf Thymus DNA and Human Serum Albumin. Eur. J. Med. Chem. 2014, 71, 148–159, DOI: 10.1016/j.ejmech.2013.11.003 34. Liu, X. F.; Zheng, C. J.; Sun, L. P.; Liu, X. K.; Piao, H. R. Synthesis of New Chalcone Derivatives Bearing 2,4-Thiazolidinedione and Benzoic Acid Moieties as Potential Anti-Bacterial Agents. Eur. J. Med. Chem. 2011, 46(8):3469–73, DOI: 10.1016/j.ejmech.2011.05.012. 35. Nielsen, S. F.; Larsen, M.; Boesen, T.; Schønning, K.; Kromann, H. Cationic Chalcone Antibiotics. Design, Synthesis, and Mechanism of Action. J. Med. Chem. 2005, 48 (7), 2667–2677, DOI: 10.1021/jm049424k 36. Teng, K. H.; Liang, P. H. Structures, Mechanisms and Inhibitors of Undecaprenyl Diphosphate Synthase: A cis-Prenyltransferase for Bacterial Peptidoglycan Biosynthesis. Bioorg. Chem. 2012, 43, 51–57, DOI: 10.1016/j.bioorg.2011.09.004 37. Sinko, W.; Wang, Y.; Zhu, W.; Zhang, Y.; Feixas, F.; Cox, C. L.; Mitchell, D. A.; Oldfield, E.; McCammon, J. A. Undecaprenyl Diphosphate Synthase Inhibitors: Antibacterial Drug Leads. J. Med. Chem. 2014, 57 (13), 5693–5701, DOI: 10.1021/jm5004649. 38. Fatha, M. A.; Czarny, T. L.; Myers, C. L.; Worrall, L. J.; French, S.; Conrady, D. G.; Wang, Y.; Oldfield, E.; Strynadka, N. C.; Brown, E. D. Antagonism Screen for Inhibitors of Bacterial Cell Wall Biogenesis Uncovers an Inhibitor of Undecaprenyl Diphosphate Synthase. Proc. Natl. Acd. Sci., USA 2015, 112 (35), 11048–11053, DOI: 10.1073/pnas.1511751112 39. Wang, Y.; Desai, J.; Zhang, Y.; Malwal, S. R.; Shin, C. J.; Feng, X.; Sun, H.; Liu, G.; Guo, R. T.; Oldfield, E. Bacterial Cell Growth Inhibitors Targeting Undecaprenyl Diphosphate Synthase and Undecaprenyl Diphosphate Phosphatase. ChemMedchem. 2016, 11 (20), 2311–219, DOI: 10.1002/cmdc.201600342 40. Malwal, S. R.; Chen, L.; Hicks, H.; Qu, F.; Liu, W.; Shillo, A.; Law, W. X.; Zhang, J.; Chandnani, N.; Han, X.; Zheng, Y.; Chen, C. C.; Guo, R. T.; AbdelKhalek, A.; Seleem, M. N.; Oldfield, E. Discovery of Lipophilic Bisphosphonates that Target Bacterial Cell Wall and Quinone Biosynthesis. J. Med. Chem. 2019, 62 (5), 2564–2581, DOI: 10.1021/acs.jmedchem.8b01878. 41. Song, J.; Malwal, S. R.; Baig, N.; Schurig-Briccio, L. A.; Gao, Z.; Vaidya, G. S.; Yang, K.; Abutaleb, N. S.; Seleem, M. N.; Gennis, R. B.; Pogorelov, T. V.; Oldfield, E.; Feng, X. Discovery of Prenyltransferase Inhibitors with In Vitro and In Vivo Antibacterial Activity. ACS Infect. Dis. 2020, 6 (11), 2979–2993, DOI: 10.1021/acsinfecdis.0c00472. 42. Kuo, C. J.; Guo, R. T.; Lu, I. L.; Liu, H. G.; Wu, S. Y.; Ko, T. P.; Wang, A. H.-J.; Liang, P. H. Structure-Based Inhibitors Exhibited Differential Activities against H. pylori and E. coli Undecaprenyl Pyrophosphate Synthases. J. Biomed. Biotechnol. 2008, 2008, 841312, DOI: 10.1155/2008/841312 43. Voskiene, A.; Mickevicius, V.; Mikulskiene, G. Synthesis and Structural Characterization of Products Condensation 4-Carboxy-1-(4-Styrylcarbonylphenyl)-2-Pyrrolidinones with Hydrazines. Arkivoc 2007, XV, 303–314, DOI: 10.3998/ark.5550190.0008.f29. 44. O'Boyle, N. M.; Banck, M.; James, C. A.; Morley, C.; Vandermeersch, T.; Hutchison, G. R.; Open Babel: An Open Chemical Toolbox 2011. J. Cheminform. 2011, 3, 33, DOI: 10.1186/1758-2946-3-33. 45. Lipinski, C. A., Lead-and Drug-Like Compounds: the Rule-of-Five Revolution. Drug Discov. Today Technol. 2004, 1 (4), 337–341, DOI: 10.1016/j.ddtec.2004.11.007. 46. Jayaram, B.; Singh, T.; Mukherjee, G.; Mathur, A.; Shekhar, S.; Shekhar, V. A Freely Accessible Web-Server for Target Directed Lead Molecule Discovery. BMC bioinformatics 2012, 13 (Suppl 17), 1−13. doi: 10.1186/1471-2105-13-S17-S7. 47. Pires, D. E. V.; Blundell, T. L.; Ascher, D. B. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J. Med. Chem. 2015, 58, 4066–4072. doi: 10.1021/acs.jmedchem.5b00104. 48. Palla. S. R.; Li, C. W.; Chao, T. L.; Lo, H. L. V.; Liu, J. J.; Pan, M. Y. C.; Chiu, Y. T.; Lin, W. C.; Hu, C. W.; Yang, C. M.; Chen, Y. Y.; Fang, J. T.; Lin, S. W.; Lin, Y. T.; Lin, H. C.; Kuo, C.J.; Wang, L. H. C.; Chang, S. Y.; Liang, P. H. Synthesis, Evaluation, and Mechanism of 1-(4-(Arylethylenylcarbonyl)phenyl)-4-Carboxy-2-Pyrrolidinones as Potent Reversible SARS-CoV-2 Entry Inhibitors. Antiviral Res. 2023, 219, 105735, DOI: 10.1016/j.antiviral.2023.105735 49. Wang, J.; Liu, H.; Zhao, J.; Gao, H.; Zhou, L.; Liu, Z.; Chen, Y.; Sui, P. Antimicrobial and Antioxidant Activities of the Root Bark Essential Oil of Periploca Sepium and Its Main Component 2-Hydroxy-4-Methoxybenzaldehyde. Molecules 2010, 15 (8), 5807–5817. https://doi.org/10.3390/molecules15085807 | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91613 | - |
| dc.description.abstract | 通過邁克爾加成、環化、醛醇縮合和去質子化設計並合成了一類1-(4-(芳基乙烯羰基)苯基)-4-羧基-2-吡咯烷酮，以抑制人跨膜蛋白酶絲氨酸2 (TMPRSS2)和弗林蛋白酶， 它們參與修飾 SARS-CoV-2 Spike 以便病毒進入。 發現最有效的抑制劑 2f (81) 可有效抑制 VeroE6 和 Calu-3 細胞中各種 SARS-CoV-2 delta 和 omicron 突變株的複製，通過與病毒預混合，抗病毒的EC50 範圍可達 0.001 至 0.026 µM。 比蛋白酶抑制活性更有效的抗病毒活性顯示，合成的化合物主要以抑制 Spike 受體結合域（RBD）：血管緊張轉化酶 2（ACE2）相互作用作為靶標，並且通過抑制 TMPRSS2 和/或 Furin 增强其抗病毒活性。 為了進一步證實 2f（81）對病毒進入的阻斷作用，使用SARS-CoV-2 Spike假病毒進行進入檢測，結果表明該化合物通過ACE2依賴性途徑抑制假病毒進入，主要是抑制Calu-3 细胞中 RBD：ACE2 相互作用和 TMPRSS2 活性。 最後，在 SARS-CoV-2 感染的體内動物模型中，倉鼠口服 25 mg/kg 2f (81) 可減少體重减輕，感染三天後鼻甲中的病毒 RNA 水平降低了 5 倍。 我們的研究结果證明了先導化合物作為 SARS-CoV-2 治療進一步臨床前研究的潛力。 | zh_TW |
| dc.description.abstract | A class of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones were designed and synthesized via Michael addition, cyclization, aldol condensation, and deprotonation to inhibit the human transmembrane protease serine 2 (TMPRSS2) and Furin, which are involved in priming the SARS-CoV-2 Spike for virus entry. The most potent inhibitor 2f (81) was found to efficiently inhibit the replication of various SARS-CoV-2 delta and omicron variants in VeroE6 and Calu-3 cells, with EC50 range of 0.001 to 0.026 µM by pre-incubation with the virus to avoid the virus entry. The more potent antiviral activities than the proteases inhibitory activities led to the discovery that the synthesized compounds also inhibited Spike’s receptor binding domain (RBD):angiotensin converting enzyme 2 (ACE2) interaction as a main target, and their antiviral activities were enhanced by inhibiting TMPRSS2 and/or Furin. To further confirm the blocking effect of 2f (81) on virus entry, SARS-CoV-2 Spike pseudovirus was used in the entry assay and the results showed that the compound inhibited the pseudovirus entry in a ACE2-dependent pathway, via mainly inhibiting RBD:ACE2 interaction and TMPRSS2 activity in Calu-3 cells. Finally, in the in vivo animal model of SARS-CoV-2 infection, the oral administration of 25 mg/kg 2f (81) in hamsters resulted in reduced body weight loss and 5-fold lower viral RNA levels in nasal turbinate three days post-infection. Our findings demonstrated the potential of the lead compound for further preclinical investigation as a potential treatment for SARS-CoV-2. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-02-20T16:12:28Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-02-20T16:12:28Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | Part I………………………………………………………………………………..VII
摘要………………………………………………………………………………....VII Abstract…………………………………………………………………………........VIII 1. Introduction………………………………………………………………...............1 2. Materials and methods…………………………………………………………….4 2.1. General methods…………………………………………………………………..4 2.2. Chemicals……………………………………………………………………….....5 2.3. TMPRSS2 preparation and IC50 measurements…………………………………...5 2.4. Furin IC50 measurements………………………………………………………….7 2.5. Antivirus EC50 and cytotoxicity CC50 measurements……………………………..8 2.6. RBD:ACE2 interaction IC50 measurements and pseudovirus assay……………..10 2.7. Pseudovirus assay………………………………………………………………...11 2.8. Expression and purification of the recombinant SARS-CoV-2 delta variant RBD and human ACE2………………………………………………………………….….12 2.9. Thermal shift experiments………………………………………………………..14 2.10. Molecular docking……………………………………………………………....14 2.11. Drug likeness analysis…………………………………………………………..15 2.12. Animal studies…………………………………………………………………..16 3. Results ………………..…………………………………………………………...18 3.1. Synthesis of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones 2a–g…………………………………………………………………………………..18 3.2. Synthesis of 4a and 4b without the carboxylate………………………………….19 3.3. Evaluation of 2a–g and 4a–b against TMPRSS2 and Furin ……………………..20 3.4. Evaluation of 2a–g and 4a–b against SARS-CoV-2……………………...............21 3.5. IC50 of the compounds against RBD:ACE2 interaction…………………..……...23 3.6. Pseudovirus assays……………………………………………………………….24 3.7. Thermal shift experiments to distinguish the target for RBD: ACE2 Inhibitors…………………………………………………………………..………….24 3.8. Binding modes of the inhibitor with TMPRSS2, Furin, and RBD………………25 3.9. Drug-likeness of the inhibitor as judged from Lipinski rule of five…….……….26 3.10. Drug-likeness of the inhibitor as judged from ADMET properties…………….27 3.11. Preliminary animal study of 2f …………………………………………………28 4. Discussion………………………………………………………………………….29 5. Figure Legends……………………………………………….…………………...39 6. Spectral data…………………………………………………….………………...63 7. References………………………………………………………………….…..….70 Part II …………………………………………………………………………..........82 摘要……………………………………………………………………………….......82 Abstract…………………………………………………………………………........83 1. Introduction………………………………………………………….………........84 2. Materials and methods…………………………….……………………………..87 2.1. Chemicals………………………………………………………………………...88 2.2. Test of the Synthesized Compounds on Inhibiting Bacteria……………..…........88 2.3. MIC Measurements …………………………………………………..….............89 2.4. CC50 measurements. ……………………………………………………..…........90 2.5. Cloning, Expression, and Purification of SaUPPS………………..…………….90 2.6. Inhibition Assay against SaUPPS……………………..………………………..92 2.7. Molecular docking……………………………………………………………....92 2.8. Drug Likeness Analysis……………………………………………………........93 3. Results and discussion…………………………………………………………...93 3.1. Synthesis of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones 2a-j…………………………………………………………………………………..93 3.2. Evaluation of the Synthesized Compounds against Bacteria…………………...94 3.3. MIC Measurements of the Active Compounds ………………..……………….95 3.4. CC50 Measurements of the Active Compounds ………………………………...96 3.5. SaUPPS IC50 Measurements of the Active Compounds ………………………..96 3.6. Computer Modeling of 2c in SaUPPS to rationalize Structure-Activity Relationship……………………………………………….……………………..97 3.7. Drug-Likeness of 2c as Judged from Lipinski Rule of Five…………………...97 3.8. Drug-Likeness of 2c as Judged from ADMET Properties……………………....98 4. Conclusions…………………………………………………………………….....99 5. Figure Legends……………………………………………………………….....106 6. Spectral data………………………………………………………………….....120 7. References……………………………………………………………………….126 8. NMR spectra of all synthesized compounds…………………………………..135 9. List of Publications……………………………………………………………...155 | - |
| dc.language.iso | en | - |
| dc.title | 1-(4-(芳基乙烯羰基)苯基)-4-羧基-2-吡咯烷酮作為有效抗病毒和抗菌劑的合成、評估和機制 | zh_TW |
| dc.title | Synthesis, evaluation, and mechanism of 1-(4-(arylethylenyl carbonyl) phenyl)-4-carboxy-2-pyrrolidinones as potent antiviral and antibacterial agents | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 陳昭岑;謝俊結;張淑媛;王慧菁;郭致榮 | zh_TW |
| dc.contributor.oralexamcommittee | Chao-Tsen Chen;Jiun-Jie Shie;Sui-Yuan Chang;Hui-Ching Wang;Chih-Jung Kuo | en |
| dc.subject.keyword | SARS-CoV-2, | zh_TW |
| dc.subject.keyword | SARS-CoV-2, | en |
| dc.relation.page | 155 | - |
| dc.identifier.doi | 10.6342/NTU202400256 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2024-02-02 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科學研究所 | - |
| 顯示於系所單位： | 生化科學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-112-1.pdf | 5.95 MB | Adobe PDF | 檢視/開啟 |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。