Nghiên cứu mối quan hệ cấu trúc–hoạt tính của các dẫn xuất quinoxalin-2(1H)-one chứa thiazol-2-amine đối với virus viêm gan C dẫn đến sự phát hiện của BH6870

Molecular Diversity - Tập 19 - Trang 829-853 - 2015
Qi-Fei Zhong1, Rui Liu1, Gang Liu1,2
1Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
2Tsinghua-Peking Center for Life Sciences and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, People’s Republic of China

Tóm tắt

Nhiễm virus viêm gan C mạn tính đại diện cho một vấn đề nghiêm trọng về sức khỏe cộng đồng toàn cầu, thường dẫn đến xơ gan, xơ hóa, và cuối cùng là ung thư tế bào gan. Dựa trên phát hiện trước đó của hợp chất dẫn đầu 2 (Liu et al. J Med Chem 54:5747–5768, 2011), 35 dẫn xuất quinoxalinone mới đã được khảo sát trong nghiên cứu này. Khảo sát mối quan hệ cấu trúc–hoạt tính (SAR) cho thấy hợp chất BH6870 (36) có tiềm năng chống HCV cao (EC₅₀ = 0.21 μM) và chỉ số an toàn tế bào tốt (SI = 47.19). Phân tích SAR chỉ ra rằng quinoxalin-2(1H)-one chứa nhóm thiazol-2-amine với thế 4-aryl là tối ưu cho hoạt tính kháng virus. Việc giới thiệu một tác nhân nhận liên kết hydro (như nhóm este hoặc amide) tại vị trí C-3 của quinoxalin-2(1H)-one có lợi cho hoạt tính kháng virus, và đặc biệt, amide N,N-disubstituted vượt trội hơn nhiều so với amide N-monosubstituted. Việc bổ sung nhiều hơn một halogen (nguyên tử flo hoặc clo) hoặc một nhóm thu hút electron mạnh trên vòng benzene của nhóm thiazole-phenyl có thể làm giảm mật độ điện tử hơn nữa và dẫn đến sự mất hoạt tính một cách đáng kể. Nhóm NH của moiety lactam rõ ràng là cần thiết cho hoạt tính chống HCV. Thiết kế và tổng hợp các dẫn xuất quinoxalin-2(1H)-one như là các chất ức chế HCV nhỏ phân tử không nucleoside mới. BH6870 (36), thể hiện tiềm năng kháng virus cao hơn và chỉ số an toàn tế bào tốt, đã được xác định.

Từ khóa


Tài liệu tham khảo

Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362. doi:10.1126/science.2523562 Tan SL, Pause A, Shi Y, Sonenberg N (2002) Hepatitis C therapeutics: current status and emerging strategies. Nat Rev Drug Discov 1:867–881. doi:10.1038/nrd937 Shepard CW, Finelli L, Alter MJ (2005) Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5:558–567. doi:10.1016/S1473-3099(05)70216-4 Simmonds P (1998) Variability of the hepatitis C virus genome. Curr Stud Hematol Blood Transfus 62:38–63. doi:10.1159/000060468 Zein NN (2000) Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 13:223–235. doi:10.1128/CMR.13.2.223-235.2000 World Health Organization (2013) Hepatitis C fact sheet no. 164. http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed July 2013 Moradpour D, Penin F, Rice CM (2007) Replication of hepatitis C virus. Nat Rev Microbiol 5:453–463. doi:10.1038/nrmicro1645 Ghany MG, Strader DB, Thomas DL, Seeff LB (2009) Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49:1335–1374. doi:10.1002/hep.22759 Lemon SM, McKeating JA, Pietschmann T, Frick DN, Glenn JS, Tellinghuisen TL, Symons J, Furman PA (2010) Development of novel therapies for hepatitis C. Antivir Res 86:79–92. doi:10.1016/j.antiviral.2010.02.003 Pockros PJ (2011) Drugs in development for chronic hepatitis C: a promising future. Expert Opin Biol Ther 11:1611–1622. doi:10.1517/14712598.2011.627851 Welsch C, Jesudian A, Zeuzem S, Jacobson I (2012) New direct-acting antiviral agents for the treatment of hepatitis C virus infection and perspectives. Gut 61:i36–i46. doi:10.1136/gutjnl-2012-302144 Fusco DN, Chung RT (2012) Novel therapies for hepatitis C: insights from the structure of the virus. Annu Rev Med 63:373–387. doi:10.1146/annurev-med-042010-085715 Asselah T, Marcellin P (2012) Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow. Liver Int 32:88–102. doi:10.1111/j.1478-3231.2011.02699.x Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364:1195–1206. doi:10.1056/NEJMoa1010494 Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R (2011) Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 364:1207–1217. doi:10.1056/NEJMoa1009482 Malcolm BA, Liu R, Lahser F, Agrawal S, Belanger B, Butkiewicz N, Chase R, Gheyas F, Hart A, Hesk D, Ingravallo P, Jiang C, Kong R, Lu J, Pichardo J, Prongay A, Skelton A, Tong X, Venkatraman S, Xia E, Girijavallabhan V, Njoroge FG (2006) SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 50:1013–1020. doi:10.1128/AAC.50.3.1013-1020.2006 Perni RB, Almquist SJ, Byrn RA, Chandorkar G, Chaturvedi PR, Courtney LF, Decker CJ, Dinehart K, Gates CA, Harbeson SL, Heiser A, Kalkeri G, Kolaczkowski E, Lin K, Luong YP, Rao BG, Taylor WP, Thomson JA, Tung RD, Wei Y, Kwong AD, Lin C (2006) Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother 50:899–909. doi:10.1128/AAC.50.3.899-909.2006 McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ (2009) Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 360:1827–1838. doi:10.1056/NEJMoa0806104 Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S (2009) Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 360:1839–1850. doi:10.1056/NEJMoa0807650 Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S (2011) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364:2405–2416. doi:10.1056/NEJMoa1012912 Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Müllhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M (2011) Telaprevir for retreatment of HCV infection. N Engl J Med 364:2417–2428. doi:10.1056/NEJMoa1013086 Kwong AD, Kauffman RS, Hurter P, Mueller P (2011) Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol 29:993–1003. doi:10.1038/nbt.2020 Sheridan C (2011) New Merck and Vertex drugs raise standard of care in hepatitis C. Nat Biotechnol 29:553–554. doi:10.1038/nbt0711-553 Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson I, Marcellin P, Manns M, Nikitin I, Poordad F, Sherman M, Zeuzem S, Scott J, Gilles L, Lenz O, Peeters M, Sekar V, De Smedt G, Beumont-Mauviel M (2013) Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology 58:1918–1929. doi:10.1002/hep.26641 Hayashi N, Seto C, Kato M, Komada Y, Goto S (2014) Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol 49:138–147. doi:10.1007/s00535-013-0875-1 Maekawa S, Enomoto N (2014) Once-daily simeprevir in combination with pegylated-interferon and ribavirin: a new horizon in the era of direct-acting antiviral agent therapy for chronic hepatitis C. J Gastroenterol 49:163–164. doi:10.1007/s00535-013-0926-7 Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, Hezode C, Hirschfield GM, Jacobson I, Nikitin I, Pockros PJ, Poordad F, Scott J, Lenz O, Peeters M, Sekar V, De Smedt G, Sinha R, Beumont-Mauviel M (2014) Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 146:430–441. doi:10.1053/j.gastro.2013.10.058 Rosenquist A, Samuelsson B, Johansson PO, Cummings MD, Lenz O, Raboisson P, Simmen K, Vendeville S, de Kock H, Nilsson M, Horvath A, Kalmeijer R, de la Rosa G, Beumont-Mauviel M (2014) Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor. J Med Chem 57:1673–1693. doi:10.1021/jm401507s Kanda T, Yokosuka O, Omata M (2013) Treatment of hepatitis C virus infection in the future. Clin Transl Med 2:9. doi:10.1186/2001-1326-2-9 Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse AW, Müllhaupt B, Schuchmann M, Bourlière M, Buti M, Roberts SK, Gane EJ, Stern JO, Vinisko R, Kukolj G, Gallivan JP, Böcher WO, Mensa FJ (2013) Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med 369:630–639. doi:10.1056/NEJMoa1213557 Nishiguchi S, Sakai Y, Kuboki M, Tsunematsu S, Urano Y, Sakamoto W, Tsuda Y, Steinmann G, Omata M (2014) Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection. Liver Int 34:78–88. doi:10.1111/liv.12254 Manns MP, Gane E, Rodriguez-Torres M, Stoehr A, Yeh CT, Marcellin P, Wiedmann RT, Hwang PM, Caro L, Barnard RJ, Lee AW (2012) Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study. Hepatology 56:884–893. doi:10.1002/hep.25743 Lawitz E, Rodriguez-Torres M, Stoehr A, Gane EJ, Serfaty L, Bhanja S, Barnard RJ, An D, Gress J, Hwang P, Mobashery N (2013) A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment. J Hepatol 59:11–17. doi:10.1016/j.jhep.2013.02.008 Barnard RJ, McHale CM, Newhard W, Cheney CA, Graham DJ, Himmelberger AL, Strizki J, Hwang PM, Rivera AA, Reeves JD, Nickle D, DiNubile MJ, Hazuda DJ, Mobashery N (2013) Emergence of resistance-associated variants after failed triple therapy with vaniprevir in treatment-experienced non-cirrhotic patients with hepatitis C-genotype 1 infection: a population and clonal analysis. Virology 443:278–284. doi:10.1016/j.virol.2013.05.013 Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T, Grasela DM, Pasquinelli C (2012) Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 366:216–224. doi:10.1056/NEJMoa1104430 McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G, Levine S, Chaniewski S, Yu F, Barry D, Chen C, Lee MS, Mosure K, Sun LQ, Sinz M, Meanwell NA, Colonno RJ, Knipe J, Scola P (2012) Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032). Antimicrob Agents Chemother 56:5387–5396. doi:10.1128/AAC.01186-12 Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Micolochick Steuer HM, Niu C, Otto MJ, Furman PA (2010) Discovery of a \(\beta \)-d-2\(^{\prime }\)-deoxy-2\(^{\prime }\)-\(\alpha \)-fluoro-2\(^{\prime }\)-\(\beta \)-\(C\)-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 53:7202–7218. doi:10.1021/jm100863x Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (2013) Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 368:34–44. doi:10.1056/NEJMoa1208953 Le Pogam S, Seshaadri A, Ewing A, Kang H, Kosaka A, Yan JM, Berrey M, Symonds B, De La Rosa A, Cammack N, Nájera I (2010) RG7128 alone or in combination with pegylated interferon-\(\upalpha \)2a and ribavirin prevents hepatitis C virus (HCV) replication and selection of resistant variants in HCV-infected patients. J Infect Dis 202:1510–1519. doi:10.1086/656774 Guedj J, Dahari H, Shudo E, Smith P, Perelson AS (2012) Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128). Hepatology 55:1030–1037. doi:10.1002/hep.24788 LaPlante SR, Bös M, Brochu C, Chabot C, Coulombe R, Gillard JR, Jakalian A, Poirier M, Rancourt J, Stammers T, Thavonekham B, Beaulieu PL, Kukolj G, Tsantrizos YS (2014) Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors: discovery of deleobuvir (BI 207127). J Med Chem 57:1845–1854. doi:10.1021/jm4011862 Larrey D, Lohse AW, Trepo C, Bronowicki JP, Arastéh K, Bourlière M, Calleja JL, Stern JO, Nehmiz G, Abdallah N, Berger KL, Marquis M, Steffgen J, Kukolj G (2013) Antiviral effect, safety, and pharmacokinetics of five-day oral administration of deleobuvir (BI 207127), an investigational hepatitis C virus RNA polymerase inhibitor, in patients with chronic hepatitis C. Antimicrob Agents Chemother 57:4727–4735. doi:10.1128/AAC.00565-13 Shih IH, Vliegen I, Peng B, Yang H, Hebner C, Paeshuyse J, Pürstinger G, Fenaux M, Tian Y, Mabery E, Qi X, Bahador G, Paulson M, Lehman LS, Bondy S, Tse W, Reiser H, Lee WA, Schmitz U, Neyts J, Zhong W (2011) Mechanistic characterization of GS-9190 (tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase. Antimicrob Agents Chemother 55:4196–4203. doi:10.1128/AAC.00307-11 Wong KA, Xu S, Martin R, Miller MD, Mo H (2012) Tegobuvir (GS-9190) potency against HCV chimeric replicons derived from consensus NS5B sequences from genotypes 2b, 3a, 4a, 5a, and 6a. Virology 429:57–62. doi:10.1016/j.virol.2012.03.025 Hebner CM, Han B, Brendza KM, Nash M, Sulfab M, Tian Y, Hung M, Fung W, Vivian RW, Trenkle J, Taylor J, Bjornson K, Bondy S, Liu X, Link J, Neyts J, Sakowicz R, Zhong W, Tang H, Schmitz U (2012) The HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function. PLoS One 7:e39163. doi:10.1371/journal.pone.0039163 Rong L, Dahari H, Ribeiro RM, Perelson AS (2010) Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2:30ra32. doi:10.1126/scitranslmed.3000544 Legrand-Abravanel F, Nicot F, Izopet J (2010) New NS5B polymerase inhibitors for hepatitis C. Expert Opin Investig Drugs 19:963–975. doi:10.1517/13543784.2010.500285 Wu S, Kanda T, Nakamoto S, Imazeki F, Yokosuka O (2013) Hepatitis C virus protease inhibitor-resistance mutations: our experience and review. World J Gastroenterol 19:8940–8948. doi:10.3748/wjg.v19.i47.8940 Liu R, Huang Z, Murray MG, Guo X, Liu G (2011) Quinoxalin-2(1\(H\))-one derivatives as inhibitors against hepatitis C virus. J Med Chem 54:5747–5768. doi:10.1021/jm200394x Chen BC, Zhao R, Bednarz MS, Wang B, Sundeen JE, Barrish JC (2004) A new strategy for the construction of the imidazo[1,5-\(a\)]quinoxalin-4-one ring system and its application to the efficient synthesis of BMS-238497, a novel and potent Lck inhibitor. J Org Chem 69:977–979. doi:10.1021/jo0355348 Kim HJ, Sharon A, Bal C, Wang J, Allu M, Huang Z, Murray MG, Bassit L, Schinazi RF, Korba B, Chu CK (2009) Synthesis and anti-hepatitis B virus and anti-hepatitis C virus activities of 7-deazaneplanocin A analogues in vitro. J Med Chem 52:206–213. doi:10.1021/jm801418v Patani GA, LaVoie EJ (1996) Bioisosterism: a rational approach in drug design. Chem Rev 96:3147–3176. doi:10.1021/cr950066q