The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus

被引：79

作者：

Chen, Yue-Lei ^{[1
]}

Tang, Jing ^{[1
]}

Kesler, Matthew J. ^{[1
]}

Sham, Yuk Y. ^{[1
]}

Vince, Robert ^{[1
]}

Geraghty, Robert J. ^{[1
]}

Wang, Zhengqiang ^{[1
]}

机构：

[1] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 01期

关键词：

2-Hydroxyisoquinoline-1,3-dione; Hepatitis C virus (HCV); NS5B polymerase; NS3; SERINE-PROTEASE; NONNUCLEOSIDE INHIBITORS; REVERSE-TRANSCRIPTASE; NATURAL-HISTORY; NS5B POLYMERASE; DUAL INHIBITORS; DISCOVERY; POTENT; 2ND-GENERATION; INTEGRASE;

D O I：

10.1016/j.bmc.2011.10.058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：467 / 479

页数：13

共 51 条

[1] Natural history of hepatitis C virus infection [J].

Amarapurkar, D .

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 2000, 15 :E105-E110

[2] Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor [J].

Arasappan, Ashok ;

Bennett, Frank ;

Bogen, Stephane L. ;

Venkatraman, Srikanth ;

Blackman, Melissa ;

Chen, Kevin X. ;

Hendrata, Siska ;

Huang, Yuhua ;

Huelgas, Regina M. ;

Nair, Latha ;

Padilla, Angela I. ;

Pan, Weidong ;

Pike, Russell ;

Pinto, Patrick ;

Ruan, Sumei ;

Sannigrahi, Mousumi ;

Velazquez, Francisco ;

Vibulbhan, Bancha ;

Wu, Wanli ;

Yang, Weiying ;

Saksena, Anil K. ;

Girijavallabhan, Viyyoor ;

Shih, Neng-Yang ;

Kong, Jianshe ;

Meng, Tao ;

Jin, Yan ;

Wong, Jesse ;

McNamara, Paul ;

Prongay, Andrew ;

Madison, Vincent ;

Piwinski, John J. ;

Cheng, Kuo-Chi ;

Morrison, Richard ;

Malcolm, Bruce ;

Tong, Xiao ;

Ralston, Robert ;

Njoroge, F. George .

ACS MEDICINAL CHEMISTRY LETTERS, 2010, 1 (02) :64-69

[3] Toward Second Generation Hepatitis C Virus NS3 Serine Protease Inhibitors: Discovery of Novel P4 Modified Analogues with Improved Potency and Pharmacokinetic Profile [J].

Arasappan, Ashok ;

Padilla, Angela I. ;

Jao, Edwin ;

Bennett, Frank ;

Bogen, Stephane L. ;

Chen, Kevin X. ;

Pike, Russell E. ;

Sannigrahi, Mousumi ;

Soares, Joana ;

Venkatraman, Srikanth ;

Vibulbhan, Bancha ;

Saksena, Anil K. ;

Girijavallabhan, Viyyoor ;

Tong, Xiao ;

Cheng, Kuo-Chi ;

Njoroge, F. George .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (09) :2806-2817

[4]

Beaulieu PL, 2007, CURR OPIN INVEST DR, V8, P614

[5] Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection [J].

Beaulieu, Pierre L. .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (02) :145-164

[6] The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir®: A change in direction in the search for a second generation HCV NS3 protease inhibitor [J].

Bennett, Frank ;

Huang, Yuhua ;

Hendrata, Siska ;

Lovey, Raymond ;

Bogen, Stephane L. ;

Pan, Weidong ;

Guo, Zhuyan ;

Prongay, Andrew ;

Chen, Kevin X. ;

Arasappan, Ashok ;

Venkatraman, Srikanth ;

Velazquez, Francisco ;

Nair, Latha ;

Sannigrahi, Mousumi ;

Tong, Xiao ;

Pichardo, John ;

Cheng, Kuo-Chi ;

Girijavallabhan, Viyyoor M. ;

Saksena, Anil K. ;

Njoroge, F. George .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (08) :2617-2621

[7] Magnesium Chelating 2-Hydroxyisoquinoline-1,3(2H,4H)-diones, as Inhibitors of HIV-1 Integrase and/or the HIV-1 Reverse Transcriptase Ribonuclease H Domain: Discovery of a Novel Selective Inhibitor of the Ribonuclease H Function [J].

Billamboz, Muriel ;

Bailly, Fabrice ;

Lion, Cedric ;

Touati, Nadia ;

Vezin, Herve ;

Calmels, Christina ;

Andreola, Marie-Line ;

Christ, Frauke ;

Debyser, Zeger ;

Cotelle, Philippe .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (06) :1812-1824

[8] 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: Influence of the alkylation of position 4 [J].

Billamboz, Muriel ;

Bailly, Fabrice ;

Lion, Cedric ;

Calmels, Christina ;

Andreola, Marie-Line ;

Witvrouw, Myriam ;

Christ, Frauke ;

Debyser, Zeger ;

De Luca, Laura ;

Chimirri, Alba ;

Cotelle, Philippe .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2011, 46 (02) :535-546

[9] Design, Synthesis, and Biological Evaluation of a Series of 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and the Reverse Transcriptase RNase H Domain [J].

Billamboz, Muriel ;

Bailly, Fabrice ;

Barreca, Maria Letizia ;

De Luca, Laura ;

Mouscadet, Jean-Francois ;

Calmels, Christina ;

Andreola, Marie-Line ;

Witvrouw, Myriam ;

Christ, Frauke ;

Debyser, Zeger ;

Cotelle, Philippe .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (24) :7717-7730

[10]

Blight K.J., 2006, C VIRUSES, P311

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