Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication

被引：36

作者：

Bassetto, Marcella ^{[1
]}

Leyssen, Pieter ^{[2
]}

Neyts, Johan ^{[2
]}

Yerukhimovich, Mark M. ^{[3
]}

Frick, David N. ^{[3
]}

Brancale, Andrea ^{[1
]}

机构：

[1] Cardiff Sch Pharm & Pharmaceut Sci, King Edward VII Ave, Cardiff CF10 3NB, S Glam, Wales

[2] Univ Leuven, Rega Inst Med Res, Leuven, Belgium

[3] Univ Wisconsin Milwaukee, Dept Chem & Biochem, Milwaukee, WI 53211 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 123卷

关键词：

Structure-based virtual screening; Substituted thieno-pyrimidines; Anti-HCV activity; HEPATITIS-C VIRUS; NS3; HELICASE; ANTIVIRAL ACTIVITY; CRYSTAL-STRUCTURE; NS5A INHIBITORS; NUCLEIC-ACID; RNA; RESISTANCE; DESIGN; TRANSLOCATION;

D O I：

10.1016/j.ejmech.2016.07.035

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A structure-based virtual screening technique was applied to the study of the HCV NS3 helicase, with the aim to find novel inhibitors of the HCV replication. A library of similar to 450000 commercially available compounds was analysed in silico and 21 structures were selected for biological evaluation in the HCV replicon assay. One hit characterized by a substituted thieno-pyrimidine scaffold was found to inhibit the viral replication with an EC50 value in the sub-micromolar range and a good selectivity index. Different series of novel thieno-pyrimidine derivatives were designed and synthesised; several new structures showed antiviral activity in the low or sub-micromolar range. (C) 2016 Elsevier Masson SAS. All rights reserved.

引用

页码：31 / 47

页数：17

共 39 条

[1]

[Anonymous], 2013, FDA APPR NEW TREATM

[2] Trypanoside, anti-tuberculosis, leishmanicidal, and cytotoxic activities of tetrahydrobenzothienopyrimidines [J].

Aponte, Jose C. ;

Vaisberg, Abraham J. ;

Castillo, Denis ;

Gonzalez, German ;

Estevez, Yannick ;

Arevalo, Jorge ;

Quiliano, Miguel ;

Zimic, Mirko ;

Verastegui, Manuela ;

Malaga, Edith ;

Gilman, Robert H. ;

Bustamante, Juan M. ;

Tarleton, Rick L. ;

Wang, Yuehong ;

Franzblau, Scott G. ;

Pauli, Guido F. ;

Sauvain, Michel ;

Hammond, Gerald B. .

BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (08) :2880-2886

[3] Hepatitis C virus replicons: potential role for drug development [J].

Bartenschlager, R .

NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (11) :911-916

[4] Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus [J].

Bassetto, Marcella ;

De Burghgraeve, Tine ;

Delang, Leen ;

Massarotti, Alberto ;

Coluccia, Antonio ;

Zonta, Nicola ;

Gatti, Valerio ;

Colombano, Giampiero ;

Sorba, Giovanni ;

Silvestri, Romano ;

Tron, Gian Cesare ;

Neyts, Johan ;

Leyssen, Pieter ;

Brancale, Andrea .

ANTIVIRAL RESEARCH, 2013, 98 (01) :12-18

[5] Dry HCl in Parallel Synthesis of Fused Pyrimidin-4-ones [J].

Bogolubsky, Andrey V. ;

Ryabukhin, Sergey V. ;

Plaskon, Andrey S. ;

Stetsenko, Svetlana V. ;

Volochnyuk, Dmitriy M. ;

Tolmachev, Andrey A. .

JOURNAL OF COMBINATORIAL CHEMISTRY, 2008, 10 (06) :858-862

[6] Antiviral activity and resistance of HCV NS5A replication complex inhibitors [J].

Gao, Min .

CURRENT OPINION IN VIROLOGY, 2013, 3 (05) :514-520

[7] Discovery of potent nucleotide-mimicking competitive inhibitors of hepatitis C virus NS3 helicase [J].

Gemma, Sandra ;

Butini, Stefania ;

Campiani, Giuseppe ;

Brindisi, Margherita ;

Zanoli, Samantha ;

Romano, Maria Pia ;

Tripaldi, Pierangela ;

Savini, Luisa ;

Fiorini, Isabella ;

Borrelli, Giuseppe ;

Novellino, Ettore ;

Maga, Giovanni .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (09) :2776-2779

[8]

Gritsenko Diana, 2015, P T, V40, P256

[9] Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism [J].

Gu, Meigang ;

Rice, Charles M. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (02) :521-528

[10] Cost Analysis of Sofosbuvir/Ribavirin Versus Sofosbuvir/Simeprevir for Genotype 1 Hepatitis C Virus in Interferon-Ineligible/Intolerant Individuals [J].

Hagan, Liesl M. ;

Sulkowski, Mark S. ;

Schinazi, Raymond F. .

HEPATOLOGY, 2014, 60 (01) :37-45

← 1 2 3 4 →