Bioorganic & Medicinal Chemistry Letters
Discovery and structure–activity relationships study of novel
thieno[2,3-b]pyridine analogues as hepatitis C virus inhibitors
Ning-Yu Wang a, Wei-Qiong Zuo a, Ying Xu a, Chao Gao a, Xiu-Xiu Zeng b, Li-Dan Zhang a,b, Xin-Yu You a,b
,
Cui-Ting Peng a,b, Yang Shen c, Sheng-Yong Yang a, Yu-Quan Wei a, Luo-Ting Yu a,
⇑
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
b Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China
c WuXi PharmaTech Co., Ltd., No. 1 Building, 288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone, Shanghai 200131, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for
combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine deriva-
tives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a
cell-based screening of our privileged small molecule library. And then, structure activity relationship
study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity
Received 16 October 2013
Revised 10 January 2014
Accepted 23 January 2014
Available online 3 February 2014
in vitro (12c, EC50 = 3.3
lM, SI >30.3, 12b, EC50 = 3.5 lM, SI >28.6, 10l, EC50 = 3.9 lM, SI >25.6, 12o,
Keywords:
EC50 = 4.5 M, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated,
l
Hepatitis C virus (HCV)
Thieno[2,3-b]pyridine
Structure activity relationship (SAR)
our preliminary optimization of this class of compounds had provided us a start point to develop new
anti-HCV agents.
Ó 2014 Elsevier Ltd. All rights reserved.
It is estimated that nearly 3% of the population all over the
world (ꢀ170 million individuals) are chronically infected by hepa-
titis C virus (HCV), which present high risk of developing liver cir-
rhosis and hepatocellular carcinoma.1 Unfortunately, there is no
vaccine hitherto available for preventing HCV infection. And the
standard strategy for treatment of HCV infection, a combination
of PEG-interferon and ribavirin, is effective for only half of people
infected by HCV genotype 1,2 which accounts for the majority of
infections in the U.S., Europe, Asia and Latin America.3 This combi-
nation therapy is lengthy and often accompanied by serious side
effects including neuropsychiatric events, flu-like symptoms and
haematological toxicities.1 Two NS3/4A protease inhibitors ap-
proved by the US Food and Drug Administration (FDA) in 2011,
Boceprevir (SCH503034) and Telaprevir (VX-950), could supple-
ment, rather than replace the standard treatment.4 The triple ther-
apy, combination either of the above-mentioned protease
of hepatitis C therapy, are still in advanced phase of development.6
So there is still a long way to go in the battle with hepatitis C, and
new anti-HCV agents are urgently needed to replace instead of
supplement the traditional strategy.
Our research group has been interested in the design, screening,
synthesis and biological evaluation of anti-HCV agents. In a previ-
ous cell-based screening of our privileged small molecule library, a
thienopyridine derivative (compound 1) which belonged to the
continuation of our study on specific hepatocellular carcinoma
(HCC) inhibitors,7 exhibited moderate anti-HCV activity, with an
EC50 of 8.2 lM in the HCV Replicon Assay and did not exhibit obvi-
ous cytotoxicity on Huh 7 cell line. Thienopyridine derivatives is an
important subunit in bioactive molecules,7,8 but their anti-HCV
activity was seldom reported. To the best of our knowledge, the
anti-HCV activity of thienopyridine derivatives is first reported
by our group. Detailed SAR investigation of compound 1 was car-
ried out for the purpose of developing compounds with improved
anti-HCV efficacy and drug-like property. Herein we report the
synthesis, the structure-activity relationship study and prelimin-
ary biological evaluation of this new class of anti-HCV agents.
The compounds described in this study were synthesized
according to Scheme 1. Briefly, treatment of ketone (2) with ethyl
trifluoroacetate or ethyl acetate under strong basic condition9
afford 1,3-diones 3 or 4, while enaminones 5 were furnished by
condensation 2 with N,N-dimethylformamide dimethyl acetal
inhibitors with PEG-interferon
a and ribavirin, increases the
sustained virologic response (SVR), a cure mark for hepatitis C
treatment, from 50% to 70% in HCV genotype 1 infected people.
However, it could hardly shorten the long treatment cycle and
sometimes appends a few more side effects.5 All-Oral interferon-
free regimens, which were considered to be the final destination
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Corresponding author. Tel.: +86 28 85164063; fax: +86 28 85164060.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.