Discovery and structure-activity relationships study of novel thieno[2,3-b]pyridine analogues as hepatitis C virus inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.01.075

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 derivatives 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 in vitro (12c, EC₅₀ = 3.3 μM, SI >30.3, 12b, EC₅₀ = 3.5 μM, SI >28.6, 10l, EC₅₀ = 3.9 μM, SI >25.6, 12o, EC ₅₀ = 4.5 μM, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents.

Full text of DOI:10.1016/j.bmcl.2014.01.075

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1581–1588
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
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
⇑
Corresponding author. Tel.: +86 28 85164063; fax: +86 28 85164060.
E-mail address: yuluot@scu.edu.cn (L.-T. Yu).
http://dx.doi.org/10.1016/j.bmcl.2014.01.075
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1582
N.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1581–1588
R4
NH2
O
R4
N
NH2
R6
N
O
N
S
NH2
13
R6
R6
CF3
R6
S
d
O
O
O
O
10
d
3
4
O
R4
R4
NH2
N
a
c
O
R6
e
R6
N
R6
N
H
X
O
O
O
b
6
9
c
2
R6
N
d
R4
R4
N
NH2
O
5
O
O
O
O
f
R6
N
8
S
R6
S
7
R3
R3
CF3
CF3
R3
CF3
O
O
O
O
g
h
OH
R2
R6
N
R6
N
X
X
R6
N
X
7, 8 or 9
12
11
Scheme 1. (a) Ethyl trifluoroacetate (for 3) or ethyl acetate (for 4), sodium methoxide, methanol/THF, rt, 40–90%; (b) DMF-DMA, reflux, 100%; (c) cyanothioacetamide (for
X = S) or cyanoacetamide (for X = O), DABCO, ethanol, reflux, 70–90%; (d) DMF, KOH (10%), ethyl bromoacetate (for 7), 4-(2-chloroacetyl)morpholine (for 10) or
chloroacetamide (for 13), 60–90%; (e) Cs2CO3, DMF, 60 °C, 30–60%; (f) tert-butyl nitrite, DMF, 60 °C, 23%; (g) LiOH, H2O/THF/methanol, >90%; (h) EDCI/HOBT, DCM, amines
(the specific R2 reactant for 12a–12q have been listed in Supporting Information), 60–90%.
(DMF-DMA). Then the key building blocks pyridine-2-(1H)-thiones
CF3
NH2
3
or pyridine-2-(1H)-ones (6) were prepared by treating 1,3-diones
4
(for R4 = –CF3 and –CH3) or enaminones (for R4 = H) with cya-
O
5
nothioacetamide (for X = S) or cyanoacetamide (for X = O) in the
2
S
NH2
N
1
6
presence of triethylenediamine(DABCO) in refluxing ethanol,
respectively.10 Subsequently, condensation 6 with corresponding
a
-halogen acyls under appropriate conditions7,11 afforded 7, 9, 10
Figure 1. The structure of compound 1 and the five regions our SAR study focused
and 13, respectively. And 8 was prepared by deamination of 7 with
tert-butyl nitrite in DMF.12,13 Finally, hydrolyzation of 7, 8 and 9
gave acids 11, which were subjected to coupling reaction with var-
ious amines yielded the target compounds 12. The conformational
restriction compound 12l was synthesized via a similar routine as
shown in Scheme 2. The structures of all the tested compounds
were fully characterized by 1H NMR, 13C NMR and ESI-MS analysis.
As shown in Figure 1, our SAR study was focused on five regions
of the thienopyridine scaffold. Compounds listed in Table 1 were
firstly synthesized to survey the SAR of C2 position. The importance
of carboxamido group was revealed by the dramatic decrease of the
on.
(EC50 >20
piperidyl-4-one substituent 12f (EC50 >20
exhibited no anti-HCV activity. Although compound 12n
(EC50 = 3.3 M, ClogP = 3.26) displayed good anti-HCV activity,
the great molecule weight and its cytotoxicity (Table 5) limit the
further optimization of this compound. The most suitable substitu-
ents in C2 position in our preliminary optimization were found to
l
M,ClogP = 5.30), 12k (EC50 >20
lM, ClogP = 6.23) and
lM, ClogP = 3.26), which
l
be formyl morpholine 12c (EC50 = 3.3
lM, ClogP = 3.32) and N,N-
potency when it was replaced by a carboxyl 11a (EC50 >20
lM,
diethylformamide 12b(EC50 = 3.5 M, ClogP = 4.22), both of which
l
ClogP = 4.66) or an ester 7a (EC50 = 19.3 M, ClogP = 5.73), indicat-
l
also possessed acceptable lipophilicity.
ing that a charged or a high lipophilicity group in this position may
be disadvantageous. The introduction of various flexible alkyls
(12a–12j) or rigid aryls (12k–12n) on the carboxamido group was
well tolerated, except for two high lipophilicity compounds 12d
Subsequent modifications of S1 position, C3 position and C4
position were summarized in Tables 2 and 3. As shown in Table 2,
it is well tolerated to replace S atom at the 1-position by O atom
(Table 2 9a & 7a, 9b & 7b, 9c & 12c, 9d & 12l). Removing the amino
CF3
O
CF3
N
CF3
NH2
CN
S
O
N
c
a
O
O
S
N
H
O
Scheme 2. Synthesis routine of compound 12l: (a) ethyl trifluoroacetate, sodium methoxide, methanol/THF, rt, 51%; (c) Cyanothioacetamide, ethanol, reflux, 81%; (d) DMF,
KOH (10%), 4-(2-chloroacetyl)morpholine, 88%.

N.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1581–1588
1583
Table 1
Table 1 (continued)
Structure–activity-relationship at C2 position
Compd
R2
ClogPa
Cytotoxicity
GT-1b replicon
EC50 (lM)
b
b
CF3
CC50
(l
M)
NH2
O
N
S
R2
N
N
N
12n
3.26
>20
3.3 0.8
N
F3C
Compd
R2
ClogPa
Cytotoxicity
GT-1b replicon
b
b
CC50
>20
>20
(
lM)
EC50
8.2 1.9
>20d
(
lM)
a
CLogP was calculated using ChemBioDraw Ultra version 12.0.
The cytotoxicity CC50 test and HCV replicon luciferase reporter assay were
performed in the HCV 1b Replicon System, for details see Supporting Information.
b
1
3.96
4.66
NH2
c
The purity of compound 12e >85%.
Result of single test.
d
11a
7a
OH
O
5.73
3.16
>20
>20
19.3 2.2
8.2 0.7
in C3 position (Table 3, 12o, EC50 = 4.5
potency against the HCV replicon was retained. But when the lipo-
philic group in C4 position trifluoromethyl (12c, EC50 = 3.3
ClogP = 3.32) was replaced by methyl (12p, EC50 = 5.8
ClogP = 2.91) or H atom (12q, EC50 = 17.2 lM, ClogP = 2.41), a
lM, ClogP = 3.79), the
12a
12b
N
N
l
l
M,
M,
4.22
3.32
>20
>20
3.5 0.5
3.3 0.3
sharp loss of replicon activity was observed as the lipophilicity
decreasing, implying that a relative lipophilic group in C4 position
is crucial to the potency against HCV. Interestingly, introduction a
H atom to C4 position while retaining the 2-carboxamido resulted
in inactive compounds with high cytotoxicity (13e, EC50 >20
CC50 <0.4 M, 13f, EC50 >20 M, CC50 <0.4 M), which corre-
sponded with our previous study about specific HCC inhibitor.7
Having identified lipophilic substituent in C4 position was
important for the replicon potency, we next shifted our focus on
investigating the SAR at C6 position. A series of aryls were intro-
duced in C6 position with formyl morpholine substitution in C2 po-
sition, As can been seen in Table 4, replacing phenyl in C6 position
with other aryls (10i–10k) impaired a little on the replicon activity,
N
12c
12d
12ec
12f
lM,
O
l
l
l
N
5.30
3.31
3.26
>20
>20
>20
>20d
9.6d
N
Boc
N
N
NH
O
except for 10h (EC50 >20 lM, ClogP = 1.12), a relative hydrophilic
compound, the potency of which was absolutely lost. However
the cyclopropyl substituted analogs (7c, 10m and 13d) showed
comparable potency to corresponding phenyl substituted analogs
(7a, 12c and 1), which indicated that introduction of much smaller
substituents in C6 position might be tolerant. The replicon activity
were also reserved when introduction of different substituents at
C6 position with ethoxycarbonyl substituent in C2 position, while
a relative small substituent in this position was more potent (com-
paring 7c and 7d with 7a and 7b). Then, compounds with various
substituted phenyls at C6 position with formyl morpholine substi-
tution at C2 position were synthesized to investigate their contribu-
tion to the potency (10a–10g). All of these analogs exhibited
various level of decrease in potency. Comparing with electron-
donating substituted analogs (CH3O-substituted, 10a–10c), weak
electron-withdrawing substituted analogs (F-substituted, 10d–
10f) at C6 position were much more detrimental to the replicon
activity, which suggested that introduction an electron-shortage
aryl ring in C6 position was harmful to the anti-HCV activity, it
could also be confirmed by the loss of potency with electron defi-
>20d
N
N
12g
12h
4.35
3.88
>20
>20
5.9 1.1
11.4 1.5
N
N
12i
12j
4.06
5.73
>20
>20
7.2 0.3
5.5 0.5
S
NH
HN
12k
12l
6.23
5.87
>20
>20
>20
cient rings 3,4-dichloro phenyl(10g, EC50 >20
(10h, EC50 >20 M) as well as the retainment of potency with elec-
tron rich moieties such as thiazole(10i, EC50 = 8.9 M), thiophene
(10j, EC50 = 6.5 M) and furan (10k, EC50 = 9.6 M), in C6 position.
lM) and pyrazinyl
l
l
HN
N
l
l
8.2 1.4
S
Finally, the comformational restriction analogue 10l (EC50 = 3.9
ClogP = 3.78) were similar in potency to 12c (EC50 = 3.3
ClogP = 3.32), suggesting that the torsion angle between the thie-
nopyridine and benzene ring was also well tolerated.
l
l
M,
M,
12m
5.28
>20
12.5 2.2
To further study the cytotoxicity, the most potent compounds
(Table 5) were selected to evaluate their cytotoxicity against
Huh7 and two other normal cell lines, HEK 293 and LO2, by MTT
S

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N.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1581–1588
Table 2
Structure–activity-relationship at S1 position
CF3
NH2
O
X
R2
R6
N
Compd
X
R2
R6
ClogPa
Cytotoxicity
GT-1b replicon
EC50 M)
CC50
(lM)
(l
O
9a
7a
9b
7b
O
S
5.14
5.73
5.03
5.61
>20
6.8 0.2
19.3 2.2
18.5 3.0
10.0 0.8
O
O
O
N
>20
>20
>20
O
S
S
S
9c
O
S
2.73
3.32
>20
>20
11.2 1.2
3.3 0.3
O
O
N
12c
HN
9d
O
S
5.27
5.87
>20
>20
9.8 1.4
8.2 1.4
S
S
HN
12l
a
CLogP was calculated using ChemBioDraw Ultra version 12.0.
Table 3
Structure–activity-relationship at C3 and C4 position
R4
N
R3
O
S
R2
R6
Compd
12c
R6
R4
R3
R2
ClogPa
Cytotoxicity
GT-1b replicon
EC50 (lM)
CC50
(lM)
N
CF3
CF3
Me
H
NH2
H
3.32
3.79
2.91
2.41
3.97
3.07
>20
3.3 0.3
4.5 0.5
5.8 0.8
17.2b
O
O
O
O
N
N
N
12o
>20
>20
>20
>20
<0.4
12p
12q
13a
NH2
NH2
NH2
NH2
CF3
H
NH2
NH2
4.0 1.5
O
O
13e
>20b

N.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1581–1588
1585
Table 3 (continued)
Compd
R6
R4
CF3
H
R3
R2
ClogPa
3.97
Cytotoxicity
GT-1b replicon
EC50 M)
CC50
(lM)
(l
O
13b
13f
NH2
NH2
NH2
NH2
>20
45%@20
>20b
l
Mc
O
3.07
<0.4
>20
O
O
13c
CF3
NH2
NH2
NH2
NH2
3.41
2.51
14.3 1.4
13g
H
>20
>20b
a
CLogP was calculated using ChemBioDraw Ultra version 12.0.
Result of single test.
The inhibition rate at 20 lM concentration of single test.
b
c
Table 4
Structure–activity-relationship at C6 position
CF3
N
NH2
O
S
R2
R6
Compd
12c
R6
R2
ClogPa
Cytotoxicity
GT-1b replicon
EC50 M)
CC50
(lM)
(l
N
3.32
3.33
3.33
>20
3.3 0.3
10.3 0.8
10.8 1.0
O
O
O
O
N
N
N
10a
>20
>20
O
O
10b
O
10c
2.77
>20
8.3 1.2
N
N
N
10d
10e
3.47
3.47
>20
>20
18.6 3.4
6.7 1.2
F
F
O
O
O
F
10f
3.47
>20
17.6 2.8
N
N
10g
10h
4.63
1.12
>20
>20
>20b
Cl
O
O
Cl
N
N
>20b
(continued on next page)

1586
N.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1581–1588
Table 4 (continued)
Compd
R6
R2
ClogPa
1.91
Cytotoxicity
GT-1b replicon
EC50 M)
CC50
(lM)
(l
N
N
10i
10j
10k
>20
8.9 1.5
6.5 0.7
9.6 1.1
S
S
O
O
O
N
N
3.21
>20
>20
2.71
O
CF3
N
NH2
O
N
10l
3.78
>20
3.9 1.3
S
O
N
10m
1
2.17
3.96
3.97
>20
>20
>20
9.7 0.9
8.2 1.9
4.0 1.5
O
NH2
NH2
13a
O
O
NH2
NH2
13b
13c
3.97
3.41
>20
>20
45%@20 l
Mc
O
14.3 1.4
13d
7a
2.81
5.73
>20
>20
12.2 0.9
19.3 2.2
NH2
O
O
7b
7c
5.61
4.58
5.12
>20
>20
>20
10.0 0.8
6.8 1.1
5.7 1.2
S
O
O
7d
O
a
CLogP was calculated using ChemBioDraw Ultra version 12.0.
Result of single test.
The inhibition rate at 20 lM concentration of single test.
b
c
assay in an extensive concentration range. All these compounds
except 13a showed high selectivity index (SI) and did not show
obvious cytotoxicity against all the three cell lines, indicating their
good in vitro safety profile and precluding the possibility that their
anti-HCV activity was due to their cytotoxicity.
Thienopyridine derivatives have been reported for various bio-
logical activities, one important biological activity was being as IKK
inhibitors.8c A recent report has shown that chemical inhibitors of
which suggested that IKKa could not mediate the HCV inhibition
activity of these compounds and the precise action mechanism of
these compounds need to be further investigated.
In conclusion, our study has identified novel thieno[2,3-b]pyri-
dine analogues as inhibitors of HCV. Previous cell-based screening
of our privileged small molecule library led to the discovery of
compound 1 characterized by a thienopyridine core. SAR studys
on five regions of the hit were carried out to improve the anti-
HCV potency. Four compounds 10l, 12b, 12c, 12o showed good
antiviral potency and high selectivity index(SI). The detailed SARs
research showed that the modifications in S1- and C3-positions
had relative small effect on the potency, while the substituents
in C2-, C4- and C6-position would significantly influence the activ-
ity. Although the mechanism of them is yet to be discovered, our
preliminary optimization of this class of compounds had provided
IKK
sis.14 To investigate whether the anti-HCV activity of above-
mentioned compounds was mediated by IKK inhibition, one of
the most related compound 13a (EC50 = 4.0 M) was selected for
evaluating the kinase inhibition activity on IKK and its homolog
IKKb. Disappointing, 13a only displayed inhibition rates of 7%
and 6% for IKK and IKKb at 10 M concentration, respectively,
a could suppress HCV infection and IKKa–induced lipogene-
a
l
a
a
l

N.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1581–1588
1587
Table 5
The cytotoxicity and selectivity index (SI)a of selected compounds against Huh7/HEK293/LO2 cell lines
Compd
Structure
EC50
(lM)
CC50 (lM)
Huh7 (SIa)
HEK293
LO2
CF3
NH2
O
N
10l
3.9 1.3
>100 (>25.6)
72.7 5.5
>100
S
N
O
CF3
NH2
O
12b
12c
3.5 0.5
>100 (>28.6)
>100 (>30.3)
>100
>100
S
N
N
CF3
NH2
O
N
3.3 0.3
85.1 7.7
94.4 5.3
S
N
O
CF3
NH2
O
N
S
N
12n
3.3 0.8
45.2 5.7 (13.7)
28.0 3.8
40.7 4.8
N
N
N
F3C
CF3
N
O
N
12o
13a
4.5 0.5
>100 (>22.2)
92.6 6.5
>100
S
O
CF3
NH2
O
4.0 1.5
46.4 8.3 (11.6)
24.7 3.4
26.2 4.1
S
NH2
N
O
a
SI: selectivity index = CC50/EC50. As all these compounds described in this study were evaluated for inhibition of HCV subgenomic RNA replication using an Huh-7 derived
cell line, the selectivity index was just calculated for this cell line.
2. Fried, M. W.; Shiffman, M. L.; Reddy, K. R.; Smith, C.; Marinos, G.; Gonçales,
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Lin, A.; Hoffman, J.; Yu, J. N. Eng. J. Med. 2002, 347, 975.
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Acknowledgments
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Xiang, M. L.; Song, X. R.; Yang, S. Y.; Yu, L. T.; Wei, Y. Q.; Zhao, Y. L.; Yang, L.
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This work was supported by The National Science and Technol-
ogy Major Project of China (2012ZX09103101-079). We thank
Changzhou Yinsheng Pharmaceutical Co., Ltd for their technical
and financial support. We also thank Lei Li of State Key Laboratory
of Biotherapy (Sichuan University) for NMR measurements.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.01.
075.
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desire compound can not be got in this method. It seems like that the