Design and synthesis of indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-1-carbothioic acid amide derivatives as novel HCV inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.06.009

An efficient synthetic methodology to provide indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-1-carbothioic acid amide derivatives is described. These conformationally restricted heterobicyclic scaffolds were evaluated as a novel class of HCV inhibitors. Introduction of an acyl group at the NH₂ of the thiourea moiety has been found to enhance inhibitory activity. The chain length and the position of the alkyl group on the indoline aromatic ring markedly influenced anti-HCV activity. The indoline scaffold was more potent than the corresponding indole and tetrahydroquinoline scaffolds and analogue 31 displayed excellent activity (EC₅₀ = 510 nM) against HCV without significant cytotoxicity (CC₅₀ >50 μM).

Full text of DOI:10.1016/j.bmcl.2009.06.009

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4134–4138
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quino-
line-1-carbothioic acid amide derivatives as novel HCV inhibitors
Iou-Jiun Kang, Li-Wen Wang, Sheng-Ju Hsu, Chung-Chi Lee, Yen-Chun Lee, Yen-Shian Wu, Tsu-An Hsu,
*
*
Andrew Yueh , Yu-Sheng Chao, Jyh-Haur Chern
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic methodology to provide indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-
1-carbothioic acid amide derivatives is described. These conformationally restricted heterobicyclic scaf-
folds were evaluated as a novel class of HCV inhibitors. Introduction of an acyl group at the NH2 of the
thiourea moiety has been found to enhance inhibitory activity. The chain length and the position of
the alkyl group on the indoline aromatic ring markedly influenced anti-HCV activity. The indoline scaffold
was more potent than the corresponding indole and tetrahydroquinoline scaffolds and analogue 31 dis-
Received 17 February 2009
Revised 19 May 2009
Accepted 1 June 2009
Available online 6 June 2009
Keyword:
KCV inhibitors
played excellent activity (EC50 = 510 nM) against HCV without significant cytotoxicity (CC50 >50 lM).
Ó 2009 Elsevier Ltd. All rights reserved.
Hepatitis C virus (HCV) is a positive-strand RNA virus that was
first identified in 1989.1 Six major genotypes and many subtypes
have been described for this member of the Flaviviridae family.2
An estimated more than 170 million people worldwide are chron-
ically infected with HCV.3 Most people with chronic hepatitis C
have no symptoms but may lead to liver cirrhosis and hepatocellu-
lar carcinoma (HCC) within the next decade.4 HCV infection is, in
many countries, the leading reason for liver transplants.5 There is
currently no vaccine or effective therapy against HCV.6 The stan-
dard of care for HCV infection is a combination therapy of injected
pegylated interferon plus oral ribavirin. However, this therapy in
patients with genotype 1 has limited efficacy and suffers from seri-
ous side effects.7 Therefore, there is an urgent need for the devel-
opment of more effective and better tolerated anti-HCV agents.
Recently, from a high throughput screening of our in-house
compound collection by using a cell-based HCV replicon assay,8
we identified an interesting thiourea compound 19 (Fig. 1) with
HCV NS4A protein,15 resulting in altered protein composition and
inactivation of the replicase complex. Therefore, it is possible that
our compounds 1 and 2 also target at the HCV NS4A protein. Fur-
ther mechanism studies on this class of compounds are currently
under active investigation and will be reported in due courses.
In this Letter, we report the synthesis of these scaffolds and
explore the structure–activity relationship requirements for these
new scaffolds.
The tetrahydroquinoline 7 was generated form commercially
available 1-naphthol 3 (Scheme 1). Nucleophilic substitution with
1,5-dibromopentane afforded compound 4. Subsequent O-alkyl-
ation of 5-hydroxyquinoline with compound 4 in the presence of
potassium carbonate in NMP (1-methyl-2-pyrrolidine) at 90 °C gave
compound5. Selectivereductionof quinoline5with sodiumborohy-
dride–nickelous chloride (NaBH4–NiCl2) system10 in methanol pro-
vided the tetrahydroquinoline 6. The desired compound 7 was then
obtained by treatment of 6 with potassium thiocyanate11 in ethanol.
Indolines 12 and 14 were synthesized by the method summa-
rized in Scheme 2. In the presence of potassium carbonate,
4-hydroxyindole 8 can undergo nucleophilic substitution with
1,5-dibromopentane to give compound 9. Subsequent O-alkylation
an EC50 of 0.49 lM. While the preliminary structure–activity rela-
tionship was explored retaining the aryl thiourea moiety, we were
interested in expanding our optimization efforts to heterobicyclic
scaffolds 2 like indole, indoline, and tetrahydroquinoline. Figure
1 is a schematic representation of our design strategy.
Tough the mechanism of this class of compounds is not yet fully
understood, they show significant activity in a cell-based HCV rep-
licon assay. Recently, it was reported that the structurally related
acylthiourea compound ACH-80615 showed potent anti-HCV activ-
ity with a unique mechanism of action. It selectively binds to the
R1
S
S
R2
N
H2N
N
H
O
N
n
H
1
2
* Corresponding author. Tel.: +886 37 246 166x35716; fax: +886 37 586 456
(J.-H.C.).
E-mail address: jhchen@nhri.org.tw (J.-H. Chern).
Figure 1. From aryl thiourea 1 to heterobicyclic scaffold 2.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.009

I.-J. Kang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4134–4138
4135
OH
OH
O(CH ) Br
2 5
K CO , KI
2
3
N
+
Br(CH ) Br
2 5
NMP, 90 ºC, 6 h
K CO , KI, NMP, 90 ºC, 6 h
2
3
3
4
O(CH ) O
O(CH ) O
2 5
2 5
KSCN, 2N HCl (aq)
EtOH, 100 ºC, 20 h
NaBH , NiCl .6H O
4
2
2
N
H
N
MeOH, THF, 0 ºC - rt, 1 h
5
6
O(CH ) O
2 5
N
S
NH
2
7
Scheme 1. Synthesis of tetrahydroquinoline 7.
OH
O(CH ) Br
2 5
O(CH ) O
2 5
Cl
Cl
OH
Br(CH ) Br, K CO , KI
2 5
2
3
K CO , KI
NMP, 90 ºC, 6 h
N
H
2
3
N
N
H
H
NMP, 90 ºC, 6 h
8
9
10
O(CH ) O
Cl
2 5
2M NH in MeOH
3
NaBH CN
TCDI, Et N
3
3
AcOH, rt, 8 h
50 ºC, 8 h
THF, 50 ºC, 3 h
N
H
11
O(CH ) O
2 5
Cl
N
S
12
H N
2
NaBH CN
3
PhCH O
2
PhCH O
2
AcOH, rt, 8 h
N
N
H
H
13
14
Scheme 2. Synthesis of indolines 12 and 14.
of 4-chlorophenol with compound 9 in the presence of potassium
carbonate in NMP at 90 °C afforded compound 10. Selective reduc-
tion of indole 10 and commercially available indole 13 with
sodium cyanoborohydride (NaBH3CN) in acetic acid12 gave indo-
lines 11 and 14, respectively. Treatment of 11 with 1,10-(thiocar-
bonyl)diimidazole (TCDI) in THF at 50 °C followed by reaction
with 2 M ammonia in methanol provided the target compound 12.
Indoles 16 and 18 were prepared according to the chemistry in
Scheme 3. The compound 10 was treated with KH13 in THF at room
temperature for 30 min followed by reaction with TCDI at ꢀ78 °C
afforded compound 15. The desired compound 16 was then
obtained by treatment of 15 with 25% ammonia solution in THF
at room temperature. The benzamide 17 was treated with t-BuOK
in THF at room temperature for 30 min followed by reaction with
15 in THF gave the target compound 18.
Indolines 21–51 were prepared from commercially available acyl
chloride 19, which was converted to acyl isothiocyanate 20 upon
reaction with ammonium thiocyanate (Scheme 4). Subsequent

4136
I.-J. Kang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4134–4138
O(CH ) O
2 5
Cl
TCDI
25% NH (aq)
3
KH
10
THF, rt, 30 min
THF, rt, 30 min
THF, -78 ºC, 2.5 h
N
S
N
N
15
O(CH ) O
2 5
Cl
N
S
16
H N
2
O(CH ) O
2 5
Cl
O
15
THF, 0 ºC - rt, 20 h
t-BuOK
O
Ph
NH
2
THF,rt, 30 min
N
Ph
N
17
S
H
18
Scheme 3. Synthesis of indoles 16 and 18.
4
5
O
O
14
NH SCN
4
PhCH O
2
R
Cl
R
NCS
20
6
Acetone, rt, 1 h
Acetone, rt, 8 h
N
7
S
19
HN
O
R
11
Acetone, rt, 8 h
21. 4-OCH Ph, R = Ph
2
22. 5-OCH Ph, R = Ph
2
23. 6-OCH Ph, R = Ph
2
24. 7-OCH Ph, R = Ph
2
O(CH ) O
2 5
Cl
N
36. R = 4-Me-Ph
S
HN
37. R = 4-MeO-Ph
38. R = 4-t-Bu-Ph
O
R
39. R = 4-N(CH ) -Ph
3 2
40. R = CH CH Ph
2
2
25. R = Ph
41. R = CH CH CH
3
2
2
26. R = PhO
42. R = Cyclopentyl
43. R = Cyclohexyl
44. R = 2-Naphthyl
45. R = 2-Furyl
27. R = 2-NO -Ph
2
28. R = 3-NO -Ph
2
29. R = 4-NO -Ph
2
30. R = 3-CN-Ph
31. R = 4-CN-Ph
32. R = 4-F-Ph
33. R = 4-Cl-Ph
34. R = 4-Br-Ph
46. R = 3-Furyl
47. R = 2-Thienyl
48. R = 3-Thienyl
49. R = 3-Pyridyl
50. R = 5-Isoxazolyl
35. R = 4-CF -Ph
51. R = 2-Benzothienyl
3
Scheme 4. General synthetic route to compounds 21–51.
addition of compounds 11 and 14 to the resulting acyl isothiocya-
nate 20, without isolation, gave the desired compounds 21–51.
Other indolines 54 and 57 were synthesized as shown in
Scheme 5. The benzenesulfonyl isothiocyanate 53 was prepared14
by coupling the starting benzenesulfonamide 52 with carbon disul-
fide in the presence of KOH and subsequent addition of thionyl
chloride to the resulting compound. Compound 11 was then
coupled with 53 to give the target compound 54. The desired
compound 57 was obtained through the reaction of o-phenyl
chlorothionoformate 55 with potassium thiocyanate and subse-
quent coupling of 11 with the resulting compound 56 in acetone.
The heterobicyclic compounds described herein were tested for
anti-HCV activity using an in vitro assay system that is suitable for
monitoring anti-HCV activities of compounds. This system is com-
posed of a human hepatocarcinoma cell line (Huh-7) supporting
multiplication of a HCV replicon. We examined compounds’ ability
to inhibit the replication of subgenomic HCV RNA in a HCV replicon
cell system.8 All compounds were also tested for their cytotoxicity

I.-J. Kang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4134–4138
4137
O
S
O
O
S
O
SOCl2
CS2, KOH
NH2
N
C
S
Benzene
0 ºC - rt, 2 h
NMP, 55 ºC, 8 h
52
53
O(CH2)5O
N
Cl
11
O
S
O
Acetone-CH2Cl2, 0 ºC - rt, 8 h
N
S
H
54
S
O
C
S
C
11
KSCN
N C S
O
Cl
EtOAc, rt, 6 h
Acetone, rt, 8 h
55
56
O(CH2)5O
N
Cl
S
N
C O
S
H
57
Scheme 5. Synthesis of indolines 54 and 57.
toward human Huh-7 cells. As shown in Figure 1, the aryl thiourea
moiety of 1 was converted to a conformationally restricted hetero-
bicyclic moiety 2. Initial leads for the heterobicyclic series are
disclosed in Table 1. Conformational restriction of 1 to give bicyclic
analogues (7, 12, 16) led to a significant decrease in activity. The
most potent heterobicycle was indoline 12, which showed an
EC50 of 4.71 lM and did not exhibit cytotoxicity up to 50 lM.
Dehydrogenation (16) or increase in ring size (7) decreased anti-
HCV activity by fivefold or more compared to 12.
compound was chosen for further study as it was identified to be
the most active compound thus far.
Several indolines with benzyl and alkyl substituents at the
different positions of the phenyl ring are described in Table 3.
The position of the benzyl group at the phenyl ring of indoline moi-
ety (21–24) impacted anti-HCV activity. The activity increased
from C-7 substitution (24) to C-6 substitution (23), C-5 substitu-
tion (22), and to C-4 substitution (21), the latter being the most
preferred pattern for sterically demanding substituents.
We then focused on the modifications of the indoline series. As
seen from Table 2, introduction of a benzoyl group (25) at the NH2
of the thiourea moiety resulted in a sixfold increase in activity
compared to the parent compound (12). Making the same change
to indole 16 to give 18 also showed an increase in activity. Replace-
ment of the benzoyl group of compound 25 with phenoxycarbonyl
(26), phenylsulfonyl (54), and phenoxythiocarbonyl (57) groups
resulted in a complete loss of activity, indicating the importance
The benzoyl substituent of the indoline scaffold was diversified
to further improve the anti-HCV activity (Table 4). We have intro-
duced substituents (27–39) into the phenyl ring of the benzoyl
moiety of compound 25. The 3- and 4-nitro analogues (28, 29)
were more active than the 2-nitro analogue (27). Interestingly,
the 3- and 4-cyano analogues (30, 31) exhibited potent inhibitory
activities with EC50s of 0.57 and 0.51 lM, respectively. In particu-
of the benzoyl group. Compound 25 has an EC50 of 0.79
l
M in
Table 2
the 1b replicon assay, and a CC50 of greater than 50
lM. This
Anti-HCV activity and cytotoxicity for heterobicyclic scaffolds
Cl
O
O
Table 1
Anti-HCV activity and cytotoxicity for heterobicyclic scaffolds
X
N
Ar
H
N
O
O
R
X
N
S
Compound
X
R
1b EC50
(l
M)
CC50
>50
(lM)
SIb
a
a
NH2
S
12
18
25
26
54
57
–(CH2)2–
–CH@CH–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
H
4.71 0.26
4.06 0.83
0.79 0.14
>50
>11
7
>63
>1
>1
>1
PhCO
PhCO
PhO–CO
PhSO2
PhO–CS
29.51 2.73
>50
SIb
a
a
Compound
X
Ar
1b EC50
>50
4.71 0.26
24.54 1.32
(l
M)
CC50 (lM)
>50
>50
>50
7
12
16
–(CH2)3–
–(CH2)2–
–CH@CH–
1-Naphthyl
4-Cl-Ph
4-Cl-Ph
>50
>50
>1
>11
1
>50
>50
24.71 1.18
a
a
Mean of triplicate well values. All experiments were performed at least twice.
In vitro selectivity index (CC50/EC50).
Mean of triplicate well values. All experiments were performed at least twice.
In vitro selectivity index (CC50/EC50).
b
b

4138
I.-J. Kang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4134–4138
Table 3
role in activity. Replacement of the phenyl ring (25) by a naphthyl
Anti-HCV activity and cytotoxicity for indolines 21–24
(44) or a heterocycle (45–51) resulted in slightly improved or re-
duced activity. The 2-furyl (45) and 2-thienyl (47) analogues were
more active than their 3-furyl (46) and 3-thienyl (48) isomers, but
were also somewhat more cytotoxic. The most potent inhibitor 31
from this SAR study was selected for further development of anti-
HCV agents.
4
5
R
O
6
N
7
S
HN
O
In conclusion, we have developed an efficient synthetic
methodology to provide indole-1-carbothioic acid amide, 2,3-dihy-
dro-indole-1-carbothioic acid amide, and 3,4-dihydro-2H-quino-
line-1-carbothioic acid amide that could be useful for preparing
conformationally restricted novel HCV inhibitors. Incorporation
of an aromatic acyl group at the NH2 of the thiourea moiety has
been found to enhance inhibitory activity. Substitution at the 4-po-
sition of the indoline was preferred over the 5, 6, and 7-positions.
In addition, the chain length of the alkyl group also influences anti-
HCV activity. The indoline scaffold is clearly favored over the
corresponding indole and tetrahydroquinoline scaffolds and is a
novel chemotype for further exploration of anti-HCV drugs.
SIb
a
a
Compound
R
1b EC50
(
lM)
CC50
>50
(lM)
21
22
23
24
4-CH2Ph
5-CH2Ph
6-CH2Ph
7-CH2Ph
3.18 0.36
4.81 0.27
5.05 0.93
>50
>16
9
9
45.21 2.63
43.80 1.48
>50
>1
a
Mean of triplicate well values. All experiments were performed at least twice.
In vitro selectivity index (CC50/EC50).
b
Table 4
Anti-HCV activity and cytotoxicity for indolines 25 and 27–51
Acknowledgment
Cl
We gratefully acknowledge the financial support of the National
Health Research Institutes in Taiwan (ROC).
O
O
References and notes
N
NH
1. Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M.
Science 1989, 244, 359.
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S
R
O
SIb
a
a
Compound
R
1b EC50
(l
M)
CC50 (lM)
25
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
Ph
0.79 0.14
1.65 0.33
0.58 0.12
0.72 0.21
0.57 0.09
0.51 0.15
0.95 0.28
0.69 0.18
0.88 0.16
1.23 0.43
1.94 0.19
2.02 0.61
1.95 0.53
42.37 1.83
13.36 0.79
31.58 1.65
25.39 1.23
42.47 2.57
2.16 0.56
0.58 0.15
1.72 0.23
0.66 0.08
1.02 0.18
2.37 0.24
2.06 0.17
1.1 0.07
>50
>50
12.13 1.18
13.62 1.45
9.75 0.86
>50
31.11 2.56
21.71 1.43
29.08 1.78
32.69 1.67
>50
34.42 1.48
>50
>50
>50
>50
>50
>50
>50
4.62 0.63
20.06 1.35
10.66 0.95
>50
11.1 0.86
37.08 1.83
>50
>63
>30
21
19
17
>98
33
31
33
27
>26
17
>26
>1
>4
>2
>2
>1
>23
8
12
3. World Health Organization. J. Viral Hepat. 1999, 6, 35.
2-NO2-Ph
3-NO2-Ph
4-NO2-Ph
3-CN-Ph
4-CN-Ph
4-F-Ph
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4-Cl-Ph
4-Br-Ph
4-CF3-Ph
4-Me-Ph
4-MeO-Ph
4-t-Bu-Ph
4-N(CH3)2-Ph
CH2CH2Ph
CH2CH2CH3
Cyclopentyl
Cyclohexyl
2-Naphthyl
2-Furyl
3-Furyl
2-Thienyl
3-Thienyl
3-Pyridyl
5-Isoxazolyl
2-Benzothienyl
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16
>49
5
18
>45
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a
Mean of triplicate well values. All experiments were performed at least twice.
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b
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lar, compound 31 proved to be more potent than the unsubstituted
compound 25 with a selectivity index of greater than 98. All other
4-substituted analogues (32–39) showed similar or slightly
reduced activity, with the exception of the 4-dimethylamino ana-
logue 39, which resulted in a considerable loss of activity. Intro-
duction of an ethylene linker (40) between the carbonyl group
and the phenyl ring showed a decrease in potency. Replacing the
phenyl ring (25) of the benzoyl moiety by an n-propyl (41) or a
cycloalkyl group (42, 43) dramatically decreased the activity. These
findings indicate that the aromatic ring seems to play an important
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