Design and synthesis of pyridine-pyrazole-sulfonate derivatives as potential anti-HBV agents

Article abstract of DOI:10.1039/c6md00008h

Hepatitis B virus (HBV) is an infectious disease, which can cause acute and chronic infections. Every year, over 7.5 million persons die due to HBV. No effective drug exists for the treatment of HBV. Thus, we designed and synthesized 16 new pyridine-pyraz

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ARTICLE
Design and synthesis of pyridine-pyrazole-sulfonate derivatives as
†
potential anti-HBV agents
Received 00th January 20xx,
Accepted 00th January 20xx
ab
ab
a
c
d
Hong Chuang, Lin-Chiang Sherlock Huang, Mohit Kapoor, Yi-Jen Liao, Cheng-Lin Yang, Chia-
e
f
a
g
b
Ching Chang, Chun-Yi Wu, Jih Ru Hwu,* Tsurng-Juhn Huang,* and Ming-Hua Hsu*
DOI: 10.1039/x0xx00000x
Hepatits B virus (HBV) is an infectious disease, which can cause acute and chronic infections. Every year, an over 7.5
million person dies due to HBV. No effective drug exists for the treatment of HBV. Thus, we designed and synthesized 16
www.rsc.org/
2
new pyridine-pyrazole-sulfonate compounds containing pyridine-SCH -pyrazole and pyridine-pyrazole derivatives. Their
1
13
structures were characterized by H-NMR, C-NMR, IR, mass spectroscopy, and high performance liquid chromatography.
All the compounds were evaluated for their anti-HBV activities and established the structure-activity relationship (SAR) in
HepG2 2.2.15 cells. We found the pyridine-pyrazole derivatives could inhibit the HBV gene expression and viral DNA
replication. Among these compounds, 2-[3-(2-nitrophenylsulfonyl)oxy-5-pyrazol-yl]pyridine 19d shown the most potent
inhibitory activity with IC50 value of 9.19 ꢀM, and high selectivity index, SI (TC50/IC50) 35.46. Hence, we believe our
compounds could serve as reservoir for anti-HBV drug development.
Instead of viral replication, recent studies showed that how to
regulate viral gene expression is a crucial step for antiviral
1
. Introduction
1
0,11
strategies.
agents is usually the result of understanding the viral lifecycle
The discovery of novel and effective antiviral
Hepatocellular carcinoma (HCC) is the fifth most common
malignancy and the third cancer-related cause of death. The
12
and performing molecular modeling by using the coordinates
of the crystal structures of viral proteins, including helicases,
hepatitis
B
virus (HBV),
a
member of the family
Hepadnaviridae, is a causative agent that frequently leads to
1
acute and chronic infections in humans.
1
3
proteases, and polymerases.
Such targeted drug
Despite the
development has been lacking for HBV, and the most common
strategy has been compound screening by using in vitro
development of a recombinant vaccine against HBV, over 400
2
million people are chronic carriers worldwide. Liver cirrhosis
,3
1
0,11,14,15
4
replication models.
identified to inhibit HBV, the next step is to determine its
mode of antiviral action. Currently, several antiviral
Once a new compound has been
and HCC occur in approximately 80% of chronic HBV carriers.
Although interferons and nucleotide analogs have been widely
used to treat chronically infected patients, the rapid
development of drug resistance is an emerging clinical
compounds have been reported to target cellular signaling
factors and disturb the viral gene regulation and genome
5
–8
problem.
Therefore, the improvement of novel antiviral
1
0,11
replication.
The regulation of HBV viral gene expression is
agents to eradicate HBV in chronic carriers is instantly needed.
After HBV infection, four viral transcripts are transcribed from
four different viral promoters (Core, X, S, and PreS), which are
a highly complex issue in molecular virology. Accordingly,
understanding how viral proteins regulate the host-signaling
network can help us to control the HBV-induced liver cancer.
3.5, 2.4, 2.1, and 0.8 kb, respectively. The 3.5-kb transcript is
translated to produce core, precore, and viral polymerase
proteins. It also serves as a pregenomic RNA template for viral nucleoside, nucleotide, or derivatives from botanical origin.
It had been reported that some anti-HBV agents were
1
6–
1
8
genome synthesis. The 2.4- and 2.1-kb transcripts encode
small, medium, and large surface (envelope) proteins; the 0.8- with two nitrogen atoms in the adjacent position, is an
kb transcript is translated to produce the X protein, a potent essential core structure had been widely used in agro-
Pyrazole (1, Figure 1), a five membered heterocyclic ring
9
transactivator for both viral and host gene promoters. chemicals, building blocks, catalysis, and in medicines.
19
Pyrazole derivatives have been reported and used as
antitumor, anti-inflammatory, antiviral, and anti-microbial
2
0
agents. Many pyrazole containing drugs approved by FDA
such as AS-19 ( ), Lonazolac ( ), Mavacoxib ( ), and
2
3
4
Fezolamine (
5
). Recently, Kasımogulları et al. reported that
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OEt
a
+
Cl
N
OEt
N
S
N
SH
O
O
O
O
10
11
12
R: 14a p-H
b
1
4b p-CH3
S
O
1
4c p-NO2
HN
NH
13
14d o-NO2
1
1
1
1
4e p-F
R
1
O
O
S
4f p-Br
4g p-OMe
c
N
S
O
4h OSO Me
2
HN
N
14
Scheme 1 Reagents and conditions: (a) K
b) hydrazine hydrate, EtOH/THF (1:1), r.t., 2.0 h, 86%; (c)
substituted phenylsulfonyl chloride or methylsulfonyl chloride,
CO , THF, 40 °C, 4.0-5.0 h, 76-87%.
2 3
CO , THF, r.t., 4.0 h, 89%;
(
K
2
3
introduced by treating 12 with hydrazine hydrate in
ethanol/THF co-solvent to give key intermediate 1,2-dihydro-
Figure 1. The structures of pyrazole, AS-19, Lonazolac,
Macacoxib, Fezolamine, thiazole, thiazolidinone, 1,3,4-
thiadiazole, and pyrazoline.
5
-[(2-pyridinylthio)methyl]-3H-Pyrazol-3-one 13
.
By treating
various substituted phenylsulfonyl chloride with the
intermediate 13 under mild condition, the desired pyrazole-
phenylsulfonyl conjugates 14 were obtained.
pyrazole-3-carboxylic acid derivatives exhibit antiproliferative
2
The synthetic route of pyridine-pyrazole derivatives is shown in
activity against tumor cells. Moreover, Bekhit et al. revealed Scheme 2. 2-Acetylpyridine 15 and diethyl carbonate 16 were
1
pyrazole derivatives conjugated with five-member heterocyclic conjugated by using sodium hydride under refluxing in toluene to
2
7
give ethyl picolinoylacetate 17. The compound 17 was treated
with hydrazine to build up the heterocyclic core of the essential
intermediate 1,2-dihydro-5-(2-pyridinyl)-3H-Pyrazol-3-one 18. The
final desired pyrazole products 19 were synthesized by treating 18
with various substituted phenylsulfonyl chloride in THF at room
temperature. All these products were obtained in good yields and
purified to more than 95% by chromatography and recrystallization
for bioactivity assays.
moieties such as thiazoles (
6
), thiazolidinones (
7), 1,3,4-
thiadiazoles (8) and pyrazolines (
9), shows dual function for
antimalarial activity against Plasmodium berghei infected mice
in vivo and against chloroquine resistant (RKL9) strain of
2
2
Plasmodium falciparum in vitro. Yang et al. published the
inhibition of succinate-ubiquinone oxidoreductase (SQR, EC
1.3.5.1, complex II), an essential component of cellular chain
and tricarboxylic acid (or Krebs) cycle, using pyrazole-4-
2
carboxamides with K = 11 nM (porcine SQR).
i
3
Herein, we
report a novel series of pyrazole derivatives conjugated with
pyridine and arenesulfonyl moiety as a new class of anti-HBV
agents. Phenylsulfonyl group plays an important role in
increasing the solubility of the molecules and triggering
2
4,25
antiviral activity.
The pyrazole core structure was attached
to pyridine ring on 3-position and phenylsulfonyl group on 5-
position. These new classes of pyrazole derivatives were
evaluated for antiviral activity, and they exhibited valuable
anti-HBV effects in HepG2 2.2.15 cells.
The designed
compounds are potential structural templates for developing
new anti-HBV agents.
2
. Results and discussion
2.1 Chemistry
The synthetic route of pyridine-SCH
.
chloroacetoacetate 11 were conjugated by using potassium
2
-pyrazole derivatives is
shown in Scheme 1 2-Mercaptopyridine 10 and ethyl 4-
Scheme 2. Reagents and conditions: (a) NaH, toluene, 110 °C, 3.0 h,
7
2%; (b) hydrazine hydrate, EtOH, r.t., 2.0 h, 79%; (c) substituted
phenylsulfonyl chloride or methylsulfonyl chloride, K CO , THF,
40°C, 4.0-5.0 h, 74-88%
2
3
carbonate as a base at room temperature to get ethyl 4-
(pyridin-2-ylthio)acetoacetate 12
2
.
6
.
The pyrazole scaffold was
2
| J. Name., 2012, 00, 1-3
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The structures of all new compounds were determined NMR spectrum of 14d displayed two characteristic singlets at
according to their spectroscopic characteristics. For example,
4.38 and 6.51 for the SCH and H-4’ proton respectively. Its
the mass spectrum of 14d from ESI analysis exhibited 392.0248, IR spectrum showed one strong absorption band at 1376 cm
which indicates a molecular formula of C15 with a which were attributed to the S=O stretching vibration.
theoretical value of 392.0249. Its C NMR spectrum showed Similarly, in case of 19d, ESI analysis exhibited 346.0376, which
5 signals, which is in accordance with the theoretical number. indicates
molecular formula of C H N O S with
Resonance at 24.31 and 96.08 was assigned to SCH and theoretical value of 346.0372. Its C NMR spectrum showed
pyrazole CH carbons respectively. Also resonance at 153.35 14 signals, which is in accordance with the theoretical number.
ppm was assigned to the N=C−O carbon. Furthermore, the H
δ
2
–1
,
12 4 5 2
H N O S
1
3
1
a
a
1
4 10 4 5
1
3
δ
2
δ
1
Table 1 Effect and selectivity index (SI) of compounds 13
,
14a–
14h
,
18, and 19a
–
19h on cytotoxicity of HepG2 2.2.15 cells,
inhibition potential of HBV viral antigen and DNA replication
Inhibition of
HBV DNA
HBsAg IC50
ꢀM)
HBsAg SI
HBeAg IC50
HBeAg
HBV DNA
Compound
TC50 (ꢀM)
replication
(
(TC50/IC50
)
(ꢀM)
SI(TC50/IC50
)
replication IC50
SI(TC50/IC50
)
(ꢀM)
1
3
1117.4
103.30
86.39
814.65
151.94
19.83
4.80
1.37
0.68
4.36
7.97
10.6
4.44
0.46
6.21
5.17
0.77
0.99
9.35
6.28
43.54
5.53
3.85
5.69
3.68
-
590.40
20.31
19.42
5.97
9.92
249.98
9.20
44.61
679.38
1368.31
69.49
32.31
-
1.89
5.09
4.45
6.41
6.68
0.46
5.69
2.02
1.22
0.78
1.94
6.71
-
524.13
18.93
14.29
5.56
6.30
197.49
6.07
38.14
738.95
1349.82
65.34
31.33
-
2.13
5.46
6.04
6.88
10.51
0.59
8.63
2.37
1.12
0.79
2.07
6.92
-
1
4a
4b
4c
1
1
38.24
14d
14e
66.25
6.25
116.22
52.38
26.19
114.93
14.53
160.51
1377.26
136.79
23.17
125.34
7.48
1
4f
4g
4h
1
90.25
1
830.46
1063.96
135.13
216.72
786.54
325.89
253.94
809.20
87.53
1
8
1
9a
1
9b
9c
1
1
9d
9e
12.02
82.85
-
27.11
3.06
-
9.19
92.07
-
35.46
2.76
-
1
45.91
210.07
15.37
287.19
-
1
9f
9g
9h
-FU
Lamivudine (3TC)
1
23.09
-
3.79
-
22.17
-
3.95
-
1
1058.08
21.68
5
-
-
-
-
352.03
-
-
-
-
2.09
46.13
TC50 : The concentration of the compound at which cell viability was reduced to 50%.; IC50 : The concentration of the compound on anti-HBV effect was
reached to 50%; 5-FU (Fluorouracil) is the positive control for cytotoxic analysis; Lamivudine (3TC) is the positive control for anti-HBV analysis.
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the pyridine-pyrazole scaffold conjugated with phenylsulfonyl
side chain (18 vs 19a 19h). Among halogen substituents, the
Resonance at
pyrazole CH carbons and N=C−O carbon respecꢀvely.
δ 94.46 and 153.35 ppm were assigned to the
–
1
Furthermore, the H NMR spectrum of 19d displayed one
p-fluoro derivatives showed better inhibition activity than the
p-bromo derivatives (14e vs 14f, and 19e vs 19f). In the case
of electron releasing group on the phenylsulfonyl side chain,
the methoxy group exhibited better activity than methyl
group in both core structures (14b vs 14g, and 19b vs 19g).
Furthermore, we found the ortho- and para-position of nitro
group shown no significant different of the activity in the
characteristic singlet at
spectrum showed one strong absorption band at 1375 cm ,
which were attributed to the S=O stretching vibration.
δ 6.51 for the H-4’ proton. Its IR
–1
2.2 Cytotoxic Effect of the Compounds on HepG2 2.2.15
Hepatoma Cells
2
pyridine-SCH -pyrazole scaffold 14. However, in the pyridine-
pyrazole derivatives 19, ortho-nitro derivative 19d was much
more active than para-nitro derivative 19c. The compound
To evaluate the structure-activity relationship (SAR) and
determine the cytotoxic effects of compounds 13
, and 19a 19h on HepG2 2.2.15 cells, the cells were
subjected to twofold serial dilution with each compound for
2 h, and the viability of the cells was measured according to
the manufacturer’s protocol. All measurements were
, 14a–14h,
1
8
–
19d was found the most potent lead molecule in this family
with IC50 of 7.48 M and high selectivity index of 43.5.
ꢀ
7
In the inhibition of HBeAg, the conjugation of
phenylsulfonyl side chains increased the inhibitory effect in
performed in four replicates, and the results were presented
as a relative percentage of the results of the control group.
The results are shown in Table 1; a decrease in the cell
viability in a dose-dependent manner was observed for all
compounds. To explore the SAR of conjugates in this new
compound library, two new series derivatives, containing
pyridine-SCH -pyrazole scaffold (cf. 13 vs 14a
–
14h).
14d, and 14f showed potent inhibitory effect
with IC50 of 5.97, 9.92, 9.20 M and SI of 6.41, 6.68, 5.69
respectively. Also, the pyridine-pyrazole derivatives (18 and
9a 19h) were displayed similar effect when conjugated with
2
Compound 14c
,
ꢀ
1
–
2
pyridine-SCH -pyrazole and pyridine-pyrazole as core
phenylsulfonyl groups. In case of pyridine-pyrazole scaffold,
o-nitro derivative 19d demonstrated potential to be a lead
structure, were synthesized and conjugated with different
sulfonyl groups. According to their TC50, 9 compounds
displayed potent inhibition tendency towards cell viability.
molecule in this family with IC50 of 12.02
7.11.
ꢀM and high SI of
2
(
Table 1
)
Compared with 13 and 18, conjugation of phenylsulfonate
with two scaffolds increase the cytotoxicity, but doesn’t for
2.4 Antiviral Effect of Compounds on HBV DNA Replication
in HepG2 2.2.15
methylsulfonate derivatives.
Such phenomena can be
14d and 14f with TC50 value
M, and also in
compound 18 vs 19a and 19g of 1063.96 vs 135.13, and 87.53
M. Pyridine-SCH -pyrazole conjugates are more cytotoxic
observed in compound 13 vs 14c
,
To investigate the antiviral activity of compounds in HBV
DNA replication, HepG2 2.2.15 cells were treated with three
noncytotoxic concentrations of compounds for 48 h. As
shown in Table 1, phenylsulfonate derivatives with two
scaffolds increase the inhibition effect on HBV replication, but
the phenomenon doesn’t exist on methylsulfonate
of, 1117.4 vs 38.24, 66.25, and 52.38
ꢀ
ꢀ
2
than pyridine-pyrazole. Thiomethyl linker between pyridine
and pyrazole increases the cytotoxicity in all derivatives
except 14g and 19g. In case of pyridine-pyrazole conjugates,
compound 14h
derivative 19d shows great effect with IC50 of 6.07
Moreover, nitro-phenylsulfonate on both scaffolds enhances
inhibition effect whether on ortho- or para-positon. (i.e. 14c
4d and 19d 5-(Pyridin-2-yl)-1H-pyrazol-3-yl-2-
.
In addition, p-bromophenylsulfonate
p-nitro derivative 19c is less cytotoxic (786.54
nitro benzene sulfonate derivative 19d (325.89
Furthermore, in case of pyridine-SCH -pyrazole scaffold, the
substituent of phenylsulfonate barely affects the cytotoxicity
cf. 14a vs 14b vs 14c vs 14d vs 14e vs 14f vs 14g). Among
ꢀ
M) than o-
ꢀ
M.
ꢀ
M).
2
,
1
)
(
nitrobenzenesulfonate 19d also exhibits the highest
selectivity index of 35.46 in these two series compounds.
pyridine-pyrazole scaffold, the phenylsulfonate was found
more cytotoxic than alkyl sulfonate in compound 19b (216.72
ꢀ
(
M) and 19h (1058.08
809.20 M) shows less cytotoxicity than p-fluoro derivative
9e (253.94 M).
ꢀ
M). Also p-bromo derivative 19f
3. Conclusions
ꢀ
In summary, we design and synthesized two new series
pyrazole core structure conjugated with sulfonyl groups. One
1
ꢀ
2.3 Antiviral Effect of Compounds on HBV Viral Antigen
Expression in HepG2 2.2.15
2
series derivatives were pyridine-SCH -pyrazole derivatives 14,
the other were pyridine-pyrazole derivatives 19
.
All the
1
13
synthesized compounds were characterized by H-NMR, C-
NMR, IR, and mass spectroscopy. All the compounds were
evaluated for their anti-HBV activities and established the
structure-activity relationship (SAR) between these two series
compounds. We found our new pyrazole derivatives could
inhibit the HBV gene expression and viral DNA replication.
The results displayed that 5-(Pyridin-2-yl)-1H-pyrazol-3-yl-2-
nitrobenzenesulfonate 19d exhibited potent activity against
Table 1 also shows the secretion of HBsAg and HBeAg in
treated HepG2 2.2.15 cell culture media. Phenylsulfonyl
group was found significant affect the activity of HBsAg
inhibition. For the inhibition of HBsAg, the conjugation of
phenylsulfonyl side chains onto the pyridine-SCH2-pyrazole
increased the overall inhibitory effect (13 vs 14a
Compound 14c and 14d displayed potent inhibitory effect
with IC50 of 4.80, 6.25 M and high selectivity index, SI
TC50/IC50) of 7.97 and 10.6 respectively. Similar effect of
increasing HBsAg inhibitory activity was also observed when
–14h).
ꢀ
HBV in HepG2 2.2.15 cells with IC50 values of 9.19
especially for the high selectivity index (TC /IC ) of 35.46,
ꢀM,
(
5
0
50
4
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the compound could be a potential lead compound for anti-
HBV therapy.
24 Hwu, J. R.; Kapoor, M.; Tsay, S.-C.; Lin, C.-C.; Hwang, K. C.;
Horng, J.-C.; Chen, I.-C.; Shieh, F.-K.; Leyssen, P.; Neyts, J.
Antiviral Res. 2015, 118, 103.
2
5 Bachovchin, D. A.; Zuhl, A. M.; Speers, A. E.; Wolfe, M. R.;
Weerapana, E.; Brown, S. J.; Rosen, H.; Cravatt, B. F. J. Med.
Chem. 2011, 54, 5229.
Acknowledgements
2
2
6 Liu, Y.; Zhao, Y.; Zhai, X.; Feng, X.; Wang, J.; Gong,; P.
Bioorg. Med. Chem. 2008, 16, 6522.
7 Allais, C.; Lieby-Muller, F.; Constantieux, T.; Rodriguez, J.
Adv. Synth. Catal. 2012, 354, 2537.
For financial support, we thank the Ministry of Science and
Technology of the Republic of China National Tsing Hua
University, and China Medical University Hospital. This work
was supported by Ministry of Science and Technology of
Taiwan (Grant MOST-104-2119-M-007-017-) (Grant MOST-
1
05-2623-E-007-009-NU)and China Medical University
Hospital Research Foundation, Taiwan (DMR-104-039) (DMR-
05-044).
1
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DOI: 10.1039/C6MD00008H
Design and Synthesis of Pyridine-Pyrazole-Sulfonate Derivatives as
Potential Anti-HBV Agents
Graphic Abstract