Non-nucleoside inhibitors of the hepatitis C virus NS5B RNA-dependant RNA polymerase: 2-Aryl-3-heteroaryl-1,3-thiazolidin-4-one derivatives

Article abstract of DOI:10.1016/j.bmcl.2008.10.023

Hepatitis C virus (HCV) NS5B RNA polymerase is crucial for replicating the HCV RNA genome and is an attractive target for developing anti-HCV drugs. A novel series of 2,3-diaryl-1,3-thiazolidin-4-one derivatives were evaluated for their ability to inhibit HCV NS5B. Of this series, compounds 4c, 5b, 5c and 6 emerged as more potent, displaying over 95% inhibition of NS5B RNA polymerase activity in vitro. The two most active compounds 4c and 5c exhibited an IC₅₀ of 31.9 μM and 32.2 μM, respectively, against HCV NS5B.

Full text of DOI:10.1016/j.bmcl.2008.10.023

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6110–6114
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Non-nucleoside inhibitors of the hepatitis C virus NS5B RNA-dependant
RNA polymerase: 2-Aryl-3-heteroaryl-1,3-thiazolidin-4-one derivatives
b
b
b
Ravindra K. Rawal a, S. B. Katti a, , Neerja Kaushik-Basu , Payal Arora , Zhenhua Pan
*
a Medicinal and Process Chemistry Division, Central Drug Research Institute, Chattar Manzil, PO Box No. 173, Lucknow, UP 226 001, India
b Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, NJ 07103, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Hepatitis C virus (HCV) NS5B RNA polymerase is crucial for replicating the HCV RNA genome and is an
attractive target for developing anti-HCV drugs. A novel series of 2,3-diaryl-1,3-thiazolidin-4-one deriv-
atives were evaluated for their ability to inhibit HCV NS5B. Of this series, compounds 4c, 5b, 5c and 6
emerged as more potent, displaying over 95% inhibition of NS5B RNA polymerase activity in vitro. The
Received 10 July 2008
Revised 19 September 2008
Accepted 6 October 2008
Available online 8 October 2008
two most active compounds 4c and 5c exhibited an IC50 of 31.9 lM and 32.2 lM, respectively, against
HCV NS5B.
Keywords:
HCV
Ó 2008 Elsevier Ltd. All rights reserved.
NS5B
RdRp
4-Thiazolidinones
Hepatitis C virus (HCV) is a blood-borne pathogen belonging to
the Flaviviridae1 family of viruses, which also includes the West
Nile, Yellow Fever, and Dengue viruses. HCV infection is one of
the most significant cause for liver cirrhosis and hepatocellular car-
cinoma2 leading to liver failure and as such is a growing medical
problem that affects an estimated 170 million individuals world-
wide.3 HCV is a positive strand RNA virus, and its genome com-
prises of 9600 base pairs that encode several structural and non-
structural proteins.4 Non-structural protein 5B (NS5B), encodes
the viral RNA dependent RNA polymerase (RdRp), which plays a
pivotal role in replicating the HCV RNA genome.5 By analogy to
AIDS, most small molecule inhibitor approaches to HCV have cen-
tered on the inhibition of essential viral targets, especially the
NS3-4A protease (analogous to HIV protease) and the NS5B RdRp
(analogous to HIV RT), although other targets are also being fol-
lowed.6 More interestingly, there is no functional counter part of
this enzyme in mammalian cells thus making it an ideal drug tar-
get.7 Several classes of potent NS5B inhibitors have been reported
in the past couple of years,8 for example, nucleoside NS5B inhibi-
tors NM2839 and R-1626,10 and non-nucleoside inhibitors HCV-
79611 and wedelolactone12 (Fig. 1) among others. However, despite
a proliferation of pharmaceutical and academic research in the past
decade, no specific antiviral agents are available for the treatment
of HCV. Therefore, development of anti-HCV drugs remains an
enormous unmet medical need for adequate therapeutic options.
4-Thiazolidinone scaffold has been gaining prominence in recent
years, due to the fact that its derivatives are known to possess
wide spectrum of activities such as antibacterial,13,14 antifungal,15,16
anticonvulsant,17,18 antiCOX-1,19 antituberculosis,20–22 antihista-
minic23 and anticancer.24 The persuasive antiviral activity of 4-thia-
zolidinone scaffold has been enlightened by several studies.
These include the inhibition of HIV-1 RT by 2,3-diaryl-1,3-thiaz-
olidin-4-ones.25–27 More recently, the inhibitory potency of 4-thia-
zolidinone ring system against HCV NS5B polymerase has been
reported by Kaushik-Basu et al.28
In this study, we have investigated the therapeutic potential
of the 4-thiazolidinone scaffold against HCV NS5B, utilizing a
series of 2,3-diaryl-1,3-thiazolidin-4-one derivatives synthesized
by our group. The synthesis of all compounds reported in Table
1 except compounds 4c, 4p, 7 and 8 have been described previ-
ously.26 Our investigations have focused on building the struc-
ture–activity relationship (SAR) around 2- and 3-positions of
the 4-thiazolidinone template in contrast to the recently re-
ported 4-oxo-2-thionothiazolidines, which carry arylsulfonamido
and arylidene substituents at 3- and 5-positions, respectively.28
Here we report the identification of a new series of 4-thiazolid-
inone derivatives as promising inhibitors of HCV NS5B polymer-
ase. These seminal findings should assist in the development of
novel 4-thiazolidinone compounds harboring potent anti-NS5B
activity.
The target compounds in this study (4a–4f, 4q, 5a–5c and 6)
were prepared by the multi-component DCC mediated reaction
protocol29 earlier reported from this laboratory as shown in
Scheme 1.
* Corresponding author. Tel.: +91 522 2212412x4280; fax: +91 522 223405/
223938.
E-mail address: setu_katti@yahoo.com (S.B. Katti).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.023

R. K. Rawal et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6110–6114
6111
O
OH
O
O
O
N
O
NH2
O
O
N
NH2
O
N
O
N3
O
HO
N
NH2
O
O
Velopicitabine
NM283
R1626
NH
O
O
O
HO
HO
F
O
OH
O
O
N
HO
O S O
Wedelolactone
(IC50 = 36.1 µM)
Benzofuran
HCV-796
Figure 1. NS5B RNA polymerase inhibitors.
In this protocol N,N-dicyclohexylcarbodiimide (DCC) is used as a
dehydrating agent to accelerate the intramolecular cyclization
resulting in faster reaction and improved yields. The reactions
were performed by reacting the appropriate heteroaryl amines
(1), substituted benzaldehydes (2) and mercapto acids (3) in the
presence of DCC at room temperature. After completion of the
reaction ranging around 1.0 h, the desired products were obtained
in excellent yields and purity as confirmed by spectral data analy-
sis. Compounds 7, 4g–4p and 4r–4s were synthesized by using the
toluene reflux protocol26 in the presence of 4 Å molecular sieve and
Table 1
Physical data of 2,3-diaryl-1,3-thiazolidin-4-one derivatives
F
S
O
R4
O
O
N
O
NH
S
N
Heteroaryl
R3
N
S
Heteroaryl
R3
R1
R1
OH
R2
R2
Comp. 4a-4s & 5a-5c
F
F
Comp. 9
Comp. 6
Compound
Heteroaryl
R1
R2
R3
R4
MWt
% yield
Mp (°C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
6-Methyl-pyridin-2-yl
6-Methyl-pyridin-2-yl
Pyridin-3-ylmethyl
Quinolin-4-yl
NMe2
F
Pyridin-3-yl
NMe2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
H
H
H
307
299
274
271
313
339
408
392
497
416
400
470
478
462
445
358
328
433
327
339
353
342
342
339
344
—
75
68
78
55
72
92
50
47
36
48
41
46
38
30
28
56
92
64
44
80
90
88
90
50
78
—
—
—
—
H
H
H
H
104–106
133–135
—
H
H
Cl
Cl
F
Br
Cl
F
Cl
Cl
F
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
F
Cl
Cl
Br
F
Cl
Cl
Cl
Cl
4-Methyl-6-trifluoromethyl-pyrimidin-2-yl
4-Methyl-6-trifluoromethyl-pyrimidin-2-yl
4-Methyl-6-trifluoromethyl-pyrimidin-2-yl
4-Methyl-6-phenyl-pyrimidin-2-yl
4-Methyl-6-phenyl-pyrimidin-2-yl
4-Phenyl-6-trifluoromethyl-pyrimidin-2-yl
4,6-Diphenyl-pyrimidin-2-yl
4,6-Diphenyl-pyrimidin-2-yl
4,6-Diphenyl-pyrimidin-2-yl
Quinolin-2-yl
Furan-2-ylmethyl
Thiophen-2-ylmethyl
5-Ethyl-[1,3,4]-thiadiazol-2-yl
Pyridin-2-yl
Pyridin-3-ylmethyl
111–115
92–94
133–137
168–170
138–140
206–208
206–208
176–178
192–194
144–146
96–98
—
110–114
85–89
—
—
—
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
5a
5b
5c
6
F
F
Cl
Br
F
Cl
Cl
Cl
Cl
Furan-2-ylmethyl
Furan-2-ylmethyl
Pyridin-2-yl
Furan-2-ylmethyl
7
1-Benzyl-piperidinyl
H
—
8a
Cl
Cl
155–158
—
9
20,40-Difluoro-4-hydroxy-biphenyl-3-carboxylic acid [2-(2-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-amide
a
Sulfoxide.

6112
R. K. Rawal et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6110–6114
O
O
HS
3a
OH
Heteroaryl
N
S
(i) or (ii)
Ar
4-Thiazolidinones
(4a-4s)
OH
HS
3b
O
O
Heteroaryl
N
S
(i)
(i)
O
N
Ar
4-Thiazolidinones
Heteroaryl NH2
+
ArCHO or
(5a-5c)
O
1a-1j
2a-2g
O
Ph
HS
3c
OH
Heteroaryl
N
S
Ar
4-Metathiazanones
(6)
O
O
HS
3a
OH
Heteroaryl
N
S
(ii)
N
Ph
Thiazaspirodecanone
(7)
NH2
NH2
N
N
N
NH2
N
NH2
N
F3C
N
NH2
Ph
N
1e
NH2
NH2
1a
Ph
1b
1c
1d
N
N
N
NH2
O
S
N
NH2
S
Ph
N
NH2
1g
1j
1f
1h
1i
Heteroaryl Amines
CHO
Cl
CHO
CHO
CHO
Cl
F
Cl
F
CHO
N
F
Br
Br
2d
2a
CHO
2b
2c
CHO
N
N
2g
2f
2e
Aromatic aldehydes
Scheme 1. Synthesis of compounds 4a–4s, 5a–5c, 6 and 7. Reagents and conditions: (i) DCC, THF, at RT; (ii) toluene, 4 Å MS at 120 °C.
p-toluene sulfonic acid (PTSA). Reaction time for these compounds
varied from 18 to 24 h and yielded the desired products in moder-
ate yields and purity. Sulfoxide (8) was synthesized by using Ox-
oneÒ (2 equiv) in methanol:water (1:1) at room temperature
stirring for 30 min. The spectral data including the elemental anal-
ysis of this compound reported in Supplemental information corre-
lates with the expected structure. Physical data for all 4-
thiazolidinone derivatives are given in Table 1.
To investigate the influence of the 4-thiazolidinone compounds
on the RdRp activity of NS5B, we employed the N-terminal His-
tagged HCV NS5BCD21 (genotype 1b), lacking the C-terminal 21-
amino acid membrane-spanning domain. Purification of
NS5BCD21 and determination of its RdRp activity was carried
out in accordance with previously described procedures.12,28 Pri-
marily, the anti-NS5B activity was evaluated for all compounds (
4a–4s, 5a–5c and 6–8) and their results are summarized in Table

R. K. Rawal et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6110–6114
6113
2. The compounds showed varied pattern of inhibition of HCV
NS5B RdRp ranging from moderate to good at 0.25 mM compound
concentration. Importantly, compounds 4c, 5b, 5c and 6 exhibited
95% or higher inhibition of NS5B at this concentration, thus reveal-
ing somewhat higher potency than compound 9.28 Further, com-
pounds 4c, 5b, 5c and 6 exhibited relatively poor anti-HIV-1 RT
activity, in contrast to the inhibition pattern seen with HCV
NS5B. Moreover, examination of the inhibitory activity of the
thiazolidin-4-one derivatives against SARS Co-V RdRp (nsp12)
and Klenow polymerase as described previously,12,28 yielded
650% inhibition at 0.5 mM concentration of these compounds
(data not shown), thus suggesting their specificity for HCV NS5B.
It may be inferred from the biological activity data reported in
Table 2 that the anti-HCV NS5B activity is sturdily dependent on
the nature of the substituent at C-2, N-3 and C-5 of the 4-thiazolid-
inone scaffold. In particular, a high activity level was observed for
compounds possessing a halophenyl and 4-dimethylaminophenyl
group at C-2, substituted/unsubstituted pyridine-2-yl, pyridine-3-
ylmethyl, substituted pyrimidin-2-yl and furan-2-ylmethyl at N-3
and unsubstituted or methyl substitution at C-5. In fact, the
compounds with the best combination of high potency were
unsubstituted pyridine-2-yl, pyridine-3-ylmethyl or furan-2-yl-
methyl substituted at N-3 of 4-thiazolidinone scaffold, derivatives
such as 4c, 5b, 5c and 6. The effect of 2,6-dihalosubstituent on the
phenyl ring at C-2 was apparent in compound 4i. This compound
was more active than the corresponding 2,6-dichloro (4g) and 2-
chloro-6-fluoro substituted (4h) compounds. Furthermore the
favorable effect of 2,6-dibromo was confirmed by the finding that
2,6-dichloro derivative (4g) possessed intermediate activity be-
tween 2,6-dibromo and 2-chloro-6-fluoro analogues. But the 2,6-
difluoro substituted compounds (4o) possessed almost same activ-
ity as 2,6-dichloro substituted compound (4m) in case of 4,6-di-
phenyl-pyrimidin-2-yl derivatives.
The introduction of pyrimidin-2-yl substituent at the N-3 atom
of the thiazolidinone ring moderated their anti-NS5B activity.
Considering the effect of the substituents on the pyrimidine ring
at N-3, introduction of 4-phenyl-6-trifluoromethyl-pyrimidin-2-yl
moiety (4l) resulted in moderate activity. Introduction of the 4-
methyl-6-phenyl-pyrimidin-2-yl moiety (4j–4k) led to substantial
decrease in their ability to inhibit NS5B. Compounds 4m, 4n and 4o
with the 4,6-diphenyl-pyrimidin-2-yl derivatives, compounds 4g
and 4i with the 4-methyl-6-trifluoromethyl-pyrimidin-2-yl deriva-
tives exhibited near equal potency.
However, introduction of the quinolin-2-yl (4p), thiophen-2-yl-
methyl (4r) and 5-ethyl-[1,3,4]-thiadiazol-2-yl (4s) at N-3 position
also resulted in a substantial decrease in their activity compared to
the pyridin-2yl, pyridine-3-ylmethyl and furan-2-ylmethyl con-
taining compounds.
Compounds 4c, 4e, 5b, 5c, 6 and 7, thus emerged as the most
potent compounds of this series with percentage inhibition in
the range of 85–98%. We therefore evaluated the IC50 values of
these compounds by monitoring the total incorporation of the
radiolabeled UTP on poly rA/U12 as a function of inhibitor concen-
tration. Compounds 4c, 4e, 5b, 5c, 6 and 7 yielded IC50 value rang-
ing from 31.9 to 79.4
and 5c exhibited an IC50 value of 31.9 and 32.2
compound 4e, 5b, 6 and 7 exhibited modest IC50 values (41.8–
79.4 M).
l
M (Table 2). The most potent compound 4c
lM whereas the
l
Table 2
Earlier reports had focused mostly on exploring the substitution
at C-2 and N-3 position of the 4-thiazolidinone scaffold.28 As a first
step towards exploring the importance of thiazolidinone scaffold
per se, we have evaluated compounds having methyl substitution
at C-5, ring expansion meta-thiazanone and sulfoxide modification.
It is apparent from the data presented in Table 2 that changes in
the basic thiazolidinone moiety either by introducing a methyl
group at C-5 (5a–5c), ring expansion (6) or spiro (7) has favorable
effect on the anti-HCV NS5B activity as opposed to the introduction
of sulfoxide (8) moiety, which decreased the activity.
In conclusion, previously synthesized novel 2,3-diaryl-1,3-
thiazolidin-4-one derivatives were evaluated against HCV NS5B
polymerase. Compounds 4c, 4e, 5b, 5c, 6 and 7 of this series
showed promise as anti-HCV NS5B agents and exhibited over
85% inhibition. Compounds 4c and 5c were the most potent of this
Anti-NS5B RdRp activity of compounds (4a–4s, 5a–5c and 6–9)
Compound
Anti-NS5B activity % inhibitiona
IC50 (lM)
4a
62.2 4.3
76.4 3.6
98 0.9
—
—
4b
4cb
31.9 1.2
—
79.4 1.1
—
—
—
—
—
—
—
—
—
—
—
—
—
4d
4e
4f
4g
4h
4i
4j
4k
64.2 4.1
84.7 4.2
75.6 2.1
72.1 1.6
63.6 2.5
76.3 2.5
63.6 2.1
65.5 2.3
66.4 2.9
73.1 3.1
70.6 3.8
73.3 2.1
60.0 2.6
72.3 1.6
62.3 3.5
62.9 1.0
73.0 3.6
95.6 0.8
97.8 0.8
94.2 2.8
85.6 4.9
68.7 5.4
92.4 2.5
—
4l
4m
4n
4o
4pb
group with IC50 values of 31.9 and 32.2 lM, respectively. All other
derivatives also exhibited greater than 60% NS5B RdRp inhibition.
Taken together our data indicate that changes at C-2, N-3 and C-
5 position of 4-thiazolidinone scaffold with appropriate substitu-
tion may provide compounds with improved potency. Thus 4-thia-
zolidinone skeleton holds promise for further activity optimization
studies.
4q
4r
4s
5a
5b
5c
—
—
41.8 1.1
32.2 1.1
52.6 1.2
71.9 1.1
—
6
7b
8b
Acknowledgments
9
48
36.1
Wedelolactone
The authors thank the Director, CDRI for support and the SAIF
for the spectral data. CDRI Communication No.: 7558. This research
was partly supported by National Institute of Health (NIH) research
Grant DK066837 to N.K.B.
a
Percentage inhibition was determined at 0.25 mM concentration of the indi-
cated compound and represents an average of at least three independent mea-
surements. NS5B RdRp activity in the absence of the inhibitor was taken as 100%
after subtraction of residual background activity. The concentration of DMSO in all
reactions was kept constant at 10%. The IC50 values of the compounds 4c, 4e, 5b, 5c,
6 and 7 were determined from dose–response curves using 8–12 concentrations of
each compound in duplicate, in two independent experiments. Curves were fitted
to data points using non-linear regression analysis and IC50 values were interpo-
lated from the resulting curves using GraphPad Prism 5.0 software. Wedelolactone
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.10.023.
(IC50 = 36.1
l
M) was included as an internal reference standard.
b
Compounds 4c, 4p, 7 and 8 are new.

6114
R. K. Rawal et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6110–6114
11. Chandra, C.; Raible, D.; Harper, D.; Speth, J.; Villano, S.; Bichier, G. DDW 2006,
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