Synthesis and anticancer and antiviral activities of new 2-pyrazoline-substituted 4-thiazolidinones

Article abstract of DOI:10.1002/jhet.1056

2-(4,5-Dihydropyrazol-1-yl)-thiazol-4-ones (2-5) have been synthesized starting from 3-phenyl-5-aryl-1-thiocarbamoyl-2-pyrazolines via [2+3]-cyclization with 2-bromopropionic acid, maleic anhydride, N-arylmaleimides, and aroylacrylic acids. The in vitro anticancer activity of, and were tested by the National Cancer Institute. Compounds, and demonstrated selective inhibition of leukemia cell lines growth at a single concentration (10^-5 M). The screening of antiviral activity for a broad panel of viruses revealed that N-(4-methoxyphenyl)-2-{2-[5-(4-methoxyphenyl)-3-phenyl-4, 5-dihydropyrazol-1-yl]-4-oxo-4,5-dihydrothiazol-5-yl}-acetamide was highly active against Tacaribe TRVL 11 573 virus strain (EC₅₀ = 0.71 μg/mL, selectivity index = 130).

Full text of DOI:10.1002/jhet.1056

Month 2013
Synthesis and Anticancer and Antiviral Activities of
New 2‐Pyrazoline‐Substituted 4‐Thiazolidinones
Dmytro Havrylyuk,a Borys Zimenkovsky,a Olexandr Vasylenko,b
a
*
and Roman Lesyk
aDepartment of Pharmaceutical, Organic and Bioorganic Chemistry
Danylo Halytsky Lviv National Medical University, Ukraine, Pekarska 69 Lviv 79010, Ukraine
bInstitute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine
Murmanska 1 Kyiv 02094, Ukraine
*
E-mail: dr_r_lesyk@org.lviv.net
Received April 14, 2011
DOI 10.1002/jhet.1056
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
2‐(4,5‐Dihydropyrazol‐1‐yl)‐thiazol‐4‐ones (2–5) have been synthesized starting from 3‐phenyl‐5‐aryl‐1‐
thiocarbamoyl‐2‐pyrazolines via [2+3]‐cyclization with 2‐bromopropionic acid, maleic anhydride, N‐aryl-
maleimides, and aroylacrylic acids. The in vitro anticancer activity of 2a, 3a, 4a, 5b, and 5c were tested
by the National Cancer Institute. Compounds 4a, 5b, and 5c demonstrated selective inhibition of leukemia
cell lines growth at a single concentration (10−5 M). The screening of antiviral activity for a broad panel
of viruses revealed that N‐(4‐methoxyphenyl)‐2‐{2‐[5‐(4‐methoxyphenyl)‐3‐phenyl‐4,5‐dihydropyrazol‐1‐
yl]‐4‐oxo‐4,5‐dihydrothiazol‐5‐yl}‐acetamide 4a was highly active against Tacaribe TRVL 11 573 virus
strain (EC50 = 0.71 μg/mL, selectivity index = 130).
J. Heterocyclic Chem., 00 , 00 (2013).
INTRODUCTION
with GI50 2.23 and 2.76 μM, respectively [17]. Recently,
we have demonstrated that thiazolidinone derivatives with
pyrazoline core V displayed promising anticancer activity
on leukemia, melanoma, lung, colon, CNS, ovarian, renal,
prostate, and breast cancers cell lines [3].
The combination of 4‐thiazolidinone scaffold with other het-
erocycles is a widely applicable approach in a drug‐like mole-
cules buildup [1–4]. The confirmation of this assertion could
be various noncondensed systems with thiazolidine, diazole
(pyrazoline or pyrazole), and related moieties that display broad
spectrum of biological activities including anti‐inflammatory
[5, 6], antinociceptive [7], antimicrobial [8–10], antifungal
[11], anticonvulsant [12], antioxidant [13] effects, and so on.
A considerable interest has been focused on the antican-
cer activity of thiazolidinone and pyrazole derivatives.
Among mentioned substances, some of heterocyclic substi-
tuted 4‐thiazolidinones were described in literature as inhi-
bitors of necroptosis (I) [14] (Fig. 1), Burkitt’s lymphoma
promotion (II) [15] or as promising agent, which possessed
significant effect against breast carcinoma (MCF7) and
cervix carcinoma (HELA) cell lines (III) [16]. The pyrazo-
line derivative IV demonstrated the most marked effects in
the NCI’s 60 human tumor cell line in vitro screen on
leukemia cancer cell lines CCRF‐CEM and RPMI‐8226
The antiviral research of 4‐thiazolidinones and pyrazo-
lines also received considerable attention. Among antecedent
derivatives, some novel compounds have been identified to
be active against vaccinia virus (VI) with EC50 of 7.0 μg/
mL [18] and tabacco mosaic virus (VII) [19]. Compound
VIII showed promising anti‐HIV activity in vitro against
IIIB (IC50 = 5.7 μM) and ROD strains (IC50 = 7.0 μM) [20].
In the present work, we described our continuous re-
search effort in the synthesis of a series of new pyrazo-
line‐substituted 4‐thiazolidinones and characterization of
these compounds for antitumor and antiviral activities.
The synthesis of 4‐thiazolidinone‐pyrazoline conjugates
can be achieved by [2+3]‐cyclization of pyrazoline‐1‐
carbothioic acid amides with equivalents of dielectrophilic
synthon [C2]2+ [1]. Following literature data, only the deri-
vatives of α‐halocarboxylic acids, phenacyl bromides, and
© 2013 HeteroCorporation

D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, and R. Lesyk
Vol 000
N‐arylmaleimides [18, 21, 22, 23] have been used in
the reactions with mentioned compounds. Therefore, we
tried to enlarge a scope of using of 1‐thiocarbamoyl
pyrazoline derivatives as N,S‐binucleophiles in [2+3]‐
cyclization.
were synthesized by reacting mentioned binucleophiles with
2‐bromopropionic acid in the presence of fused sodium
acetate in refluxing acetic acid. Reaction of 3‐phenyl‐5‐
aryl‐1‐thiocarbamoyl‐2‐pyrazolines with maleic anhydride,
N‐arylmaleimides, and aroylacrylic acids [22, 23] resulted
in the formation of the corresponding compounds 3a and
b, 4a–c, and 5a–d, respectively.
The [2+3]‐cyclization of 3‐phenyl‐5‐aryl‐1‐thiocarbamoyl‐
2‐pyrazolines with equivalents of dielectrophilic synthon
[C2]2+ consists of two steps: coupling of 3‐phenyl‐5‐aryl‐1‐
thiocarbamoyl‐2‐pyrazolines 1a–c isoform to double bond
of maleic anhydride, N‐arylmaleimides, or aroylacrylic acids
and following spontaneous cyclization of intermediate to
4‐thiazolidone cycle [32] (Scheme 2).
RESULTS AND DISCUSSION
Chemistry. The general methods for synthesis of target
pyrazoline substituted 4‐thiazolidinones are depicted in
Scheme 1.
Aiming the synthesis of new 4‐thiazolidinones with
pyrazoline moiety in position 2 of basic scaffold, we used
an approach to obtaining of 4‐thiazolidinone ring, which
realizes on [2+3]‐cyclization of 3‐phenyl‐5‐aryl‐1‐thiocarba-
moyl‐2‐pyrazolines 1a–c with equivalents of dielectrophilic
synthon [C2]2+ [1]. The target 2‐[5‐aryl‐3‐phenyl‐4,
5‐dihydropyrazol‐1‐yl]‐5‐methylthiazol‐4‐ones 2a and b
The characteristic data of the new 4‐thiazolidinones are
presented in the experimental part. The analytical and
spectral data (1H‐ and 13C‐NMR) confirm the structure
and purity of the synthesized compounds.
Scheme 1. Synthesis of 2‐[5‐aryl‐3‐phenyl‐4,5‐dihydropyrazol‐1‐yl]‐thiazol‐4‐ones. Reagents, conditions and yields: (a) AcONa, AcOH, reflux 1 h, 68–
75%; (b) AcOH, reflux 1 h, 63–78%.
R
O
NH2CSNHNH2
O
O
O
N
OH
N
Me
O
Ar
OH
N
N
N
O
Br
N
R
O
S
N
a
b
N
S
O
Ar
S
Me
O
N
NH2
O
O
R
Ar
R
2a R = OMe
2b R = Cl
1a R = OMe
1b R = Cl
1c R = NMe2
O
O
O
b
b
5a R = OMe; Ar = 4-F-C6H4
5b R = Cl; Ar = Ph
5c R = Cl; Ar = 4-F-C6H4
5d R = Cl; Ar = 4-Cl-C6H4
N
N
S
OH
N
N
O
N
N
S
Ar
N
H
3a R = NMe2
3b R = Cl
O
R
4a R = OMe; Ar = 4-OMe-C6H4
4b R = OMe; Ar = 4-AcO-C6H4
4c R = Cl; Ar = 4-AcO-C6H4
R
Scheme 2. The mechanism of the [2+3]‐cyclization of 3‐phenyl‐5‐aryl‐1‐thiocarbamoyl‐2‐pyrazolines with equivalents of dielectrophilic synthon [C2]2+
.
Ph
N
O
O
N
S
O
O
N
Ar
S
NH2
S
+
N
O
N
Ph
N
Ar
N
NH
Ph
O
N
Ph
Ar
SH
N
Ar
NH
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis and Anticancer and Antiviral Activities of
New 2-Pyrazoline-Substituted 4-Thiazolidinones
Month 2013
The compounds 2a and b exist as a mixture of two dia-
stereomers I and II in the ratio of 1:1. Probably, this phe-
nomenon can be explained by keto‐enol tautomerism of
mentioned derivatives in positions 4–5 (Scheme 3). The di-
astereomeric equilibrium of these compounds was con-
The chemical shifts of the protons HA, HM, and HX for
pyrazoline moiety were assigned to about δ ∼ 3.33–3.48,
δ ∼ 4.09–4.17, and δ ∼ 5.66–5.85, respectively, and
for 5‐(2‐oxoethyl)‐4‐thiazolidinone fragments to about
δ ∼ 2.58–3.58, δ ∼ 3.05–3.97, and δ ∼ 4.24–4.45. The NH
proton of compounds 4a–c was found as singlet at
δ ∼ 9.87–10.22.
Evaluation of anticancer activity in vitro. Synthesized
pyrazoline‐substituted 4‐thiazolidinones (2a, 3a, 4a, 5b,
5c) were submitted and evaluated at single concentration
of 10−5 M toward panel of approximately sixty cancer
cell lines representing leukemia, melanoma, lung,
colon, CNS, ovarian, renal, prostate, and breast cancers.
1
firmed through the analysis of the H‐NMR spectral data.
Thus, the protons of the methyl group in position 5 of thia-
zolidinone core were observed as two doublet at δ = 1.44–
1.45 and δ = 1.47–1.48, and the proton at C5 forms a
multiplet at δ = 4.13–4.21. Besides, in the 1H‐NMR spectra
of compounds 2a and b, the protons of the CH2-CH moiety
of the pyrazoline fragments showed the characteristic pattern
of an AMX spin system [4]. The chemical shifts of the pro-
tons HA, HM, and HX were determined to be δ = 3.43–3.46,
δ = 4.07–4.13, and δ = 5.74–5.83, respectively, with cou-
pling constants JAM = 18.1–18.2, JAX = 11.1–11.3, and
JMX = 4.5 Hz. Protons of two CH2-CH groups of
Tested
2‐[5‐aryl‐3‐phenyl‐4,5‐dihydropyrazol‐1‐yl]‐
thiazol‐4‐ones demonstrated a moderate activity in the
in vitro screen on the tested cell lines, as well as some
distinctive patterns of selectivity (Table 1). Compound
2a was moderate active on a nonsmall cell lung cancer
HOP‐92 sell line (GP = 59.48%), compounds 4a and 5c
1
compounds 3a and b, 4a–c, and 5a–d in the H‐NMR
spectra showed characteristic patterns of two AMX systems.
Scheme 3. Diastereomers of compounds 2a and b.
O
O
OH
N
N
N
Me
H
N
H
N
N
N
S
N
Me
N
S
S
Me
I
II
R
R
R
Table 1
Anticancer screening data in concentration 10−5M.
60 cell lines assay in 1 dose 10−5 M conc
Mean growth
%
Growth % of the most sensitive cell
lines
Compounds
Range of growth %
The most sensitive cell lines
2a
101.48
59.48–160.51
HOP‐92 (Non‐Small Cell Lung Cancer)
UO‐31 (Renal Cancer)
UO‐31 (Renal Cancer)
RPMI (Leukemia)
59.48
69.89
77.31
32.76
53.77
55.39
40.76
57.46
49.76
54.56
3a
4a
101.34
78.60
77.31–115.90
32.76–142.11
K‐562 (Leukemia)
MOLT‐4 (Leukemia)
RCF‐7 (Breast cancer)
HCT‐15 (Colon cancer)
EKVX (Non‐small cell lung cancer)
A549/ATCC (Non‐small cell lung
cancer)
NCI‐H460 (Non‐small cell lung
cancer)
59.21
PC‐3 (Prostate cancer)
RXF 393 (Renal Cancer)
RPMI (Leukemia)
58.91
57.68
60.70
63.54
60.01
63.60
68.76
5b
5c
92.19
96.04
57.68–137.51
K‐562 (Leukemia)
MOLT‐4 (Leukemia)
RPMI (Leukemia)
63.60–132.43
UO‐31 (Renal cancer)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, and R. Lesyk
Vol 000
were active on a leukemia RPMI cell line (GP = 32.76 and
CONCLUSIONS
63.60%, respectively) and 5b—on a renal cancer RXF 393
cell line (GP = 57.68%). In general, the compounds 4a,
5b, 5c, selectively inhibit the growth of leukemia cell
lines, what correspond to the previous observation of 4‐
thiazolidinones antitumor activity [33–37].
Evaluation of antiviral activity. Antiviral activity of 4a
and 5c was determined aganinst corona viruses (SARS
CoV), influenza types A and B viruses (Flu A, Flu B),
arenavirus (Junin), and biodefense viruses (Tacaribe,
Pichinde) using standart AACF screening assay
protocols [28–30]. The obtained results are summarized
in Table 2.
The compound 5c showed low activity against strains of
influenza viruses (SI = ∼ 1.3/3.6). Especially, noteworthy
antiviral activity of compounds 4a, which possessed insig-
nificant activity against Candid 1 strain of Junin virus (SI =
4/6) and Pichinde virus (SI = 9) but characterized by a high
effect (EC50 = 0.71 μg/mL, SI = 130) on Tacaribe TRVL
11 573 virus strain by NR test. The results of a repeated
test by the VYR‐method (virus yield reduction) confirmed
the considerable activity of the compound 5c (SI = 15)
against Tacaribe TRVL 11 573 virus strain.
New hybrid compounds combining 4‐thiazolidinones
with 4,5‐dihydropyrazoles have been synthesized with
high yields via [2+3]‐cyclization using 3‐phenyl‐5‐aryl‐1‐
thiocarbamoyl‐2‐pyrazolines and bromopropionic acid,
maleic anhydride, N‐arylmaleimides, or aroylacrylic acids
as a starting compounds. Five of synthesized compounds
were tested and displayed moderate antitumor activity
against leukemia, lung, renal, prostate, and breast cancers
cell lines. The preliminary results of antiviral activity
allowed to identify the active compound 4a, which has
shown the best antiviral activity against Tacaribe TRVL
11 573 virus strain (EC50 = 0.71 μg/mL; SI = 130).
EXPERIMENTAL
The starting 3‐phenyl‐5‐aryl‐1‐thiocarbamoyl‐2‐pyrazolines
1a–c [21] were obtained according to the known synthetic
method.
Physical measurement. Melting points were measured in
open capillary tubes on
a BUCHI B‐545 melting point
apparatus and are uncorrected. Elemental analyses (C, H, N)
were performed using the Perkin‐Elmer 2400 CHN analyzer.
The analyses indicated by the symbols of the elements or
Obtained results are seemed as promised regarding fur-
ther investigations of N‐aryl‐[2‐(4,5‐dihydropyrazol‐1‐yl)‐
4‐oxo‐4,5‐dihydrothiazol‐5‐yl]‐acetamides as perspective
antiviral agents.
1
functions were within 0.4% of the theoretical values. The H‐
NMR spectra were recorded using the Varian Gemini 300 MHz
and 13C‐NMR spectra using Varian Mercury‐400 100 MHz in
Table 2
Antiviral activity of synthesized 2‐[5‐aryl‐3‐phenyl‐4,5‐dihydropyrazol‐1‐yl]‐thiazol‐4‐one derivatives (4a, 5c).
EC50, or
EC90* μg/
mL
CC50
μg/
mL
,
SIa
(CC50
EC50
/
)
Compounds
Assay
Virus
Virus Strain
Cell Line
Commentb
4a
Neutral Red
Neutral
Red
Flu A (H3N2)
Flu A (H5N1)
Wisconsin/67/2005
Vietnam/1203/
2004H
MDCK
MDCK
35
33
>100
>100
>2.9
>3
NA
NA
Neutral
Red
Neutral
Red
Neutral
Red
Flu B
SARS
Malaysia/2506/2004
MDCK
45
49
>100
49
>2.2
1
NA
NA
HA
Urbani
Vero‐
76
Vero‐
76
Tacaribe
TRVL 11573
0,71
89
130
Viral CPE
VYR
Viral CPE
Neutral
Red
Tacaribe
Tacaribe
Pichinde
Junin
TRVL 11573
TRVL 11573
An 4763
Vero 76
Vero 76
Vero
0,86
2.29*
2.1
28
34
18
27
32
15
9
MA
MA
SA
Candid 1
Vero
7.2
4
SA
Viral CPE
Neutral Red
Neutral
Red
Junin
Flu A (H3N2)
Flu A (H5N1)
Candid 1
Wisconsin/67/2005
Vietnam/1203/
2004H
Vero
MDCK
MDCK
5.7
37
77
32
>100
>100
6
SA
NA
NA
5c
>2.7
>1.3
Neutral
Red
Neutral
Red
Flu B
SARS
Malaysia/2506/2004
MDCK
Vero 76
28
32
>100
>3.6
NA
NA
Urbani
53
1,7
aThe table presents the results of antiviral activity against strains for which the selectivity index, SI ≥ 1.
bNA, not active; HA, highly active; MA, moderately active; SA, slightly active.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis and Anticancer and Antiviral Activities of
New 2-Pyrazoline-Substituted 4-Thiazolidinones
Month 2013
Antitumor agents
Antiviral agents
F
Me
N
O
S
N
O
O
O
N
S
I
N
N
NH
N
N
N
S
N
H
S
VI
II
Me
O
O
Ph
N
N
N
N
Ph
equivalent of dielectrophilic
Ar
N
N
H
Me
S
N
N
Me
O
synthon [C2]2+
N
N
S
N
Ar
N
O
N
S
VII
NH2
S
O
N
S
N
O
R
III
N
R
Ar2
N
Ph
O
N
O
O
N
N
N
N
N
S
OH
H
N
Ar1
Me
N
O
Ar3
Me
VIII
O
Me
Me
V
IV
Me
Figure 1. Structures of 4‐thiazolidinones and diazoles with anticancer and antiviral activities.
DMSO‐d6 or DMSO‐d6 + CCl4 mixture using tetramethylsilane
as an internal standard. Chemical shifts are reported in ppm
units using δ scale.
Chemistry. Synthesis of 2‐(5‐aryl‐3‐phenyl‐4,5‐dihydropyrazol‐
1‐yl)‐5‐methylthiazol‐4‐one (2a, 2b). A mixture of pyrazoline‐1‐
carbothioic acid amide (5 mmol), sodium acetate (5 mmol), and
2‐bromopropionic acid (5 mmol) was refluxed for 1 h in 10 mL
of acetic acid. After cooling, the reaction mixture was poured
into cold water. A solid material that precipitated out was filtered,
dried, and recrystallized with DMF:ethanol mixture (1:2).
C19H16ClN3OS: C, 61.70; H, 4.36; N, 11.36; Found: C, 61.82; H,
4.50; N, 11.21%.
General procedure for synthesis of [2‐(5‐aryl‐3‐phenyl‐4,
5‐dihydropyrazol‐1‐yl)‐4‐oxo‐4,5‐dihydrothiazol‐5‐yl]‐acetic acids
(3a, 3b), N‐aryl‐2‐[2‐(5‐aryl‐3‐phenyl‐4,5‐dihydropyrazol‐1‐yl)‐4‐
oxo‐4,5‐dihydrothiazol‐5‐yl]‐acetamides (4a–c) and 2‐(5‐aryl‐3‐
phenyl‐4,5‐dihydropyrazol‐1‐yl)‐5‐(2‐oxo‐2‐arylethyl)‐thiazol‐4‐ones
(5a–d). A mixture of pyrazoline‐1‐carbothioic acid amide (5 mmol)
and maleic anhydride or appropriate N‐arylmaleimide (5 mmol), or
β‐aroylacrylic acid (5 mmol) was refluxed for 1 h in 10 mL of acetic
acid. After cooling to the room temperature, precipitated white
powder was filtered off, washed with water and methanol, and
recrystallized with DMF:ethanol mixture (1:2).
2‐[5‐(4‐Methoxyphenyl)‐3‐phenyl‐4,5‐dihydropyrazol‐1‐
yl]‐5‐methylthiazol‐4‐one (2a). Yield 75%, mp 136–137°C.
1H‐NMR (300 MHz, DMSO‐d6 + CCl4): 7.85 (d, 2H, J = 7.1
Hz, arom.); 7.56–7.50 (m, 3H, arom.); 7.16 (d, 2H, J = 8.4 Hz,
arom.); 6.92 (d, 2H, J = 7.1 Hz, arom.); 5.74 (dd, 1H, J = 11.3,
4.5 Hz, CH2CH); 4.21–4.13 (m, 1H, CHCH3); 4.07 (dd, 1H, J =
18.2, 11.3 Hz, CH2CH); 3.72 (s, 3H, OCH3); 3.43 (dd, 1H, J =
18.2, 4.5 Hz, CH2CH); 1.47, 1.44 (d, d, 3H, CH3). 13C‐NMR
(100 MHz, DMSO‐d6): δ 190.1 (C═O), 176.4 (C═N, thiaz.),
161.1 (C═N, pyraz.), 159.4, 132.9, 131.9, 130.3, 129.5, 127.8,
127.7, 126.7, 114.7, 63.7 (CHCH2), 55.6 (O-CH3), 49.3 (CHCH3),
43.9 (CHCH2), 19.2 (CHCH3). Calcd. for C20H19N3O2S: C, 65.73;
H, 5.24; N, 11.50; Found: C, 65.89; H, 5.13; N, 11.69%.
{2‐[5‐(4‐Dimethylaminophenyl)‐3‐phenyl‐4,5‐dihydro-
pyrazol‐1‐yl]‐4‐oxo‐4,5‐dihydrothiazol‐5‐yl}‐acetic acid
1
(3a). Yield 76%, mp 200–202°C. H‐NMR (300 MHz, DMSO‐
d6 + CCl4): 12.68 (brs, 1H, COOH); 7.87 (d, 2H, J = 8.1 Hz, arom.);
7.57–7.52 (m, 3H, arom.); 7.05 (d, 2H, J = 7.5 Hz, arom.); 6.89 (d,
2H, J = 8.1 Hz, arom.); 5.66 (dd, 1H, J = 10.9, 2.4 Hz, CH2CH,
pyraz.); 4.34 (dd, 1H, J = 11.2, 2.3 Hz, CH2CH, thiaz.); 4.10 (dd,
1H, J = 17.9, 10.9 Hz, CH2CH, pyraz.); 3.43 (dd, 1H, J = 17.9, 2.4
Hz, CH2CH, pyraz.); 3.05 (dd, 1H, J = 18.1, 11.2 Hz, CH2CH, thiaz.);
2.87 (s, 6H, N(CH3)2); 2.73 (dd, 1H, J = 18.1, 2.3 Hz, CH2CH, thiaz.).
13C‐NMR (100 MHz, DMSO‐d6): δ 188.1 (C═O), 176.9 (C═N,
thiaz.), 172.8 (C═O), 161.4 (C═N, pyraz.), 150.5, 133.5, 131.9,
130.4, 129.1, 128.4, 127.8, 112.9, 63.9 (CHCH2), 50.5 (CHCH2),
45.2 (N- (CH3)2), 43.8 (CHCH2), 38.1 (CHCH2). Calcd. for
C22H22N4O3S: C, 62.54; H, 5.25; N, 13.26; Found: C, 62.41; H,
5.38; N, 13.12%.
2‐[5‐(4‐Chlorophenyl)‐3‐phenyl‐4,5‐dihydropyrazol‐1‐yl]‐
1
5‐methylthiazol‐4‐one (2b). Yield 68%, mp 199–200°C. H‐
NMR (300 MHz, DMSO‐d6 + CCl4): 7.85 (d, 2H, J = 7.1 Hz,
arom.); 7.57–7.51 (m, 3H, arom.); 7.45 (d, 2H, J = 6.9 Hz, arom.);
7.28 (d, 2H, J = 8.2 Hz, arom.); 5.83 (dd, 1H, J = 11.1, 4.9 Hz,
CH2CH); 4.21–4.15 (m, 1H, CHCH3); 4.13 (dd, 1H, J = 18.1,
11.1 Hz, CH2CH); 3.46 (dd, 1H, J = 18.1, 4.9 Hz, CH2CH); 1.48,
1.45 (d, d, 3H, CH3). 13C‐NMR (100 MHz, DMSO‐d6): δ 189.9
(C═O), 176.5 (C═N, thiaz.), 161.0 (C═N, pyraz.), 139.8, 132.9,
132.1, 130.2 129.5, 128.3, 128.2, 127.8, 63.5 (CHCH2),
49.4 (CHCH3), 43.8 (CHCH2), 19.2 (CHCH3). Calcd. for
{2‐[5‐(4‐Chlorophenyl)‐3‐phenyl‐4,5‐dihydropyrazol‐1‐
yl]‐4‐oxo‐4,5‐dihydrothiazol‐5‐yl}‐acetic acid (3b). Yield
1
66%, mp 205–207°C. H‐NMR (300 MHz, DMSO‐d6 + CCl4):
12.75 (brs, 1H, COOH); 7.86 (d, 2H, J = 6.8 Hz, arom.); 7.57–7.51
(m, 3H, arom.); 7.44 (d, 2H, J = 7.1 Hz, arom.); 7.27 (d, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, and R. Lesyk
Vol 000
J = 7.3 Hz, arom.); 5.83 (dd, 1H, J = 10.9, 2.7 Hz, CH2CH, pyraz.);
4.36 (dd, 1H, J = 10.3, 3.4 Hz, CH2CH, thiaz.); 4.17 (dd, 1H, J =
18.1, 10.9 Hz, CH2CH, pyraz.); 3.45 (dd, 1H, J = 18.1, 2.7 Hz,
CH2CH, pyraz.); 3.05 (dd, 1H, J = 16.4, 10.3 Hz, CH2CH, thiaz.);
2.73 (dd, 1H, J = 16.4, 3.4 Hz, CH2CH, thiaz.). 13C‐NMR (100
MHz, DMSO‐d6): δ 188.0 (C═O), 177.3 (C═N, thiaz.), 172.8
(C═O), 161.1 (C═N, pyraz.), 139.8, 132.8, 132.1, 130.2, 129.5,
128.4, 128.2, 127.8, 63.4 (CHCH2), 50.8 (CHCH2), 43.8 (CHCH2),
37.8 (CHCH2). Calcd. for C20H16ClN3O3S: C, 58.04; H, 3.90; N,
10.15; Found: C, 58.15; H, 3.78; N, 10.27%.
Calcd. for C28H23ClN4O4S: C, 61.48; H, 4.24; N, 10.24; Found:
C, 61.32; H, 4.48; N, 10.40%.
5‐[2‐(4‐Fluorophenyl)‐2‐oxoethyl]‐2‐[5‐(4‐methoxyphenyl)‐
3 ‐ phenyl‐ 4,5‐dihydropyrazol‐1‐yl]‐ thiazol‐ 4‐ one (5a).
1
Yield 63%, mp 121–122°C. H‐NMR (300 MHz, DMSO‐d6 +
CCl4): 8.07 (dd, 2H, J = 8.8, 5.2 Hz, arom.); 7.82 (d, 2H, J =
6.8 Hz, arom.); 7.49–7.47 (m, 3H, arom.); 7.26 (t, 2H, J = 8.8
Hz, arom); 7.18 (d, 2H, J = 8.8 Hz, arom.); 6.86 (d, 2H, J = 8.4
Hz, arom.); 5.77 (dd, 1H, J = 11.2, 3.2 Hz, CH2CH, pyraz.); 4.32
(dd, 1H, J = 11.2, 4.0 Hz, CH2CH, thiaz.); 4.09 (dd, 1H, J = 18.8,
11.2 Hz, CH2CH, pyraz.); 3.90 (dd, 1H, J = 16.4, 11.2 Hz, CH2CH,
thiaz.); 3.75 (s, 3H, OCH3); 3.39 (dd, 1H, J = 18.8, 3.2 Hz, CH2CH,
pyraz.); 3.32 (dd, 1H, J = 16.4, 4.0 Hz, CH2CH, thiaz.). 13C‐NMR
(100 MHz, DMSO‐d6): δ 196.9 (C═O), 188.7 (C═O), 177.5
(C═N, thiaz.), 165.8 (d, JCF = 200.0 Hz, 1C), 161.2 (C═N, pyraz.),
139.5, 136.2, 134.2, 132.9, 131.8 (d, JCF = 30.0 Hz, 2C), 130.3,
129.5, 128.4, 127.8, 116.3 (d, JCF = 10.0 Hz, 2C), 114.7, 63.7
(CHCH2), 55.6 (O-CH3), 49.7 (CHCH2), 43.9 (CHCH2), 42.9
(CHCH2). Calcd. for C27H22FN3O3S: C, 66.52; H, 4.55; N, 8.62;
Found: C, 66.69; H, 4.38; N, 8.82%.
N‐(4‐Methoxyphenyl)‐2‐{2‐[5‐(4‐methoxyphenyl)‐3‐ phenyl‐
4,5‐dihydropyrazol‐1‐yl]‐4‐ oxo‐ 4,5‐ dihydrothiazol‐ 5‐ yl}‐
acetamide (4a). Yield 65%, mp 224–225°C. 1H‐NMR (300
MHz, DMSO‐d6 + CCl4): 9.87 (s, 1H, NH); 7.83 (d, 2H, J = 6.8
Hz, arom.); 7.46–7.51 (m, 5H, arom.); 7.17 (d, 2H, J = 8.4 Hz,
arom.); 6.88 (d, 2H, J = 8.4 Hz, arom.); 6.80 (d, 2H, J = 8.8 Hz,
arom.); 5.75 (dd, 1H, J = 11.2, 3.6 Hz, CH2CH, pyraz.); 4.29
(dd, 1H, J = 7.8, 4.0 Hz, CH2CH, thiaz.); 4.14 (dd, 1H, J = 18.4,
11.2 Hz, CH2CH, pyraz.); 3.75 (s, 3H, OCH3); 3.73 (s, 3H,
OCH3); 3.36 (dd, 1H, J = 18.4, 3.6 Hz, CH2CH, pyraz.); 3.19 (dd,
1H, J = 16.4, 7.8 Hz, CH2CH, thiaz.); 2.58 (dd, 1H, J = 16.4, 4.0
Hz, CH2CH, thiaz.). 13C‐NMR (100 MHz, DMSO‐d6): δ 188.5
(C═O), 177.4 (C═N, thiaz.), 168.5 (C═O), 161.2 (C═N, pyraz.),
159.4, 155.8, 133.0, 132.5, 132.0, 130.3, 129.5, 127.8, 127.5,
121.2, 114.7, 114.4, 63.4 (CHCH2), 55.6 (O-CH3), 55.2 (O-CH3),
50.9 (CHCH2), 43.9 (CHCH2), 40.3 (CHCH2). C28H26N4O4S: C,
65.35; H, 5.09; N, 10.89; Found: C, 65.57; H, 5.18; N, 10.67%.
N‐(4‐Acetoxyphenyl)‐2‐{2‐[5‐(4‐methoxyphenyl)‐3‐phenyl‐
5‐[2‐Phenyl‐2‐oxoethyl]‐2‐[5‐(4‐chlorophenyl)‐3‐phenyl‐
4,5‐dihydropyrazol‐1‐yl]‐thiazol‐4‐one (5b). Yield 64%, mp
215–217°C. 1H‐NMR (300 MHz, DMSO‐d6 + CCl4): 8.00 (d, 2H,
J = 7.7 Hz, arom.); 7.85 (d, 2H, J = 7.2 Hz, arom.); 7.67 (t, 1H, J
= 7.1 Hz, arom.); 7.56–7.52 (m, 5H, arom.); 7.44 (d, 2H, J = 7.9
Hz, arom.); 7.31 (d, 2H, J = 7.9 Hz, arom.); 5.85 (dd, 1H, J =
11.0, 3.3 Hz, CH2CH, pyraz.); 4.45 (dd, 1H, J = 10.5, 3.3 Hz,
CH2CH, thiaz.); 4.16 (dd, 1H, J = 18.3, 11.0 Hz, CH2CH, pyraz.);
3.97 (dd, 1H, J = 18.7, 10.5 Hz, CH2CH, thiaz.); 3.54 (dd, 1H, J =
18.7, 3.3 Hz, CH2CH, thiaz.); 3.45 (dd, 1H, J = 18.3, 3.3 Hz,
CH2CH, pyraz.). 13C‐NMR (100 MHz, DMSO‐d6): δ 198.2
(C═O), 188.7 (C═O), 177.7 (C═N, thiaz.), 161.1 (C═N, pyraz.),
139.8, 136.2, 134.2, 132.9, 132.1, 130.2, 129.5, 129.4, 129.3,
128.6, 128.3, 127.8, 63.5 (CHCH2), 49.8 (CHCH2), 43.8 (CHCH2),
42.9 (CHCH2). Calcd. for C26H20ClN3O2S: C, 65.89; H, 5.25; N,
8.87; Found: C, 65.72; H, 5.40; N, 9.00%.
4,5‐dihydropyrazol‐1‐yl]‐4‐oxo‐4,5‐dihydrothiazol‐5‐yl}‐
acetamide (4b). Yield 72%, mp 230–232°C. 1H‐NMR (300
MHz, DMSO‐d6 + CCl4): 10.21 (s, 1H, NH); 7.82 (d, 2H, J =
7.8 Hz, arom.); 7.59–7.44 (m, 5H, arom.); 7.15 (d, 2H, J = 8.7
Hz, arom.); 7.05 (d, 2H, J = 8.9 Hz, arom.); 6.90 (d, 2H, J = 8.4
Hz, arom.); 5.75 (dd, 1H, J = 11.1, 3.6 Hz, CH2CH, pyraz.); 4.36
(dd, 1H, J = 11.4, 3.5 Hz, CH2CH, thiaz.); 4.09 (dd, 1H, J =
18.3, 11.1 Hz, CH2CH, pyraz.); 3.72 (s, 3H, OCH3); 3.33 (dd,
1H, J = 18.3, 3.6 Hz, CH2CH, pyraz.); 3.24 (dd, 1H, J = 16.4,
11.4 Hz, CH2CH, thiaz.); 2.67 (dd, 1H, J = 16.4, 3.5 Hz, CH2CH,
thiaz.); 2.23 (s, 3H, COCH3). 13C‐NMR (100 MHz, DMSO‐d6): δ
188.5 (C═O), 177.4 (C═N, thiaz.), 169.8 (C═O), 169.1 (C═O),
161.3 (C═N, pyraz.), 159.4, 146.5, 136.9, 132.9, 132.0, 130.3,
129.5, 127.8, 127.7, 122.5, 120.5, 114.7, 63.7 (CHCH2), 55.6
(O-CH3), 50.8 (CHCH2), 43.9 (CHCH2), 40.3 (CHCH2), 21.3
(CO-CH3). Calcd. for C29H26N4O5S: C, 64.19; H, 4.83; N,
10.33; Found: C, 64.31; H, 4.68; N, 10.20%.
5‐[2‐(4‐Fluorophenyl)‐2‐oxoethyl]‐2‐[5‐(4‐chlorophenyl)‐
3‐phenyl‐ 4,5‐dihydropyrazol‐1‐yl]‐ thiazol‐ 4‐ one (5c).
Yield 69%, mp 200–202°C. 1H‐NMR (300 MHz, DMSO‐d6
+CCl4): 8.09–8.06 (m, 2H, arom.); 7.85 (d, 2H, J = 6.8 Hz, arom.);
7.55–7.51 (m, 3H, arom.); 7.43 (d, 2H, J = 8.0 Hz, arom); 7.35–
7.30 (m, 4H, arom.); 5.85 (dd, 1H, J = 11.1, 3.6 Hz, CH2CH,
pyraz.); 4.44 (dd, 1H, J = 10.7, 2.6 Hz, CH2CH, thiaz.); 4.15
(dd, 1H, J = 18.1, 11.1 Hz, CH2CH, pyraz.); 3.95 (dd, 1H, J =
18.8, 10.7 Hz, CH2CH, thiaz.); 3.52 (dd, 1H, J = 18.8, 2.6 Hz,
CH2CH, thiaz.); 3.44 (dd, 1H, J = 18.1, 3.6 Hz, CH2CH, pyraz.).
13C‐NMR (100 MHz, DMSO‐d6): δ 196.8 (C═O), 188.7
(C═O), 177.6 (C═N, thiaz.), 165.8 (d, JCF = 200.0 Hz, 1C),
161.1 (C═N, pyraz.), 139.8, 132.9, 131.9 (d, JCF = 30.0 Hz,
N‐(4‐Acetoxyphenyl)‐2‐{2‐[5‐(4‐chlorphenyl)‐3‐phenyl‐4,
5‐dihydropyrazol‐1‐yl]‐4‐oxo‐4,5‐dihydrothiazol‐5‐yl}‐
acetamide (4c). Yield 78%, mp 235–237°C. 1H‐NMR (300
MHz, DMSO‐d6 + CCl4): 10.22 (s, 1H, NH); 7.86 (d, 2H, J =
7.3 Hz, arom.); 7.60–7.50 (m, 5H, arom.); 7.45 (d, 2H, J = 8.1
Hz, arom.); 7.29 (d, 2H, J = 5.9 Hz, arom.); 7.08 (d, 2H, J =
8.6 Hz, arom.); 5.84 (dd, 1H, J = 11.1, 3.6 Hz, CH2CH, pyraz.);
4.24 (dd, 1H, J = 10.1, 3.0 Hz, CH2CH, thiaz.); 4.13 (dd, 1H, J =
16.5, 11.1 Hz, CH2CH, pyraz.); 3.48 (dd, 1H, J = 16.5, 3.6 Hz,
CH2CH, pyraz.); 3.26 (dd, 1H, J = 16.4, 10.0 Hz, CH2CH,
thiaz.); 2.73 (dd, 1H, J = 16.4, 3.0 Hz, CH2CH, thiaz.); 2.25
(s, 3H, COCH3). 13C‐NMR (100 MHz, DMSO‐d6): δ 188.5
(C═O), 177.6 (C═N, thiaz.), 169.8 (C═O), 169.0 (C═O),
161.1 (C═N, pyraz.), 146.5, 139.9, 136.9, 132.9, 132.0, 129.5,
129.4, 128.4, 128.3, 127.8, 122.5, 120.5, 63.5 (CHCH2), 50.8
(CHCH2), 43.8 (CHCH2), 43.7 (CHCH2), 21.3 (CO-CH3).
2C), 131.6, 130.2, 129.5, 129.3, 128.3, 127.8, 116.3 (d, JCF
=
10.0 Hz, 2C), 63.5 (CHCH2), 49.8 (CHCH2), 43.8 (CHCH2),
42.9 (CHCH2). Calcd. for C26H19ClFN3O2S: C, 63.48; H, 3.89;
N, 8.54; Found: C, 63.57; H, 3.70; N, 8.68%.
5‐[2‐(4‐Chlorophenyl)‐2‐oxoethyl]‐2‐[5‐(4‐chlorophenyl)‐
3‐phenyl‐4,5‐dihydropyrazol‐1‐yl]‐thiazol‐4‐one (5d).
1
Yield 74%, mp 203–205°C. H‐NMR (300 MHz, DMSO‐d6 +
CCl4): 8.02 (d, 2H, J = 8.3 Hz, arom.); 7.85 (d, 2H, J = 7.4 Hz,
arom.); 7.62 (d, 2H, J = 8.3 Hz, arom.); 7.56–7.50 (m, 3H, arom);
7.45 (d, 2H, J = 7.9 Hz, arom.); 7.29 (d, 2H, J = 8.29 Hz, arom.);
5.85 (dd, 1H, J = 10.9, 3.2 Hz, CH2CH, pyraz.); 4.44 (dd, 1H, J =
10.7, 2.6 Hz, CH2CH, thiaz.); 4.15 (dd, 1H, J = 18.1, 10.9 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis and Anticancer and Antiviral Activities of
New 2-Pyrazoline-Substituted 4-Thiazolidinones
Month 2013
CH2CH, pyraz.); 3.97 (dd, 1H, J = 19.2, 10.7 Hz, CH2CH,
thiaz.); 3.58 (dd, 1H, J = 19.2, 2.6 Hz, CH2CH, thiaz.); 3.47
(dd, 1H, J = 18.1, 3.2 Hz, CH2CH, pyraz.). 13C‐NMR (100
MHz, DMSO‐d6): δ 196.7 (C═O), 188.7 (C═O), 177.4 (C═N,
thiaz.), 161.2 (C═N, pyraz.), 139.7, 136.2, 133.0, 132.2, 131.8,
131.6, 130.2, 129.5, 129.4, 128.4, 128.2, 127.8, 63.4 (CHCH2),
49.7 (CHCH2), 43.8 (CHCH2), 42.7 (CHCH2). Calcd. for
C26H19Cl2N3O2S: C, 61.42; H, 3.77; N, 8.26; Found: C, 61.57;
H, 3.60; N, 8.41%.
Methods for assay of cytotoxicity. In the CPE inhibition
tests, two wells of uninfected cells treated with each concentration
of tested compounds was run in parallel with the infected, treated
wells. At the time CPE was determined microscopically. The
toxicity control cells were also examined microscopically for
any changes in cell appearance compared with normal control
cells run in the same plate. These changes may be enlargement,
granularity, cells with ragged edges, filmy appearance, rounding,
detachment from the surface of the well, or other changes. These
changes were given a designation of T (100% toxic), PVH
(partially toxic–very heavy–80%), PH (partially toxic–heavy–
60%), P (partially toxic–40%), Ps (partially toxic–slight–20%),
or 0 (no toxicity–0%), conforming to the degree of cytotoxicity
seen. A 50% cell inhibitory (cytotoxic) concentration (CC50)
was determined by regression analysis of these data.
Pharmacology Primary anticancer assay. Primary anticancer
assay was performed at
∼ 60 human tumor cell lines
panel derived from nine neoplastic diseases (leukemia,
melanoma, lung, colon, CNS, ovarian, renal, prostate, and
breast cancers), in accordance with a protocol of the Drug
Evaluation Branch, National Cancer Institute, Bethesda [24–28].
Tested compounds were added to the cultures at a single
concentration (10−5 M), and the cultures were incubated for 48
h. End point determinations were made with a protein‐binding
Acknowledgments. The authors are grateful to Dr. V. L. Narayanan
from Drug Synthesis and Chemistry Branch, National Cancer
Institute, Bethesda, MD, USA, for in vitro evaluation of anticancer
activity and to Dr. Chris Tseng, from Division of Microbiology
and Infectious Diseases NIAID/NIH, Bethesda, USA, for in vitro
evaluation of antiviral activity.
dye, sulforhodamine
B (SRB). Results for each tested
compound were reported as a percent of growth of the treated
cells when compared with the untreated control cells.
Methods for assay of antiviral activity. Primary antiviral assay
was performed at a biodefense viruses panel (Tacaribe, Pichinde,
Junin) and a respiratory viruses panel [Flu A (H3N2), Flu A
(H5N1), Flu B, SARS] with a protocol of the NIAID’s
antimicrobial acquisition and coordinating [29–31]. Results for
each tested compound were reported as virus‐inhibitory
concentration, 50% endpoint (EC50), or 90% effective
concentration (EC90) and cell‐inhibitory concentration, 50%
endpoint (CC50) were determined. A general selectivity index (SI)
was calculated as a ration of (CC50)/(EC50). An SI of 3 or greater
indicates that confirmatory testing is needed.
Inhibition of viral cytopathic effect. This test, run in
96‐well flat‐bottomed microplates, was used for the initial
antiviral evaluation of compounds. In this cytopathic effect
(CPE) inhibition test, four log10 dilutions of each test
compound (e.g., 1000, 100, 10, 1 μg/mL) were added to three
cups containing the cell monolayer; within 5 min. On the next
step, the virus was added, and the plate was sealed and incubated
at 37°C. CPE read microscopically when untreated infected
controls develop a 3 to 4+ CPE (∼ 72–120 h). A known positive
control drug was evaluated in parallel with test drugs in each test.
This drug was ribavirin for influenza, Tacaribe, Pichinde, and
Junin viruses and alferon for SARS virus. The data are expressed
as 50% effective concentrations (EC50).
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