Synthesis and Primary Antitumor Screening of 4-[5-(1H-Indol-3-ylmethylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanamides

Article abstract of DOI:10.1134/S1070428020070040

Abstract: A preparative procedure was developed for the synthesis of 4-[5-(1-R-1H-indol-3-ylmethylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoic acids which were converted to acid chlorides, and the latter reacted with aromatic and heterocycli

Full text of DOI:10.1134/S1070428020070040

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 7, pp. 1146–1152. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 7, pp. 1021–1029.
Synthesis and Primary Antitumor Screening
of 4-[5-(1H-Indol-3-ylmethylidene)-4-oxo-2-sulfanylidene-
1
,3-thiazolidin-3-yl]butanamides
a
b,
V. Ya. Horishny and V. S. Matiychuk *
a
Danylo Halytsky Lviv National Medical University, Lviv, 79010 Ukraine
b
Ivan Franko National University of Lviv, Lviv, 79005 Ukraine
*
e-mail: v_matiychuk@ukr.net
Received March 11, 2020; revised April 5, 2020; accepted April 6, 2020
Abstract—A preparative procedure was developed for the synthesis of 4-[5-(1-R-1H-indol-3-ylmethylidene)-4-
oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoic acids which were converted to acid chlorides, and the latter
reacted with aromatic and heterocyclic amines to afford a series of previously unknown 4-[5-(1H-indol-3-
ylmethylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanamides. The synthesized compounds showed
a moderate antitumor activity against most malignant tumor cells. UO31 renal cancer cell line turned out to be
most sensitive to most of the tested compounds.
Keywords: organic synthesis, 2-sulfanylidene-1,3-thiazolidin-4-one, indole, antitumor activity
DOI: 10.1134/S1070428020070040
The chemistry of indole began to develop due to the
study of indigo, a substance known to mankind long
before the emergence of organic chemistry as a science.
The unique properties of the indole ring became clear
after the structures of many proteins, various alkaloids,
and neurotransmitters have been determined and
a large number of pharmacological agents of this class
have been introduced into medical practice. Today, the
indole heterocycle is considered privileged [1, 2], and
research in the field of indole chemistry is performed
by scientists working in different areas.
The present work continues our studies of bio-
logically important heterocyclic compounds [6–20].
Herein, we report the synthesis and antitumor activity
of 4-[5-(1H-indol-3-ylmethylidene)-4-oxo-2-sulfanyli-
dene-1,3-thiazolidin-3-yl]butanamides. It should be
noted that 5-(1H-indol-3-ylmethylidene)-2-sulfanyli-
dene-1,3-thiazolidin-4-one derivatives have been found
to exhibit a broad spectrum of biological activity,
including antimicrobial [21, 22], antiviral [23], and
antitumor [24, 25], as well as inhibitory activity against
various enzymes [26–29].
Initial 4-[5-(1H-indol-3-ylmethylidene)-4-oxo-2-
sulfanylidene-1,3-thiazolidin-3-yl]butanoic acids 3a
and 3b were prepared by the condensation of 1H-in-
dole-3-carbaldehyde (1a) and its N-methyl derivative
Similarly to indole, rhodanine (2-sulfanylidene-1,3-
thiazolidin-4-one) and related heterocycles are also
considered privileged. Compounds containing this
pharmacophore exhibit a broad spectrum of biological
activities. Biological properties of thiazolidin-4-one
derivatives have been reviewed in [3–5].
1
b with 4-(4-oxo-2-sulfanylidene-1,3-thiazolidin-3-
yl)butanoic acid (2). The optimal conditions for this
transformation were boiling acetic acid as a solvent
and the presence of sodium acetate as a base. The
Nevertheless, in-depth studies of the indole and
2
-sulfanylidene-1,3-thiazolidin-4-one heterocyclic
1
structure of 3a and 3b was confirmed by H NMR
systems, synthesis of hybrids based thereon and study
of their biological activity, and establishment of the
relevant structure–activity relationships are of un-
doubted interest both from both theoretical viewpoint
and in terms of directed search for potential drugs.
spectra which contained signals from methylene
protons of the aliphatic chain as two triplets and one
multiplet at δ 1.85–4.14 ppm. The CH= proton res-
onated at δ 8.00–8.10 ppm, indicating Z configuration
of the exocyclic double C=C bond.
1146

SYNTHESIS AND PRIMARY ANTITUMOR SCREENING
1147
Scheme 1.
O
CHO
O
OH
N
+
N
O
OH
S
N
O
S
N
S
O
S
N
R
R
1
a, 1b
2
3a, 3b
O
1
2
HNR R (5a–5e)
Et
R1
SOCl2
N
3
N
Cl
N
S
S
R2
N
N
S
O
S
O
R
R
4
a, 4b
6–10
1
, 3, 4, 6–10, R = H (a), Me (b).
O
O
H
N
N
S
N
O
N
S
S
O
N
S
O
N
OH
R
R
6
a, 6b
7a, 7b
O
O
H
N
H
N
N
N
S
S
O
S
S
O
N
N
OH
N
N
H
R
R
8
a, 8b
9a, 9b
O
H
N
Me
N
S
Me
O
S
N
N
O
R
Ph
1
0a, 10b
Acids 3a and 3b were converted to acid chlorides
a and 4b by treatment with thionyl chloride in
a classical alicyclic amine, and its reaction with acid
chlorides 4 can be used to estimate the reactivity of the
latter. Tyramine (5c) and tryptamine (5d) are simple
alkaloids, and introduction of the corresponding frag-
ments into organic molecules often gives rise to
pharmacological activity. Likewise, a similar result is
obtained by introduction of pharmacophoric p-amino-
phenol (5b) and aminophenazone (5c) fragments.
4
anhydrous toluene under reflux until the initial acid
completely dissolved. Acid chlorides 4a and 4b were
isolated as orange crystalline solids soluble in benzene,
dioxane, acetone, and DMF and insoluble in saturated
hydrocarbons.
The target amides 6–10 were synthesized by reac-
tions of 4a and 4b with aliphatic, aromatic, and
heterocyclic amines 5a–5e (Scheme 1) in 1,4-dioxane.
The amines used were morpholine (5a), p-aminophenol
5b), tyramine [5c, 4-(2-aminoethyl)phenol], trypt-
amine (5d), and 4-amino-1,5-dimethyl-2-phenyl-1,2-
dihydro-3H-pyrazol-3-one (5e). Morpholine (5a) is
The structures of amides 6–10 are shown in
1
Scheme 1. They were confirmed by H NMR spectra
which, as well as the spectra of 3a and 3b, showed
signals at δ 1.85–4.12 ppm from aliphatic methy-
lene protons [(CH ) , (CH ) ]; the exocyclic CH=
(
2
3
2 2
proton resonated as a singlet at δ 8.05–8.10 ppm,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

1148
HORISHNY, MATIYCHUK
Table 1. Cytotoxicity of compounds 6–10 at a concentration of 10–5 M against 60 cancer cell lines
Mitotic activity in 60 cancer cell lines, GP, %
Compound
Most sensitive cancer cell lines, GP, %
no.
average
range
UO-31 (renal cancer) 73.93
IGROV1 (ovarian cancer) 81.04
6
a
98.67
73.93–127.05
UO-31 (renal cancer) 75.79
IGROV1 (ovarian cancer) 77.91
6
b
99.48
96.27
95.44
98.18
75.79–124.96
67.77–133.75
71.31–113.28
67.00–127.84
UO-31 (renal cancer) 67.77
IGROV1 (ovarian cancer) 73.08
7
a
UO-31 (renal cancer) 71.31
MOLT-4 (leukemia) 77.20
7
b
UO-31 (renal cancer) 67.00
IGROV1 (ovarian cancer) 72.55
8
a
UO-31 (renal cancer) 42.20
CCRF-CEM (leukemia) 44.56
SK-MEL-5 (melanoma) 47.89
MOLT-4 (leukemia) 50.35
8
b
81.83
42.20–126.36
K-562 (leukemia) 54.04
HL-60(TB) (leukemia) 55.83
MDA-MB-468 (breast cancer) 58.63
MCF7 (breast cancer) 59.06
M14 (melanoma) 36.82
K-562 (leukemia) 46.55
UO-31 (renal cancer) 49.71
9
a
87.40
79.67
36.82–115.54
35.50–108.43
UO-31 (renal cancer) 35.50
HL-60(TB) (leukemia) 37.22
K-562 (leukemia) 49.60
9
b
SK-MEL-5 (melanoma) 56.16
CCRF-CEM (leukemia) 57.53
1
0a
93.80
94.20
54.11–117.36
69.45–120.83
A498 (renal cancer) 54.11
UO-31 (renal cancer) 69.45
SF-268 (central nervous system cancer) 75.01
A549/ATCC (non-small-cell lung cancer) 83.34
1
0b
and the NH signal appeared in the region δ 9.75–
growth percentage (GP, %) relative to control [30–33].
The results are summarized in Table 1. It is seen that all
compounds 6–10 showed a moderate antitumor activ-
ity. Among them, the most active were 9b (mean GP =
1
0.30 ppm.
The in vitro antitumor activity of the synthesized
compounds was studied by highly efficient biological
screening according to the Developmental Therapeutic
Program of the National Cancer Institute (National
Institute of Health, Bethesda, Maryland, USA) [30–33]
on 60 cancer cell lines encompassing virtually all
spectrum of human cancers (including leukemia, non-
small-cell lung cancer, epithelial colon cancer,
melanoma, ovarian cancer, and breast cancer).
Compounds 6–10 were tested at a concentration of
7
9.67%) and 9a (mean GP = 87.40%) derived from
tryptamine and 8b (mean GP = 81.83%) derived from
tyramine. The highest activity was observed for com-
pound 9b against UO-31 renal cancer cell line (GP =
3
5.50%), and this cancer cell line turned out to be the
most sensitive to the majority of the other compounds
tested.
In summary, we have developed a convenient
procedure for the synthesis of 4-[5-(1H-indol-3-yl-
–
5
1
0
M. Their activity was evaluated as cancer cell
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

SYNTHESIS AND PRIMARY ANTITUMOR SCREENING
1149
1
methylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-
yl]butanamides. The synthesized compounds have
been found to exhibit a moderate antitumor activity
against a panel of human cancer cell lines.
(3b). Yield 83%, mp 223–225°C. H NMR spectrum,
δ, ppm: 2.04–1.89 m (2H, NCH CH ), 2.30 t (2H,
2
2
NCH , J = 7.4 Hz), 3.97 s (3H CH ), 4.14 t (2H,
CH CO, J = 7.1 Hz), 7.33–7.22 m (2H, indole), 7.48 d
2
3
2
(
1H, indole, J = 7.6 Hz), 7.79 s (1H, indole), 7.88 d
13
EXPERIMENTAL
(1H, indole, J = 7.3 Hz), 8.00 s (1H, CH=). C NMR
spectrum, δ , ppm: 22.13, 31.01, 33.42, 43.53, 110.10,
C
1
The H NMR spectra were recorded from solutions
1
10.95, 114.31, 118.62, 123.40, 125.32, 127.26,
in DMSO-d on a Varian Mercury VX-400 spec-
trometer at 400 MHz using tetramethylsilane as
internal standard.
6
133.89, 136.95, 166.74, 173.71, 192.41. Found, %:
C 56.75; H 4.35; N 7.69. C H N O S . Calculat-
1
7
16
2
3 2
ed, %: C 56.65; H 4.47; N 7.77.
-[5-(1H-Indol-3-ylmethylidene)-4-oxo-2-sul-
fanylidene-1,3-thiazolidin-3-yl]butanoyl chlorides
a and 4b (general procedure). A 50-mL round-bottom
flask was charged with 2 mmol of acid 3a or 3b,
.2 mL of thionyl chloride, and 3 mL of anhydrous
4
-(4-Oxo-2-sulfanylidene-1,3-thiazolidin-3-yl)-
4
butanoic acid (2). A flat-bottom flask equipped with
a reflux condenser was charged with 50 mmol of
γ-aminobutyric acid, 5.7 g (5.5 mmol) of carbon
disulfide, 5.6 g (100 mmol) of potassium hydroxide,
and 15 mL of water. The mixture was stirred with
a magnetic stirrer, and a solution of 5.2 g (5.5 mmol) of
chloroacetic acid preliminarily neutralized with
4
1
toluene, and the mixture was refluxed for 10 min until
it became homogeneous. The hot solution was poured
into 5 mL of petroleum ether, the mixture was cooled,
and the precipitate was filtered off, washed with
petroleum ether, dried, and recrystallized from toluene–
petroleum ether.
5
.5 mmol of sodium hydrogen carbonate in 25 mL of
water was added dropwise with stirring over a period
of 15 min. The mixture was left to stand at ~20°C
for 2 days, 20 mL of 6 N aqueous HCl was added
to the resulting solution, and the mixture was
refluxed for 1 h. The mixture was cooled, and
the precipitate was filtered off and recrystallized
twice in succession from dilute acetic acid and ethanol.
Yield 91%, mp 121–122°C.
4
-[5-(1H-Indol-3-ylmethylidene)-4-oxo-2-sul-
fanylidene-1,3-thiazolidin-3-yl]butanoyl chloride
(4a). Yield 63%, mp 163–165°C.
4-[5-(1-Methyl-1H-Indol-3-ylmethylidene)-4-
oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoyl
chloride (4b). Yield 92%, mp 154–155°C.
4
-[5-(1H-Indol-3-ylmethylidene)-4-oxo-2-
sulfanylidene-1,3-thiazolidin-3-yl]butanoic acids 3a
and 3b (general procedure). A round-bottom flask
equipped with a refulx condenser was charged with
5-(1H-Indol-3-ylmethylidene)-4-oxo-2-sul-
fanylidene-1,3-thiazolidin-3-yl]butanamides 6–10
(general procedure). Amine 5a–5e, 2.1 mmol, was
dissolved in 4 mL of anhydrous 1,4-dioxane with slight
heating, a solution of 1 mmol of acid chloride 4a or 4b
in 4 mL of anhydrous 1,4-dioxane was added, and the
mixture was heated at 90–95°C for 10 min. The mix-
ture was cooled and diluted with water acidified with
a few drops of aqueous HCl, and the precipitate was
filtered off, washed with water, dried, and recrystallized
from acetic acid.
1
.1 g (5 mmol) of acid 2, 6 mmol of 1H-indole-3-
carbaldehyde 1a or 1b, 0.41 g (5 mmol) of anhydrous
sodium acetate, and 5 mL of acetic acid. The mixture
was refluxed for 3 h and cooled, and the solid product
was filtered off, washed with acetic acid and water,
dried, and recrystallized from acetic acid.
4
-[5-(1H-Indol-3-ylmethylidene)-4-oxo-2-sul-
fanylidene-1,3-thiazolidin-3-yl]butanoic acid (3a).
1
Yield 67%, mp 227–229°C. H NMR spectrum, δ,
5
-(1H-Indol-3-ylmethylidene)-3-[4-(morpholin-
ppm: 1.95–1.85 m (2H, NCH CH ), 2.29 t (2H, NCH ,
2
2
2
4-yl)-4-oxobutyl]-2-sulfanylidene-1,3-thiazolidin-4-
J = 7.2 Hz), 4.08 t (2H, CH CO, J = 6.9 Hz), 7.30–
1
2
one (6a). Yield 98%, mp 205–207°C. H NMR spec-
7.19 m (2H, indole), 7.51 d (1H, indole, J = 7.8 Hz),
7.91 s (1H, indole), 7.96 d (1H, indole, J = 7.5 Hz),
8.08 s (1H, =CH), 12.15 s (1H, COOH), 12.39 s
trum, δ, ppm: 1.97–1.84 m (2H, NCH CH ), 2.38 t
2
2
(
2H, NCH , J = 7.1 Hz), 3.42–3.36 m and 3.59–3.47 m
2
(
4H each, morpholine), 4.08 t (2H, CH CO, J =
2
(
1H, NH). Found, %: C 55.29; H 4.01; N 8.01.
6
.9 Hz), 7.31–7.19 m (2H, indole), 7.51 d (1H, indole,
C H N O S . Calculated, %: C 55.47; H 4.07;
1
6
14
2
3
2
J = 7.8 Hz), 7.91 s (1H, indole), 7.96 d (1H, indole,
J = 7.6 Hz), 8.07 s (1H, CH=), 12.39 s (1H, NH).
Found, %: C 57.72; H 5.17; N 10.01. C H N O S .
N 8.09.
-[5-(1-Methyl-1H-indol-3-ylmethylidene)-4-oxo-
-sulfanylidene-1,3-thiazolidin-3-yl]butanoic acid
4
2
0
21
3
3 2
2
Calculated, %: C 57.81; H 5.09; N 10.11.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

1150
HORISHNY, MATIYCHUK
5
-(1-Methyl-1H-indol-3-ylmethylidene)-3-
N-[2-(4-Hydroxyphenyl)ethyl]-4-[5-(1-methyl-
1H-indol-3-ylmethylidene)-4-oxo-2-sulfanylidene-
1,3-thiazolidin-3-yl]butanamide (8b). Yield 84%,
[
1
1
4-(morpholin-4-yl)-4-oxobutyl]-2-sulfanylidene-
,3-thiazolidin-4-one (6b). Yield 82%, mp 186–
88°C. H NMR spectrum, δ, ppm: 1.95–1.86 m (2H,
1
1
mp 208–210°C. H NMR spectrum, δ, ppm: 1.93–
NCH CH ), 2.38 t (2H, NCH , J = 6.8 Hz), 3.42–
1. 84 m (2H, NCH2CH2CH2), 2. 12 t (2H,
NCH2CH2CH2, J = 7.6 Hz), 2.56 t (2H C6H4CH2CH2,
J = 7.6 Hz), 3.17 d.d (2H, C6H4CH2CH2, J = 13.9,
6.7 Hz), 3.95 s (3H, CH3), 4.04 t (2H, CH2CO, J =
7.0 Hz), 6.65 d (2H, C6H4, J = 8.4 Hz), 6.96 d (2H,
2
2
2
3
1
6
.36 m (4H, morpholine), 3.54 d (4H, morpholine, J =
6.8 Hz), 3.94 s (3H, CH ), 4.06 t (2H, CH CO, J =
.6 Hz), 7.27 t (1H, indole, J = 7.4 Hz), 7.34 t (1H,
3
2
indole, J = 7.4 Hz), 7.57 d (1H, indole, J = 8.1 Hz),
.00–7.94 m (2H, indole), 8.03 s (1H, CH=).
Found, %: C 58.86; H 5.29; N 9.91. C H N O S .
C H , J = 8.3 Hz), 7.28 t (1H, indole, J = 7.4 Hz),
8
6
4
7.35 t (1H, indole), 7.58 d (1H, indole, J = 8.1 Hz),
7.87 t (1H, indole, J = 5.6 Hz), 7.98 d (1H, indole, J =
8.5 Hz), 8.05 s (1H, =CH), 9.17 s (1H, OH). Found, %:
2
1
23
3
3 2
Calculated, %: C 58.72; H 5.40; N 9.78.
N-(4-Hydroxyphenyl)-4-[5-(1H-indol-3-yl-
methylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-
C 62.55; H 5.17; N 8.84. C H N O S . Calculat-
2
5
25
3
3 2
ed, %: C 62.61; H 5.25; N 8.76.
3
-yl]butanamide (7a). Yield 97%, mp 219–221°C.
1
N-[2-(1H-Indol-3-yl)ethyl]-4-[5-(1H-indol-3-yl-
methylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-
H NMR spectrum, δ, ppm: 2.02–1.92 m (2H,
NCH CH ), 2.32 t (2H, NCH , J = 7.5 Hz), 4.11 t
2
2
2
3
-yl]butanamide (9a). Yield 99%, mp 179–181°C.
(
2H, CH CO, J = 6.9 Hz), 6.65 d (2H, C H , J =
2 6 4
1
H NMR spectrum, δ, ppm: 1.94–1.89 m (2H,
NCH CH CH ), 2.14 t (2H, NCH CH CH , J =
8
.7 Hz), 7.31–7.24 m (2H, indole), 7.33 d (2H, C H ,
6 4
2
2
2
2
2
2
J = 8.7 Hz), 7.51 d (1H, indole, J = 7.8 Hz), 7.91 s (1H,
indole), 7.96 d (1H, indole, J = 7.7 Hz), 8.09 s (1H,
7
3
7
.5 Hz), 2.80 t (2H, NCH CH , J = 7.4 Hz), 3.32–
2 2
.27 m (2H, NCH CH ), 4.07 t (2H CH CO, J =
2
2
2
=
(
CH), 9.13 s (1H, OH), 9.64 s (1H, CONH), 12.38 s
1H, NH). Found, %: C 60.21; H 4.28; N 9.75.
C H N O S . Calculated, %: C 60.39; H 4.38;
.0 Hz), 6.94 t (1H, indole, J = 7.2 Hz), 7.04 t (1H,
indole, J = 7.6 Hz), 7.13 s (1H, indole), 7.34–7.19 m
2
2
19
3
3 2
(
(
3H, indole), 7.51 t (2H, indole, J = 7.6 Hz), 7.91 d
1H, indole, J = 2.8 Hz), 7.96 d (2H, indole, J =
N 9.60.
N-(4-Hydroxyphenyl)-4-[5-(1-methyl-1H-indol-
7
1
.0 Hz), 8.10 s (1H, =CH), 10.81 s (1H, CONH),
2.36 s (1H, NH). Found, %: C 63.78; H 5.04;
3
-ylmethylidene)-4-oxo-2-sulfanylidene-1,3-thia-
zolidin-3-yl]butanamide (7b). Yield 90%, mp 223–
N 11.55. C H N O S . Calculated, %: C 63.91;
2
6
24
4
2 2
1
2
25°C. H NMR spectrum, δ, ppm: 2.03–1.91 m (2H,
NCH CH ), 2.32 t (2H, NCH , J = 7.4 Hz), 3.95 s (3H,
H 4.95; N 11.47.
2
2
2
N-[2-(1H-Indol-3-yl)ethyl]-4-[5-(1-methyl-1H-in-
dol-3-ylmethylidene)-4-oxo-2-sulfanylidene-1,3-
thiazolidin-3-yl]butanamide (9b). Yield 88%,
CH ), 4.10 t (2H, CH CO, J = 6.9 Hz), 6.65 d (2H,
3
2
C H , J = 8.8 Hz), 7.38–7.23 m (4H, Harom), 7.58 d
6
4
(1H, indole, J = 8.1 Hz), 8.01–7.95 m (2H, indole),
1
mp 134–136°C. H NMR spectrum, δ, ppm: 1.95–
8
.05 s (1H, =CH), 9.17 br.s (1H, OH), 9.65 s (1H,
1
. 8 5 m (2H, NC H C H C H ), 2. 15 t (2 H,
2 2 2
CONH). Found, %: C 61.01; H 4.48; N 9.46.
C H N O S . Calculated, %: C 61.18; H 4.69;
NCH CH CH , J = 7.5 Hz), 2.80 t (2H, NCH CH , J =
2
2
2
2
2
23
21
3
3
2
7.4 Hz), 3.32–3.27 m (2H, NCH CH ), 3.94 s (3H,
2 2
N 9.31.
CH ), 4.06 t (2H, CH CO, J = 7.2 Hz), 6.94 t (1H,
3
2
N-[2-(4-Hydroxyphenyl)ethyl]-4-[5-(1H-indol-3-
ylmethylidene)-4-oxo-2-sulfanylidene-1,3-thiazo-
indole, J = 7.4 Hz), 7.04 t (1H, indole, J = 7.4 Hz),
7.13 d (1H, indole, J = 2.1 Hz), 7.37–7.24 m (3H,
indole), 7.50 d (1H, indole, J = 7.9 Hz), 7.58 d (1H,
indole, J = 8.1 Hz), 8.01–7.93 m (3H, indole), 8.06 s
(1H, =CH), 10.78 s (1H, CONH). Found, %: C 64.34;
lidin-3-yl]butanamide (8a). Yield 89%, mp 198–
1
2
01°C. H NMR spectrum, δ, ppm: 1.86 d (2H,
NCH CH CH , J = 7.1 Hz), 2.11 t (2H, NCH CH CH ,
2
2
2
2
2
2
H 5.35; N 11.01. C H N O S . Calculated, %:
J = 7.6 Hz), 2.59 t (2H, C H CH CH , J = 7.6 Hz),
27 26
4
2 2
6
4
2
2
C 64.52; H 5.21; N 11.15.
3
.15 d.d (2H, C H CH CH , J = 14.2, 6.4 Hz), 4.04 t
6 4 2 2
(
8
(
7
2H, CH CO, J = 7.0 Hz), 6.64 d (2H, C H , J =
N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)-4-[5-(1H-indol-3-ylmethylidene)-4-
oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butan-
2
6
4
.4 Hz), 6.95 d (2H, C H , J = 8.4 Hz), 7.29–7.23 m
6 4
2H, indole), 7.51 d (1H, indole, J = 7.9 Hz), 7.99–
.87 m (2H, indole), 8.09 s (1H, =CH), 9.17 s (1H,
1
amide (10a). Yield 96%, mp 253–255°C. H NMR
OH), 12.40 s (1H, NH). Found, %: C 61.78; H 5.03;
N 8.89. C H N O S . Calculated, %: C 61.91;
spectrum, δ, ppm: 1.95–2.00 m (2H, NCH CH ), 2.13 s
2
2
(3H, CH ), 2.36 t (2H, NCH , J = 7.4 Hz), 3.03 s (3H,
24
23
3
3
2
3
2
H 4.98; N 9.02.
CH ), 4.12 t (2H, CH CO, J = 7.2 Hz), 7.37–7.20 m
3 2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

SYNTHESIS AND PRIMARY ANTITUMOR SCREENING
1151
(
6H, Harom), 7.53–7.47 m (3H, indole), 7.90 d (1H,
indole, J = 2.6 Hz), 7.96 d (1H, indole, J = 7.7 Hz),
.10 s (1H, =CH), 9.08 s (1H, CONH), 12.35 s
1H, NH). Found, %: C 61.17; H 4.86; N 13.01.
C H N O S . Calculated, %: C 61.00; H 4.74;
9. Obushak, M.D., Matiychuk, V.S., and Turytsya, V.V.,
Tetrahedron Lett., 2009, vol. 50, p. 6112.
https://doi.org/10.1016/j.tetlet.2009.08.024
8
(
10. Zubkov, F.I., Ershova, J.D., Zaytsev, V.P.,
Obushak, M.D., Matiychuk, V.S., Sokolova, E.A.,
Khrustalev, V.N., and Varlamov, A.V., Tetrahedron Lett.,
2
7
25
5
3 2
N 13.17.
2
010, vol. 51, p. 6822.
N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)-4-[5-(1-methyl-1H-indol-3-yl-
methylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-
https://doi.org/10.1016/j.tetlet.2010.10.046
11. Pokhodylo, N.T., Matiychuk, V.S., and Obushak, M.D.,
Tetrahedron, 2009, vol. 65, p. 2678.
https://doi.org/10.1016/j.tet.2009.01.086
3
-yl]butanamide (10b). Yield 90%, mp 239–241°C.
1
H NMR spectrum, δ, ppm: 2.01–1.89 m (2H,
NCH CH ), 2.12 s (3H, CH ), 2.35 t (2H, NCH , J =
1
2. Chaban, T., Matiychuk, V., Ogurtsov, V., Chaban, I.,
Harkov, S., and Nektegaev, I., Pharmacia, 2018,
vol. 65, p. 51.
2
2
3
2
7
.4 Hz), 3.35 s (3H, CH ), 3.95 s (3H, CH ), 4.10 t
3 3
(2H, CH CO, J = 7.0 Hz), 7.38–7.24 m (5H, Ph), 7.49 t
2
1
1
1
3. Pokhodylo, N.T., Savka, R.D., Matiichuk, V.S., and
Obushak, N.D., Russ. J. Gen. Chem., 2009, vol. 79,
p. 309.
(2H, indole, J = 7.7 Hz), 7.58 d (1H, indole, J =
8
(
.0 Hz), 8.02–7.98 d (2H, indole, J = 6.9 Hz), 8.06 s
1H, CH=), 9.12 s (1H, NH). Found, %: C 61.77;
H 5.08; N 12.97. C H N O S . Calculated, %:
https://doi.org/10.1134/S1070363209020248
2
8
27
5
3 2
4. Zimenkovskii, B.S., Kutsyk, R.V., Lesyk, R.B.,
Matyichuk, V.S., Obushak, N.D., and Klyufinska, T.I.,
Pharm. Chem. J., 2006, vol. 40, p. 303.
C 61.63; H 4.99; N 12.83.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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