Synthesis, Characterization, and Anticancer Screening of Some New Bithiazole Derivatives

Article abstract of DOI:10.1134/S1070428020060202

Abstract: Twenty new bithiazole derivatives were synthesized by condensation of2-{2-[(1-arylethylidene)hydrazinylidene]thiazolidin-4-ylidene}hydrazine-1-carbothioamideswith halo ketones, halo esters, and α-keto hydrazonoyl halides. The structuresof all pr

Full text of DOI:10.1134/S1070428020060202

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 6, pp. 1096–1107. © Pleiades Publishing, Ltd., 2020.
Synthesis, Characterization, and Anticancer Screening
of Some New Bithiazole Derivatives
a,
b
c,d,
e
N. A. Abdel Latif *, E. M. H. Abbas , T. A. Farghaly **, and H. M. Awad
a
Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research
Centre, Dokki, Giza, 12622 Egypt
b
Department of Chemistry of Natural and Microbial Products, National Research Center, Dokki, Cairo, 12622 Egypt
c
Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613 Egypt
d
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University,
Makkah Al-Mukkarramah, 21955 Saudi Arabia
e
Tanning Materials and Leather Technology Department, National Research Centre, Dokki, Giza, 12622 Egypt
e-mail: *nehad_km@yahoo.com; **thoraya-f@hotmail.com; tamohamed@uqu.edu.sa
Received November 11, 2019; revised March 18, 2020; accepted March 22, 2020
Abstract—Twenty new bithiazole derivatives were synthesized by condensation of 2-{2-[(1-arylethylidene)-
hydrazinylidene]thiazolidin-4-ylidene}hydrazine-1-carbothioamides with halo ketones, halo esters, and α-keto
1
hydrazonoyl halides. The structures of all prepared compounds were proposed on the basis of their IR, H and
1
3
C NMR, and mass spectra. All the synthesized compounds were screened for their cytotoxicity against three
human cancer cell lines, HCT-116 (human colorectal carcinoma), MCF-7 (human breast adenocarcinoma), and
HepG2 (human hepatocellular carcinoma). Two compounds (12d and 12b) had significantly more potent anti-
cancer activity on HCT-116 human colorectal carcinoma cells. In the case of MCF-7 human breast cancer cells,
three compounds (12b, 4b and 4a) were significantly more potent than the reference drug doxorubicin. Nine of
the synthesized compounds (8a, 7a, 9b, 12d, 12c, 7b, 10a, 5a and 12b) showed a significantly higher activity
than that of doxorubicin against HepG2 human liver cancer cells.
Keywords: thiazole, thiazolidinone, anticancer activity, HepG2, HCT-116, MCF-7
DOI: 10.1134/S1070428020060202
Thiazole derivatives are among the most medically
matory [9]. One of the most powerful biological activ-
ities of 1,3-thiazoles is their anticancer activity against
various types of cancer. In vitro antitumor examination
studies of several thiazole analogs showed their potent
and selective inhibitory activity at the nanomolar level
significant compounds molecules as they have a broad
spectrum of biological activities such as antiviral [1],
antibacterial [2], antitubercular [3], antiprotozoal [4],
anthelmintic [5], antifungal [6–8], and anti-inflam-
O
H
NH
2
N
NH2
H N
H
N
2
N
N
O
O
O
H
H N
2
Me
HO
Me
N
Me
O
O
H N
O
O
H
N
2
S
Me
N
Me
N
N
S
O
H
S
Me
Me
O
N
NH
N
HO
OH
O
N
S
HO
Me
O
N
O
S
Me Me
H
Me
Me
OH
O
OH
OH
OH
O
NH2
Myxothiazol
Bleomycin
Fig. 1. Drugs containing two thiazole rings.
1
096

SYNTHESIS, CHARACTERIZATION, AND ANTICANCER SCREENING
1097
Scheme 1.
O
Me
S
H
N
HCl, EtOH
NH2
Me
+
H N
2
N
N
H
NH2
S
X
X
1
a, 1b
2a, 2b
S
HN
Me
Me
N
BrCH COOEt
NaOAc, EtOH
H NNHC(=S)NH2
HCl, EtOH
2
2
N
S
N
H
N
N
N
S
HN
X
N
O
H
X
H
3
a, 3b
4a, 4b
X = Br (a), NO (b).
2
against different types of human cancer cell lines such
as leukemia, breast, lung, CNS, colon, renal, mela-
noma, ovarian, and prostate cancer cell lines [10–20].
In addition, several known drugs were found to have
more than one thiazole ring as presented in Fig. 1.
Insertion of more than one thiazole ring into a drug
molecule enhances its pharmaceutical activity [21–24].
Thus, many pharmacists and chemists seek to design
and synthesize biologically active compounds contain-
ing many thiazole rings [25, 26]. Recent statistics
indicated a rise in deaths from cancer, so that scientists
are devoting their efforts to discovering new drugs with
high efficacy and minimal side effects. Taking into
account the information stated above and our research
data on bioactive thiazole moiety [10–13, 27–30], we
decided to prepare new bi-thiazole derivatives and
study their anticancer activity hoping to obtain more
potent drugs than doxorubicin.
ketones [31–33]. In this context, we started with the
synthesis of two thiosemicarbazones 4a and 4b by
condensation of 4-bromo- and 4-nitroacetophenones 1a
and 1b with thiosemicarbazide in ethanol in the pres-
ence of HCl as shown in Scheme 1. Thiosemicarba-
zones 4a and 4b were identified by the presence of five
singlet signals at δ 4.60, 6.46, 7.36, 7.64 and 8.80 ppm
for the CH and four D O-exchangeable NH protons
2
2
(4a). The presence of two one-proton NH singlets
instead of one two-proton signal for the NH of 4a
2
and 4b is due to intramolecular hydrogen bonding
(Scheme 1, Fig. 2) [34]. The mass spectra of 4a and
4b showed the molecular ion peaks at m/z 385 and
351 with the base peaks at m/z 301 and 244,
respectively.
Bithiazoles 5–8 were prepared through the conden-
sation of thiosemicarbazones 4a and 4b with various
halo carbonyl compounds such as chloroacetone, sub-
stituted phenacyl bromides, ethyl bromoacetate, and
ethyl-2-bromopropionate (Scheme 2). The spectral data
The best and efficient method to generate a thiazole
ring is the reaction of thiosemicarbazones with α-halo
S
Me
N
N
H
HN
N
N
S
N
H
NH
Br
H
4
a
CH3
NH
CH2
NH
NH
1
2
11
10
9
8
7
6
5
4
3
2
1
δ, ppm
1
Fig. 2. H NMR spectrum of compound 4a.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

1098
ABDEL LATIF et al.
Scheme 2.
S
5'
Me
N
ClCH COMe
2
N
N
N
H
NaOAc, EtOH
S
N
5
HN
Me
Br
5
S
Me
N
BrCH COAr
NaOAc, EtOH
2
N
N
N
H
S
N
HN
Ar
X
6
a–6d
4
a, 4b
S
Me
N
BrCH COOEt
2
N
N
N
H
NaOAc, EtOH
S
N
HN
O
X
7
a, 7b
S
Me
N
BrCH(Me)COOEt
NaOAc, EtOH
N
N
N
H
S
N
Me
HN
O
Br
8
4
, 7, X = Br (a), NO (b); 6, X = Br, Ar = Ph (a), 4-BrC H (b); X = NO , Ar = Ph (c), 4-BrC H (d).
2 6 4 2 6 4
for new compounds 5–8 proved their structures. For
instance, the H NMR spectrum of 5 showed a charac-
Scheme 3. The IR spectra of all bithiazoles 9–12
showed all characteristic absorption bands for func-
tional groups present in their molecules (see Supple-
mentary Materials). For example, the IR spectrum of
12b displayed absorption bands at ν 3425 (broadened,
1
teristic one-proton singlet at δ 6.30 ppm due to 4-H
1
proton of the newly formed thiazole ring. The H NMR
spectrum of bithiazolone derivative 7a displayed two
–
1
singlet signals for the two thiazole CH groups at
NH), 1705 (C=O), and 1620 cm (C=N). In the
2
1
δ 3.2 and 3.85 ppm in addition to signals for two NH,
H NMR spectrum of 9a we observed a quartet signal
aromatic, and CH protons. The mass spectra of all
at δ 4.23 ppm due to CH protons and a triplet at
3
2
derivatives 5–8 contained the molecular ion peaks with
the expected m/z values; as an example, the fragmen-
tation pattern for bithiazole 7b is shown in Fig. 3.
δ 1.22 ppm for the CH group of the ester moiety in
3
addition to the singlet at δ 2.15 ppm for the methyl
4
group on C of the terminal thiazole ring. The mass
spectum of 9b showed the molecular ion peak at
m/z 461 and the base peak at m/z 230.
In continuation of the synthesis of new bithiazole
derivatives, cyclocondensations of 4a and 4b with
ethyl 2-chloroacetoacetate, chloroacetylacetone, and
α-ketohydrazonoyl chlorides afforded the correspond-
ing new bithiazole derivatives 9–12 as outlined in
Concerning mechanistic aspects of the described
reactions, they are likely to begin with nucleophilic
substitution of the halogen atom in halo carbonyl
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

SYNTHESIS, CHARACTERIZATION, AND ANTICANCER SCREENING
1099
S
Me
N
N
N
N
S
N
H
HN
O
O N
2
S
7
b, m/z 391 [M]+
N
N
N
N
H
N
1
00
m/z 153
S
Me
N
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
N
NH
·
S
S
N
N
O N
2
HN
N
m/z 236
O
H
m/z 214
O N
2
m/z 123
5
0
100
150
200
250
300
350
m/z
Fig. 3. Mass fragmentation of compound 7b.
compounds by the sulfur atom of 4a or 4b with elim-
ination of HX, and the subsequent cyclization involves
elimination of water molecule in the case of formation
of compounds 5, 6, and 9–11 or ethanol molecule in the
reactions leading to 7, 8, and 12.
against HCT-116 human colorectal carcinoma cells;
four compounds (4a, 9a, 9b, and 11c) had slightly
lower anticancer activities; and the other compounds
had significantly lower activities compared to that of
doxorubicin. In the case of MCF-7 human breast
cancer cells, three compounds (12b, 4a, and 4a) were
significantly more potent, three compounds (12d, 5a,
and 9b) had comparable activities; seven compounds
Anticancer screening. All the prepared compounds
were examined in vitro for their activities on HCT-116,
MCF-7, and HepG2 human cancer cells using the MTT
assay. The percentages of viable cells were calculated
and compared to those of the control and doxorubicin
used as reference drug. All compounds suppressed the
three human cell lines in a dose-dependent manner
(10a, 11a, 8a, 9a, 11c, 6d, and 7b) had slightly lower
anticancer activities; and the other compounds were
significantly less active than doxorubicin. In the case
of HepG2 human liver cancer cells, nine compounds
(
8a, 7a, 9b, 12d, 12c, 7b, 10a, 5a, 12b) showed
(
Figs. 5–7 in ESM). The efficacy of the synthesized
significantly higher anticancer activities, two com-
pounds (4b and 12a) had comparable activities, six
compounds (6c, 12e, 6b, 6d, 4a, and 11a, respectively)
had slightly lower activities, and the other compounds
were significantly less active than doxorubicin (Table 1).
compounds was estimated by comparing their cytotoxic
effect with the cytotoxicity of the reference drug. The
data in Table 1 show that two compounds, 12b and
1
2d, showed significantly higher anticancer activities
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

1100
ABDEL LATIF et al.
Scheme 3.
S
Me
N
MeC(O)CHClC(O)OEt
,4-dioxane, Et N
N
N
N
H
S
1
N
3
COOEt
HN
Me
Br
9
a, 9b
S
Me
N
MeC(O)CHClC(O)Me
N
N
N
H
O
1
,4-dioxane, Et N
N
S
3
HN
Me
Me
Br
1
0
4
a, 4b
Cl
H
Me
N
S
N
Ar
Me
N
H
N
O
N
N
H
S
1
,4-dioxane, Et N
N
3
N
N
N
Ar
Me
X
1
1a–11d
Cl
H
EtO
N
S
N
Ar
Me
N
H
N
O
N
N
H
1
,4-dioxane, Et N
S
3
N
N
N
HN Ar
O
X
1
2a–12e
4
, 9, X = Br (a), NO (b); 11, X = Br, Ar = 4-MeC H (a), 3-MeC H (b), 4-ClC H (c); X = NO , Ar = 3-MeC H (d);
2 6 4 6 4 6 4 2 6 4
1
2, X = Br, Ar = 4-MeC H (a), 4-ClC H (b); X = NO , Ar = 4-MeC H (c), 3-MeC H (d), 4-ClC H (e).
6 4 6 4 2 6 4 6 4 6 4
From the above results one can conclude that com-
pounds 12b, 9b, and 12d are nonspecifically acting
proved to be more potent than nearly all cyclized thia-
zole compounds when tested against MCF-7 (IC50
=
drug candidates for all three cancer types; compounds
19.9 and 16.3 μM, respectively); they showed higher
cytotoxic effect against HCT-116 (IC50 = 13.0 and
15.0 μM, respectively) than cyclized thiazole com-
pounds 5–7. Bithaizole carboxylates 9a and 9b showed
remarkable cytotoxic effects against both HCT-116
4
b and 5a are nonspecifically active on both human
breast and liver cancer types but are inactive against
human colon cancer; compound 4a is nonspecifically
active candidate drug on human colon and breast
cancer types but not active on human liver cancer type.
In addition, compounds 8a, 7a, 12c, 7b, 10a, and 12a
are specifically active against human liver cancer but
are not active against both human colon and breast
cancer types.
(IC50 = 13.5 and 13.2 μM, respectively) and MCF-7
cell lines (IC = 24.7 and 21.4 μM, respectively), and
5
0
the nitrophenyl derivative 9b (IC50 = 28.8 μM) was
about 1.5 times more active than bromo analog 9a
(
IC50 = 44.2 μM) when tested against HepG2.
At first glance, it is possible to notice that the
insertion of two thiazole rings in the same molecule
enhances the anticancer activity, especially against
HepG2. Intermediate thiosemicarbazones 4a and 4b
Generally, arylhydrazinylidene thiazolones 12 (IC50 =
29.4–33.4 μM) were more active than 4-methylthia-
zoles 11 (IC50 = 37.1–50.1 μM) against HepG2 cells.
Within the series 12a–12d, compound 12b and 12d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

SYNTHESIS, CHARACTERIZATION, AND ANTICANCER SCREENING
1101
Table 1. Half maximum inhibitory concentrations (IC , ꢀM) of compounds 4–12 on the three cancer cell lines according to
5
0
the MTT assay
Compound no.
HCT-116
13.0±1.9
15.0±2.5
20.2±3.5
16.3±3.1
17.1±2.5
20.1±3.2
19.4±3.1
19.1±3.1
19.2±2.9
17.4±3.1
13.5±1.8
13.2±2.1
19.6±3.1
15.9±2.5
20.8±3.2
13.9±2.2
24.5±3.4
17.0±2.2
11.5±1.5
17.7±2.5
11.4±1.7
19.0±2.9
12.0±2.1
MCF-7
19.9±2.3
16.3±2.1
21.4±2.9
32.7±4.3
31.0±3.9
29.6±3.5
25.9±4.2
32.8±4.1
26.0±3.5
24.6±3.1
24.7±3.8
21.4±3.3
23.6±3.1
24.4±3.2
27.9±3.3
25.6±2.9
30.9±3.5
32.9±3.8
14.4±1.8
28.3±3.4
20.7±3.2
26.4±3.7
20.5±2.1
HepG2
36.2±4.5
32.5±4.1
30.0±3.2
40.6±3.9
34.5±3.7
33.3±3.5
35.6±3.9
28.0±3.5
29.5±3.6
23.5±2.3
44.2±3.8
28.8±3.5
29.9±3.5
37.1±4.1
40.4±4.9
50.1±4.9
39.0±4.8
33.0±4.3
30.8±3.3
29.5±3.9
29.4±3.5
34.3±3.6
32.7±3.2
4
4
5
6
6
6
6
7
7
8
9
9
1
a
b
a
a
b
c
d
a
b
a
b
0
1
1a
1b
1c
1d
1
1
1
1
1
1
1
1
2a
2b
2c
2d
2e
Doxorubicin
were the most active against the three tested cell lines,
and they were more potent than 4-methylthiazole
derivatives 11c and 11d.
pounds were confirmed by studying their IR, NMR,
and mass spectra. The synthesized compounds were
screened for their cytotoxicity against three human
cancer cell lines. Some new bithiazole derivatives
proved to be potent against the tumor cell lines tested,
and in several cases their activity exceeded that of
doxorubicin taken as reference drug.
4
-Bromophenyl 4,5-dihydrothiazoles 11a–11c ex-
hibited higher anticancer effect against HCT-116 and
MCF-7 cell lines than the nitro containing congeners.
The effect of bromine atom on the cytotoxicity against
HCT-116 was also clearly seen in compounds 6a and
EXPERIMENTAL
6
b (IC = 16.3 and 17.1 μM, respectively) which were
50
more potent than their nitro-substituted analogs 6c and
d (IC50 = 20.1 and 19.4 μM, respectively). On the
other hand, nitrophenyl bithiazole derivatives 6c, 6d,
b, and 9d showed a higher cytotoxic effect on MCF-7
The melting points were determined with a Stuart
SMP3 melting point apparatus using 0.5-mm glass
capillaries. The IR spectra were recorded on
a Shimadzu IR-3600 FT-IR spectrometer from samples
prepared as KBr pellets. The NMR spectra were
recorded on a Bruker Avance 400 spectrometer at
6
7
than the bromo-containing analogs.
In summary, new bioactive bithiazole derivatives
have been designed and prepared by the reaction of
two thiazole thiosemicarbazones with α-halo ketones.
The proposed structures of all new bithiazole com-
1
13
400 MHz for H or 100 MHz for C NMR, using
DMSO-d as solvent and reference. The mass spectra
6
(electron impact, 70 eV) were recorded on a Shimadzu
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

1102
ABDEL LATIF et al.
GCMS-QP 1000EX instrument. The elemental anal-
yses were obtained with an Elementar Vario-LIII
CHNS analyzer (Germany).
275 (49), 228 (45), 154 (34), 114 (47), 82 (40), 75 (24).
Found, %: C 37.42; H 3.37; N 21.80. C H BrN S .
Calculated, %: C 37.41; H 3.40; N 21.81.
1
2
13
6 2
Compounds 2a and 2b (general procedure).
A mixture of compound 1a or 1b (10 mmol) and
thiosemicarbazide (10 mmol) in anhydrous ethanol
2-(2-{[1-(4-Nitrophenyl)ethylidene]hydrazinyli-
dene}-1,3-thiazolidin-4-ylidene)hydrazine-1-carbo-
thioamide (4b). Yield 84%, yellow solid, mp 155–
–
1
(15 mL) containing a few drops of concentrated aque-
157°C. IR spectrum, ν, cm : 3478, 3356, 3195 (NH,
1
ous HCl was refluxed for 3 h. The solid product was
filtered off, dried, and recrystallized from ethanol [35].
NH ). H NMR spectrum (DMSO-d ), δ, ppm: 2.20 s
2
6
(3H, CH ). 4.71 s (2H, 5-H), 7.51–7.72 d.d (4H, Harom),
3
7
.83 s (1H, NH, D O exchangeable), 8.86 s (1H, NH,
2
2
-[1-(4-Bromophenyl)ethylidene]hydrazine-1-
D O exchangeable), 9.4 s (1H, NH, D O exchange-
able), 10.2 s (1H, NH, D O exchangeable). Mass spec-
trum (EI), m/z (I , %): 351.41 (23) [M] , 338 (74), 301
2
2
carbothioamide (2a). Yield 80%, white solid,
mp 188–190°C; published data [35]: mp 189–191°C.
2
+
rel
2
-[1-(4-Nitrophenyl)ethylidene]hydrazine-1-
(56), 250 (62), 244 (100), 121 (14). Found, %: C 41.03;
carbothioamide (2b). Yield 90%, yellow solid,
mp 185–186°C; published data [36]: mp 184–186°C.
H 3.71; N 27.93. C H N O S . Calculated, %:
C 41.01; H 3.73; N 27.90.
1
2
13
7
2 2
Compounds 3a and 3b (general procedure). Ethyl
bromoacetate (1.67 mL, 10 mmol) was added to a mix-
ture of thiosemicabazone 2a or 2b (10 mmol) and an-
hydrous sodium acetate (1.64 g, 20 mmol) in anhydrous
ethanol (30 mL), and the mixture was refluxed for
2
-[(2-{[1-(4-Bromophenyl)ethylidene]hydra-
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyli-
dene]-4-methyl-2,3-dihydro-1,3-thiazole (5). A mix-
ture of equimolar amounts (10 mmol) of thiazolethio-
semicarbazone 4a and chloroacetone in 20 mL of anhy-
drous ethanol containing anhydrous sodium acetate
(1.64 g, 20 mmol) was refluxed for 10 h. The dark
brown solid was filtered off, dried, and recrystallized
from chloroform. Yield 80%, dark brown solid,
1
0 h. After cooling, the solid product was filtered off,
washed with cold water, dried, and recrystallized from
ethanol [35, 36].
2
-{[1-(4-Bromophenyl)ethylidene]hydrazinyli-
–
1
mp 170–172°C. IR spectrum, ν, cm : 3425, 3178
NH), 1610, 1589 (C=N). H NMR spectrum
DMSO-d ), δ, ppm: 2.16 s (3H, CH ), 2.47 s (3H,
dene}-1,3-thiazolidin-4-one (3a). Yield 78%, brown
solid, mp 198–200°C; published data [35]: mp 198–
1
(
(
6
3
2
00°C.
CH ), 4.02 s (2H, 5′-H), 6.30 s (1H, 5-H), 7.52–7.89 m
3
2
-{[1-(4-Nitrophenyl)ethylidene]hydrazinyli-
(
4H, H), 10.23 s and 11.30 s (1H each, NH, D O-
exchangeable). Mass spectrum (EI), m/z (I , %):
24 (24) [M + 1] , 423 (27) [M] , 399 (70), 256 (53),
43 (40), 60 (100). Found, %: C 42.48; H 3.39;
2
dene}-1,3-thiazolidin-4-one (3b). Yield 78%, yellow
solid, mp 224–226°C; published data [36]: mp 224–
rel
+
+
4
1
2
26°C.
Compounds 4a and 4b (general procedure).
N 19.78. C H BrN S . Calculated, %: C 42.56;
1
5
15
6 2
A mixture of compound 3a or 3b (10 mmol) and
H 3.57; N 19.85.
thiosemicarbazide (10 mmol) in anhydrous ethanol
Compounds 6a–6d, 7a, 7b, and 8 (general proce-
dure). A mixture of compound 4a or 4b (10 mmol),
phenacyl bromide, 4-bromophenacyl bromide, ethyl
bromoacetate, or ethyl-2-bromopropionate (10 mmol),
and anhydrous sodium acetate (1.64 g, 20 mmol) in
anhydrous ethanol (30 mL) was refluxed for 10 h. The
colored precipitate was collected by filtration, dried,
and recrystallized from ethanol.
(15 mL) containing a few drops of concentrated aque-
ous HCl was refluxed for 3 h. The solid product was
filtered off, dried, and recrystallized from ethanol.
2
-(2-{[1-(4-Bromophenyl)ethylidene]hydrazinyli-
dene}-1,3-thiazolidin-4-ylidene)hydrazine-1-carbo-
thioamide (4a). Yield 82%, pale yellow solid,
–
1
mp 140–142°C. IR spectrum, ν, cm , 3440, 3411,
1
3
2
244 (NH, NH ). H NMR spectrum (CDCl , δ, ppm):
2-[(2-{[1-(4-Bromophenyl)ethylidene]hydra-
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyli-
dene]-4-phenyl-2,3-dihydro-1,3-thiazole (6a). Yield
79%, brown solid, mp 190–192°C. IR spectrum, ν,
2
3
.61 s (3H, CH ), 4.60 s (2H, 5-H), 6.46 s (1H, NH,
3
D O exchangeable), 7.36 s (1H, NH, D O exchange-
2
2
able), 7.54 d (2H, J = 8.44 Hz, Harom), 7.59 d (2H, J =
–
1
1
8
8
.48 Hz, Harom), 7.64 s (1H, NH, D O exchangeable),
cm : 3425, 3356 (NH), 1597, 1558 (C=N). H NMR
2
.80 s (1H, NH, D O exchangeable). Mass spectrum
spectrum (DMSO-d ), δ, ppm: 2.31 s (3H, CH ), 4.10 s
2
6
3
+
(EI), m/z (I , %): 385 (15) [M] , 339 (55), 301 (100),
(2H, 5′-H), 5.46 s (1H, 5-H), 7.28–7.97 m (11H, Harom,
rel
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

SYNTHESIS, CHARACTERIZATION, AND ANTICANCER SCREENING
1103
+
+
NH). Mass spectrum (EI), m/z (I , %): 487 (10)
(EI), m/z (I , %): 426 (17) [M + 1] , 425 (27) [M] ,
rel
rel
+
+
[
M + 2] , 485 (25) [M] , 482 (72), 351 (100), 267 (28),
41 (57), 174 (90), 156 (67). Found, %: C 49.35;
H 3.44; N 17.41. C H BrN S . Calculated, %:
418 (45), 397 (29), 287 (100), 226 (32), 150 (64), 93
(13). Found, %: C 39.50; H 3.05; N 19.68.
C H BrN OS . Calculated, %: C 39.53; H 3.08;
2
2
0
17
6
2
14 13
6
2
C 49.49; H 3.53; N 17.31.
N 19.76.
4
-(4-Bromophenyl)-2-[(2-{[1-(4-bromophenyl)-
2-[(2-{[1-(4-Nitrophenyl)ethylidene]hydrazinyli-
dene}-1,3-thiazolidin-4-ylidene)hydrazinylidene]-
1,3-thiazolidin-4-one (7b). Yield 75%, orange solid,
ethylidene]hydrazinylidene}-1,3-thiazolidin-4-yli-
dene)hydrazinylidene]-2,3-dihydro-1,3-thiazole
6b). Yield 80%, brown solid, mp 167–169°C. IR spec-
trum, ν, cm : 3429, 3278 (NH), 1601, 1558 (C=N).
Mass spectrum (EI), m/z (I , %): 565 (12) [M + 1] ,
–
1
(
mp 183–185°C. IR spectrum, ν, cm : 3480, 3357
–1
(NH), 1715 (C=O), 1618, 1604 (C=N). Mass spectrum
+
+
(EI), m/z (I , %): 391 (35) [M] , 382 (52), 337 (41),
rel
rel
5
(
21 (22), 376 (41), 277 (34), 268 (41), 142 (25), 106
100), 91 (24). Found, %: C 42.43; H 2.75; N 14.73.
C H Br N S . Calculated, %: C 42.57; H 2.86;
322 (33), 300 (36), 262 (33), 181 (43), 170 (44), 154
(100), 82 (19). Found, %: C 42.87; H 3.24; N 25.0.
C H N O S . Calculated, %: C 42.96; H 3.35;
2
0
16
2
6
2
14 13
7
3 2
N 14.89.
N 25.05.
2
-[(2-{[1-(4-Nitrophenyl)ethylidene]hydrazinyli-
2-[(2-{[1-(4-Bromophenyl)ethylidene]hydra-
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyli-
dene]-5-methyl-1,3-thiazolidin-4-one (8). Yield 80%,
pale yellow solid, mp 205–207°C. IR spectrum, ν,
dene}-1,3-thiazolidin-4-ylidene)hydrazinylidene]-4-
phenyl-2,3-dihydro-1,3-thiazole (6c). Yield 77%,
yellow solid, mp 155–157°C. IR spectrum, ν, cm :
479, 3348 (NH), 1558 (C=N). H NMR spectrum
–
1
1
–1
3
(
cm : 3400, 3134 (NH), 1715 (C=O), 1624, 1593
1
DMSO-d ), δ, ppm: 2.48 s (3H, CH ), 3.70 s (2H,
(C=N). H NMR spectrum (DMSO-d , δ, ppm: 2.34 s
6
3
6
5
8
′-H), 5.45 s (1H, 5-H), 7.17–8.34 m (9H, Harom),
(3H, CH ), 2.48 s (3H, CH ), 4.10 s (2H, 5′-H), 4.50 s
3
3
.44 s and 11.61 s (1H each, NH, D O exchangeable).
(1H, NH, D O exchangeable), 7.61–7.77 m (4H,
2
2
1
3
C NMR spectrum (DMSO-d ), δ , ppm: 14.3 (CH ),
Harom), 11.92 s (1H, NH, D O exchangeable). Mass
6
C
3
2
+
3
1
9.0 (CH ), 105.0, 118.0, 123.7, 124.2, 125.1, 126.0,
26.9, 128.0, 128.2, 129.0, 134.5, 144.6, 147.4, 154.4.
spectrum (EI), m/z (I , %):439 (11) [M] , 421 (55),
2
rel
374 (52), 119 (68), 104 (100). Found, %: C 41.00;
H 3.41; N 19.10. C H BrN OS . Calculated, %:
+
Mass spectrum (EI), m/z (I , %): 451 (31) [M] , 424
rel
15 15
6
2
(
2
16), 400 (32), 393 (48), 366 (100), 349 (29), 312 (42),
83 (30), 158 (39), 141 (53), 93 (44). Found, %:
C 53.15; H 3.65; N 21.68. C H N O S . Calculat-
C 41.01; H 3.44; N 19.13.
Bithiazoles 9a, 9b, 10, 11a–11d, and 12a–12e
2
0
17
7
2 2
(
general procedure). A mixture of thiazole derivative
ed, %: C 53.20; H 3.80; N 21.72.
4
a or 4b (10 mmol) and ethyl-2-chloroacetoacetate,
4
-(4-Bromophenyl)-2-[(2-{[1-(4-nitrophenyl)-
chloroacetylacetone, or hydrazonoyl chloride
(10 mmol) in 30 mL of 1,4-dioxane containing triethyl-
amine (1.01 mL, 10 mmol) was heated under reflux for
6 h. After cooling, the dark colored precipitate was
filtered off, washed with water, dried, and recrystallized
from anhydrous ethanol.
ethylidene]hydrazinylidene}-1,3-thiazolidin-4-
ylidene)hydrazinylidene]-2,3-dihydro-1,3-thiazole
6d). Yield 83%, brown solid, mp 197–200°C. IR spec-
(
–1
trum, ν, cm : 3479, 3317 br (NH), 1558 (C=N). Mass
+
spectrum (EI), m/z (I , %): 531 (6) [M + 1] , 530 (22)
rel
+
[
M] , 509 (35), 490 (40), 71 (100). Found, %: C 45.16;
Ethyl 2-[(2-{[1-(4-bromophenyl)ethylidene]hy-
drazinylidene}-1,3-thiazolidin-4-ylidene)hydra-
zinylidene]-4-methyl-2,3-dihydro-1,3-thiazole-
5-carboxylate (9a). Yield 80%, dark brown solid,
H 3.23; N 18.34. C H BrN O S . Calculated, %:
C 45.29; H 3.04; N 18.49.
2
0
16
7
2 2
2
-[(2-{[1-(4-Bromophenyl)ethylidene]hydra-
–
1
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyli-
dene]-1,3-thiazolidin-4-one (7a). Yield 78%, yel-
lowish brown solid, mp 166–169°C. IR spectrum, ν,
mp 198–200°C. IR spectrum, ν, cm : 3430, 3202
1
(NH), 1700 (C=O), 1615, 1555 (C=N). H NMR spec-
trum (DMSO-d ), δ, ppm: 1.22 t (3H, CH ), 2.15 s (3H,
6
3
–1
cm : 3425 (NH), 1720 (C=O), 1612, 1566 (C=N).
CH ), 2.31 s (3H, CH ), 4.23 q (2H, CH ), 4.51 s (2H,
3 3 2
1
H NMR spectrum (DMSO-d , δ, ppm: 2.49 s (3H,
5′-H), 6.3 s (1H, NH, D O exchangeable), 7.54–7.98 m
6
2
CH ), 3.2 s (2H, 5′-H), 3.85 s (2H, 5-H), 4.50 s (1H,
(4H, Harom), 10.25 s (1H, NH, D O exchangeable).
3
2
+
NH, D O exchangeable), 7.61–7.78 m (4H, Harom),
Mass spectrum (EI), m/z (I , %): 497 (9) [M + 2] , 495
2
rel
+
1
1.92 s (2H, NH, D O exchangeable). Mass spectrum
(11) [M] , 489 (21), 489 (38), 392 (39), 351 (100), 325
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

1104
ABDEL LATIF et al.
(47), 242 (28), 73 (75). Found, %: C 43.53; H 3.74;
C H BrN S . Calculated, %: C 48.80; H 3.91;
22 21 8 2
N 16.84. C H BrN O S . Calculated, %: C 43.64;
N 20.69.
1
8
19
6
2 2
H 3.87; N 16.96.
2
-[2-(2-{[1-(4-Bromophenyl)ethylidene]hydra-
Ethyl 2-[(2-{[1-(4-nitrophenyl)ethylidene]hydra-
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyli-
dene]-4-methyl-2,3-dihydro-1,3-thiazole-5-carbox-
ylate (9b). Yield 75%, brown solid, mp 212–215°C. IR
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyl]-
5-[(E)-(4-chlorophenyl)diazenyl]-4-methyl-
1,3-thiazole (11c). Yield 75%, brown solid, mp 187–
–
1
190°C. IR spectrum, ν, cm : 3425–3248 br (NH),
1
–
1
1
2
7
597 (C=N). H NMR spectrum (DMSO-d ), δ, ppm:
spectrum, ν, cm : 3480, 3357 (NH), 1701 (C=O),
6
.42 s (3H, CH ), 2.60 s (3H, CH ), 4.50 s (2H, 5′-H),
.17–7.90 m (8H, Harom), 10.71 s and 11.08 s (1H each,
NH, D O exchangeable). C NMR spectrum
1
4
619, 1556 (C=N). Mass spectrum (EI), m/z (I , %):
61 (11) [M] , 448 (46), 230 (100). Found, %: C 46.70;
3
3
rel
+
1
3
H 4.03; N 21.18. C H N O S . Calculated, %:
2
1
8
19
7
4 2
(
DMSO-d ), δ , ppm: 15.6, 17.0, 40.6, 116.2, 118.5,
C 46.84; H 4.15; N 21.24.
6 C
119.7, 123.4, 124.9, 126.2, 127.1, 129.3, 129.6, 129.9,
1
-{2-[(2-{[1-(4-Bromophenyl)ethylidene]hydra-
1
32.0, 136.7, 142.9, 152.2. Mass spectrum (EI), m/z
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyli-
dene]-4-methyl-2,3-dihydro-1,3-thiazole-5-yl}-
ethanone (10). Yield 77%, brown solid, mp 207–
+
(I , %): 563 (18) [M] , 436 (25), 372 (35), 266 (20),
rel
2
25 (45), 202 (100), 174 (29), 103 (25), 78 (20).
Found, %: C 44.70; H 3.50; N 19.85. C H BrClN S .
2
1
18
8 2
–
1
2
(
(
09°C. IR spectrum, ν, cm : 3185 br (NH), 1716
Calculated, %: C 44.89; H 3.23; N 19.94.
-Methyl-5-[(E)-(3-methylphenyl)diazenyl]-2-[2-
2-{[1-(4-nitrophenyl)ethylidene]hydrazinylidene}-
,3-thiazolidin-4-ylidene)hydrazinyl]-1,3-thiazole
11d). Yield 72%, brown solid, mp 191–193°C. IR
1
C=O), 1612, 1554 (C=N). H NMR spectrum
DMSO-d ), δ, ppm: 2.30 s, 2.38 s, and 2.48 s (3H
4
6
(
1
each, CH ); 3.83 s (2H, 5′-H), 4.50 s (1H, NH, D O
3
2
exchangeable), 7.41–7.78 m (4H, Harom), 11.7 s (1H,
(
NH, D O exchangeable). Mass spectrum (EI), m/z
2
–1
spectrum, ν, cm : 3479, 3356 (NH), 1581 (C=N).
Mass spectrum (EI), m/z (I , %): 509 (17) [M + 2] ,
+
(
I , %): 465 (34) [M] , 418 (65), 229 (50), 91 (40), 60
rel
+
rel
(60), 43 (100). Found, %: C 43.76; H 3.51; N 18.24.
4
77 (70), 419 (100), 382 (35), 288 (66), 268 (63).
C H BrN OS . Calculated, %: C 43.87; H 3.68;
17
17
6
2
Found, %: C 51.92; H 4.33; N 24.71. C H N O S .
2
2
21
9
2 2
N 18.06.
-[2-(2-{[1-(4-Bromophenyl)ethylidene]hydra-
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyl]-
Calculated, %: C 52.06; H 4.17; N 24.84.
-[2-(2-{[1-(4-Bromophenyl)ethylidene]hydra-
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyl]-5-
2-(4-methylphenyl)hydrazinylidene]-1,3-thiazol-
2
2
4
1
1
-methyl-5-[(E)-(4-methylphenyl)diazenyl]-
[
,3-thiazole (11a). Yield 73%, orange solid, mp 165–
4
(5H)-one (12a). Yield 77%, yellow solid, mp 207–
–
1
68°C. IR spectrum, ν, cm : 3425, 3232 (NH), 1604
–1
2
09°C. IR spectrum, ν, cm : 3389, 3255 (NH), 1712
1
(
(
(
(
(
C=N). H NMR spectrum (DMSO-d , δ, ppm): 2.0 s
3H, CH ), 2.38 s (3H, CH ), 2.148 s (3H, CH ), 3.55 s
2H, 5′-H),7.0–7.93 m (8H, Harom), 9.01 s and 10.59 s
1H each, NH, D O exchangeable). Mass spectrum
1
6
(
(
C=O), 1612, 1598 (C=N). H NMR spectrum
DMSO-d ), δ, ppm: 2.17 s (3H, CH ), 2.38 s (3H,
3
3
3
6
3
CH ),3.84 s (2H, 5′-H), 6.8–7.8 m (8H, Harom); 10.41 s,
3
2
10.77 s, and 11.76 s (1H each, NH, D O exchangeable).
2
+
EI), m/z (I , %): 541 (13) [M] , 537 (30), 444 (24),
+
rel
Mass spectrum (EI), m/z (I , %): 543 (24) [M] , 531
rel
2
70 (23), 69 (100). Found, %: C 48.60; H 4.15;
(
21), 523 (32), 504 (48), 433 (55), 386 (34), 354
(34), 256 (50), 209 (39), 173 (55), 155 (61), 120
33), 111 (71), 89 (42). Found, %: C 46.34; H 3.41;
N 20.60. C H BrN S . Calculated, %: C 48.80;
2
2
21
8 2
H 3.91; N 20.69.
-[2-(2-{[1-(4-Bromophenyl)ethylidene]hydra-
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyl]-
(
N 20.58. C H BrN OS . Calculated, %: C 46.41;
2
21 19
8
2
H 3.52; N 20.62.
4
1
1
1
5
-methyl-5-[(E)-(3-methylphenyl)diazenyl]-
2
-[2-(2-{[1-(4-Bromophenyl)ethylidene]hydra-
,3-thiazole (11b). Yield 71%, orange solid, mp 177–
zinylidene}-1,3-thiazolidin-4-ylidene)hydrazinyl]-5-
[2-(4-chlorophenyl)hydrazinylidene]-1,3-thiazol-
4(5H)-one (12b). Yield 78%, yellow solid, mp 207–
209°C. IR spectrum, ν, cm : 3425 br (NH), 1705
(C=O), 1620 (C=N). H NMR spectrum (DMSO-d ), δ,
–
1
80°C. IR spectrum, ν, cm : 3447, 3233 (NH), 1592,
560, 1541 (C=N). Mass spectrum (EI), m/z (I , %):
rel
+
+
–1
43 (9) [M + 2] , 540 (43) [M – 1] , 513 (34), 469
1
(52), 340 (46), 174 (100), 131 (53), 121 (70), 106
77), 91 (20). Found, %: C 48.71; H 4.04; N 20.56.
6
(
ppm: 2.16 s (3H, CH ), 2.48 s (3H, CH ), 3.2 s (2H,
3
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

SYNTHESIS, CHARACTERIZATION, AND ANTICANCER SCREENING
1105
5
1
′-H), 7.23–8.03 m (8H, Harom); 10.56 s, 10.8 s, and
using the MTT assay, which is based on the reduction
of the tetrazolium salt by mitochondrial dehydro-
genases in viable cells [37–39]. Cells were dispensed
1
3
2.6 s (1H each, NH, D O exchangeable). C NMR
2
spectrum (DMSO-d ), δ , ppm: 15.4, 40.9, 115.8,
6
C
4
1
1
22.2, 124.3, 125.3, 126.0, 127.9, 128.1, 129.0, 129.5,
29.6, 131.2, 131.9, 143.2, 175.2. Mass spectrum (EI),
in a 96 well sterile microplate (1×10 cells per well)
and were incubated at 37°C with tested compounds or
doxorubicin (positive control) at different concentra-
tions in DMSO for 48 h in a serum-free medium prior
to the MTT assay. After incubation, media were care-
fully removed, 40 μL of MTT (2.5 mg/mL) was added
to each well, and the wells were incubated for an addi-
tional 4 h. The purple formazan dye crystals were
solubilized by adding 200 μL of DMSO. The absor-
bance was measured at λ 570 nm using a Spectra Max
Paradigm Multi-Mode microplate reader. The relative
cell viability was expressed as the mean percentage of
viable cells compared to the untreated control cells.
All experiments were conducted in triplicate and
repeated on three different days. The IC values were
+
+
m/z (I , %): 564 (28) [M + 1] , 563 (44) [M] , 557
rel
(
3
(
44), 545 (49), 490 (60), 477 (65), 365 (68), 334 (88),
08 (52), 287 (67), 257 (46), 205 (53), 185 (100), 155
37), 152 (81), 77 (34). Found, %: C 42.58; H 2.73;
N 19.78. C H BrClN OS . Calculated, %: C 42.60;
20
16
8
2
H 2.86; N 19.87.
-[2-(4-Methylphenyl)hydrazinylidene]-2-[2-(2-
[1-(4-nitrophenyl)ethylidene]hydrazinylidene}-1,3-
5
{
thiazolidin-4-ylidene)hydrazinyl]-1,3-thiazol-4(5H)-
one (12c). Yield 79%, yellow solid, mp 197–200°C. IR
–
1
spectrum, ν, cm : 3420, 3345 (NH), 1718 (C=O),
609 (C=N). Mass spectrum (EI), m/z (I , %): 509
1
rel
+
(13) [M] , 461 (42), 422 (100), 79 (94). Found, %:
5
0
C 49.48; H 3.54; N 24.61. C H N O S . Calculat-
2
1
19
9
3
2
determined by SPSS probit analysis (IBM, Armonk,
NY, USA) and are represented as mean ± standard
deviation (Table 1).
ed, %: C 49.50; H 3.76; N 24.74.
-[2-(3-Methylphenyl)hydrazinylidene]-2-[2-(2-
[1-(4-nitrophenyl)ethylidene]hydrazinylidene}-1,3-
5
{
thiazolidin-4-ylidene)hydrazinyl]-1,3-thiazol-4(5H)-
one (12d). Yield 71%, brown solid, mp 217–219°C. IR
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
SUPPLEMENTARY MATERIALS
–
1
spectrum, ν, cm : 3487, 3235 (NH), 1708 (C=O),
624, 1596, 1560 (C=N). Found, %: C 49.37; H 3.66;
N 24.59. C H N O S . Calculated, %: C 49.50;
1
2
1
19
9
3 2
H 3.76; N 24.74.
-[2-(4-Chlorophenyl)hydrazinylidene]-2-[2-(2-
[1-(4-nitrophenyl)ethylidene]hydrazinylidene}-1,3-
Supplementary materials are available for this article at
https://doi.org/10.1134/S1070428020060202 and are acces-
sible for authorized users.
5
{
thiazolidin-4-ylidene)hydrazinyl]-1,3-thiazol-4(5H)-
one (12e). Yield 77%, dark brown solid, mp 207–
REFERENCES
–
1
2
09°C. IR spectrum, ν, cm : 3417, 3170 (NH), 1705
(
5
4
C=O), 1597 (C=N). Mass spectrum (EI), m/z (I , %):
30 (16) [M + 1] , 529 (17) [M] , 483 (29), 456 (100),
02 (85). Found, %: C 45.25; H 3.12; N 23.76.
rel
1
. Ghaemmaghami, S., May, B.C.H., Renslo, A.R., and
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+
+
C H ClN O S . Calculated, %: C 45.33; H 3.04;
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0
16
9
3
2
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3
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

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