Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин
A versatile and efficient protocol for the synthesis of library of N-(2,4-diarylthiazol-5-yl)benzamidines is described. We obtained a library of 25 diversity with different of substituents in four positions in key framework. The synthesized amidine derivatives were evaluated for their i...
Gespeichert in:
| Datum: | 2022 |
|---|---|
| Автори та афіліації: |
|
| Ключові слова: | keywords |
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | Englisch |
| Veröffentlicht: |
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2022
|
| Schlagworte: | |
| Online Zugang: | https://bioorganica.com.ua/index.php/journal/article/view/31 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Ukrainica Bioorganica Acta |
| Завантажити файл: |  |
Institution
Ukrainica Bioorganica Acta| _version_ | 1871193565683515392 |
|---|---|
| author | Severin, Oleksandr O. Kachaeva, Maryna V. Pilyo, Stepan G. Shablykina, Olga V. Moskvina, Viktoriia S. Brovarets, Volodymyr S. |
| author_facet | Severin, Oleksandr O. Kachaeva, Maryna V. Pilyo, Stepan G. Shablykina, Olga V. Moskvina, Viktoriia S. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Oleksandr O. Severin",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Stepan G. Pilyo",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Olga V. Shablykina",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine; Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
},
{
"author": "Viktoriia S. Moskvina",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine; Taras Shevchenko National University of Kyiv, Kyiv, Ukraine "
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine "
}
] |
| author_sort | Severin, Oleksandr O. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:53Z |
| description | A versatile and efficient protocol for the synthesis of library of N-(2,4-diarylthiazol-5-yl)benzamidines is described. We obtained a library of 25 diversity with different of substituents in four positions in key framework. The synthesized amidine derivatives were evaluated for their in vitro anticancer activity. Analysis of anticancer activity on 60 cancer cell lines showed a decrease of proliferation of Colon Cancer and Leukemia cell lines by more than half and allowed to establish the structure-activity relationship. |
| doi_str_mv | 10.15407/bioorganica2022.02.014 |
| first_indexed | 2025-07-17T12:19:35Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
UDC 547.789.1 + 615.281.8 + 615.277.3
DOI: hpps://doi.org/10.15407/bioorganica2022.02.014
14
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
The N-(2,4-diarylthiazol-5-yl)benzamidines library creation and the
effect of these compounds on cancer growth
Oleksandr O. Severin1, Maryna V. Kachaeva1, Stepan G. Pilyo1, Olga V. Shablykina1,2,
Viktoriia S. Moskvina1,2*, Volodymyr S. Brovarets1
1 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
2 Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
Abstract: A versatile and efficient protocol for the synthesis of library of N-(2,4-diarylthiazol-5-yl)benzamidines is described. We
obtained a library of 25 diversity with different substituents in four positions in key framework. The synthesized amidine derivatives
were evaluated for their in vitro anticancer activity. Analysis of anticancer activity on 60 cancer cell lines showed decreased proliferation
of Colon Cancer and Leukemia cell lines by more than half and allowed to establish the structure-activity relationship.
Keywords: N-(2,4-diarylthiazol-5-yl)benzamidines; combinatorial library; anticancer activity.
Introduction
Among the most successful heterocycles in medical
chemistry [1], 1,3-thiazole derivatives occupy an important
place. They are convenient and perspective objects for
researchers not only due to the pharmacophore nature of the
basic heterocycle, but also due to the ease of synthesis and
wide possibilities of variation of substituents in positions 2,
4, 5 [2], since the nature of the substituents in thiazole
rarely changes with the type of biological activity of the
molecule [3, 4]. All of the above fully contains thiazoles
with an amino group in position 5. On the one hand, among
5-aminothiazoles, a substance with anticancer (Figure 1,
structure 1 [5]), antimicrobial (Figure 1, structure 2 [6]),
antioxidant properties activity were found (Figure 1,
structure 3 [7]), as well as substances that can be useful in
the treatment of prion diseases (Figure 1, structure 4 [8]).
Received:
Revised:
Accepted:
Published online:
14.09.2022
28.09.2022
31.10.2022
30.12.2022
Corresponding author. Tel.: +380-44-239-3342;
e-mail: v.moskvina@gmail.com (V.S. Moskvina)
ORCID: 0000-0001-5556-9147
Figure 1. Examples of bioactive 5-aminothiazoles.
On the other hand, the synthetic methods of
5-aminothiazoles allow to vary the substituents in the
heterocycle within quite wide limits, and the thiazole cycle
is stable enough to allow for a number of modifications of
the amino group. Among the variety of possibilities, we
were interested in the synthesis of thiazoles with an amidine
fragment in position 5.
© Severin O.O. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:v.moskvina@gmail.com
https://orcid.org/0000-0001-5556-9147
O.O. Severin, M.V. Kachaeva et al.
15
NH2
S
O
O
N
N
S
S
N
N
NH2
H2N
Famotidine
histamine H2 receptor antagonist
stomach acid production decreasing
N
N
N
N
H
S
Olanzapine
atypical antipsychotic
(schizophrenia, bipolar disorder)
H2
Figure 2. Examples of bioactive amidines.
The amidine fragment is found in the structure of well-
known drugs such as Olanzapine [9] and Famotidine [10]
(Figure 2). One of the reasons for the biological activity of
amidines may be their effect on L-Arginine metabolism
[11]; there are data on the biological activity of platinum
amidine complexes [12], as well as on the inflammatory
activity of heterocyclic amidine derivatives [13].
In this work, we present a simple route to generate a
library of 2,4-diarylthiazoles with an amidine (benz-
imidamide) moiety in the 5-position of the heterocycle and
a preliminary evaluation of their prospects as anticancer
agents.
Results and Discussion
Synthesis
Based on the previous developments of our scientific
group in the field of bioactive thiazole derivatives as
anticancer agent [14-16], we chose the following path for
the synthesis of target structures. Thiazoles 5 containing an
amide group in 5-position of the thiazole ring were
synthesized by the reaction between α-chloroalkylamides
and aromatic thioamides (Scheme 1). They can be obtained
from acetophenone and the corresponding amides of
carboxylic acids, some of which have been synthesized
previously [17, 18].
Scheme 1. Synthesis of target thiazoles 7 with amidine group and scope of substituents.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
16
N
NS
Np-Tol
7{1-2-1-15}
NCS 832689
N
NS
Np-Tol
7{1-2-1-16}
NCS 832690
N
NS
N
N
p-Tol
7{1-2-1-3}
NCS 832691
N
NS
N
N
p-Tol
7{1-2-1-6}
NCS 832692
N
NS
N
N
7{1-1-1-3}
NCS 832693
N
NS
N
N
OMe
7{1-1-1-7}
NCS 832694
N
NS
N
N
7{1-1-1-6}
NCS 832695
N
NS
N
N
7{1-1-1-4}
NCS 832696
N
NS
N
N
F
7{1-1-1-8}
NCS 834018
N
NS
N
N
7{1-1-1-2}
NCS 834019
N
S N
p-TolH2N
7{1-2-1-1}
NCS 834020
N
S N
H2N
7{1-1-1-1}
NCS 834021
N
NS
N
N
p-Tol
7{1-2-1-4}
NCS 834022
N
NS
N
N
p-Tol
O
OEt
7{1-2-1-5}
NCS 834023
N
NS
N
N
p-Tol
OMe 7{1-2-1-7}
NCS 834024
N
NS
N
N
p-Tol F
7{1-2-1-9}
NCS 834025
N
N
S
Np-Tol
7{1-2-1-25}
NCS 834026
N
NS
Np-Tol
7{1-2-1-22}
NCS 834027
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph Ph
Ph
Ph
PhPh
Figure 3. Scope of the 20 products 7 selected for anticancer activity research, and their NCS code (E-isomers, as the most possible confi-
guration).
To form an amidine fragment, the amide group of
compounds 5 was converted to a chloroamidine by reaction
with PCl5 (substances 6 in Scheme 1). By reacting
compounds 6 with ammonia or secondary aliphatic amines,
thiazoles 7 containing amides and a new fragment were
obtained. An important advantage of this method of
synthesizing amidines, among other approaches [19], is the
possibility of varying the substituents in the amidine
fragment.
Intermediate compounds 6, in their individual state, were
not isolated, because they hydrolyze quite quickly when in
contact with the moisture of the environment, therefore, for
example, the registration of their spectra should be carried
out under special conditions, since when using the usual
procedure, the sample will always contain an admixture of
the corresponding amide 5. Transformation 5 → 6 → 7 was
carried out in anhydrous solvents, without isolating
compounds 6 in an individual state (see Experimental
section). The final products – thiazoles with an amidine
fragment – are numbered in the format 7{A-B-C-D}, where
A – is the sequence number of the Ar1 substituent, B – is the
sequence number of the Ar2 substituent, C – is the sequence
number of the Ar3 substituent, and D – is the sequence
number of the NR1R2 group (Scheme 1).
Using substrates that allowed for 4 variations of the Ar1
substituent, 5 variations of Ar2, and 4 variations of Ar3, as
well as a set of 25 amines of the general formula HNR1R2.
From the obtained library of compounds, 18 substances
O.O. Severin, M.V. Kachaeva et al.
17
were tested for anticancer activity; their structures are
shown in Figure 3; 1H- and 13C-NMR and IR spectral data
are given for this representative set of compounds in the
experimental part.
Table 2. The effect of compounds on the growth of cancer
cells, determined by single-dose assay (C = 10–5 M); GP –
Growth Percent, %; N75 – number of lines with
0 GP 75%; N50 – number of lines with 0 GP 50%
Compd
(NCS
code)
GP,
Mean
GP,
Range
N75 N50
The most significant
inhibition, GP
7{1-1-1-1}
(834021)
85.7 60.0 10 –
53.8 HT29 (Colon Cancer)
54.2 KM12 (Colon Cancer)
56.1 HCT-15 (Colon Cancer)
7{1-2-1-1}
(834020)
77.5 74.3 17 4
26.7 CCRF-CEM (Leukemia)
28.5 K-562 (Leukemia)
41.4 KM12 (Colon Cancer)
7{1-1-1-2}
(834019)
75.1 111.7 18 9
9.9 HT29 (Colon Cancer)
16.7 HCT-15 (Colon Cancer)
17.8 K-562 (Leukemia)
21.1 SR (Leukemia)
24.5 KM12 (Colon Cancer)
7{1-1-1-3}
(832693)
76.6 81.5 23 4
31.8 OVCAR-4 (Ovarian
Cancer)
32.6 HT29 (Colon Cancer)
32.8 K-562 (Leukemia)
7{1-1-1-4}
(832696)
95.0 49.1 2 –
72.4 NCI-H226 (Non-Small
Cell Lung Cancer)
7{1-1-1-6}
(832695)
102.6 40.5 – – 84.9 UACC-62 (Melanoma)
7{1-1-1-7}
(832694)
100.3 42.7 – –
79.6 NCI-H226 (Non-Small
Cell Lung Cancer)
7{1-1-1-8}
(834018)
98.9 39.4 – –
80.1 NCI-H522 (Non-Small
Cell Lung Cancer)
7{1-2-1-15}
(832689)
106.4 24.8 – – –
7{1-2-1-16}
(832690)
107.7 24.6 – – –
7{1-2-1-3}
(832691)
100.2 69.7 1 –
53.3 HL-60(TB) (Leukemia)
78.1 KM12 (Colon Cancer)
79.0 NCI-H460 (Non-Small
Cell Lung Cancer)
7{1-2-1-4}
(834022)
89.4 84.7 11 –
57.2 HCT-116 (Colon Cancer)
64.3 K-562 (Leukemia)
64.9 PC-3 (Prostate Cancer)
7{1-2-1-5}
(834023)
82.9 78.1 17 –
53.1 CAKI-1 (Renal Cancer)
53.7 ACHN (Renal Cancer)
57.5 HS 578T (Breast Cancer)
7{1-2-1-6}
(832692)
104.9 19.9 – – –
7{1-2-1-7}
(834024)
95.5 46.6 1 – 70.4 UACC-62 (Melanoma)
7{1-2-1-9}
(834025)
99.2 53.3 1 – 74.2 UACC-62 (Melanoma)
7{1-2-1-22}
(834027)
100.1 39.0 – – 78.9 UO-31 (Renal Cancer)
7{1-2-1-25}
(834026)
101.2 43.6 – – 83.0 CAKI-1 (Renal Cancer)
Biological assay
The anticancer activity of synthesized compounds was
tested according to the Developmental Therapeutic Program
(DTP) of the National Cancer Institute (NCI, Bethesda,
Maryland, USA) on 60 cancer cell lines [20]; a description
of the technique is also given in [21].
The most significant data, expressed as a percentage of
inhibition of the growth of cancer cells, are systematized in
Table 2.
No derivatives with high cytotoxicity were found among
the investigated substances. The most active of them (NCS
834019, 832693, 834020) were able to slow down the
growth of a small number of cancer cell lines (4-9 out of
60) by more than half. Three more substances with low
anticancer activity (NCS 834021, 834022, 834023) can be
distinguished from the array by analyzing the number of
lines whose growth was 75% or less of the initial one; the
inhibitory ability of all other substances can be considered
insignificant.
The N-methylpiperazine derivative (NCS 834019) shows
the highest activity, the corresponding N-ethylpiperazine
derivative (NCS 832693) is slightly inferior to it. When an
aromatic substituent is introduced in the 4th position of the
piperazine residue, the molecule completely loses its ability
to slow down the growth of cancer cells; derivatives of
1,2,3,4-tetrahydroisoquinoline and methylcyclohexylamine
also did not show a noticeable anticancer effect.
No derivatives with high cytotoxicity were found among
the investigated substances. The most active of them (NCS
834019, 832693, 834020) were able to slow down the
growth of a small number of cancer cell lines (4-9 out of
60) by more than half. Three more substances with low
anticancer activity (NCS 834021, 834022, 834023) can be
distinguished from the array by analyzing the number of
lines whose growth was 75% or less of the initial one; the
inhibitory ability of all other substances can be considered
insignificant.
The N-methylpiperazine derivative NCS 834019 shows
the highest activity, the corresponding N-ethylpiperazine
derivative (NCS 832693) is slightly inferior to it. When an
aromatic substituent is introduced in the 4th position of the
piperazine residue, the molecule completely loses its ability
to slow down the growth of cancer cells; derivatives of
1,2,3,4-tetrahydroisoquinoline and methylcyclohexylamine
also did not show a noticeable anticancer effect.
Replacing the phenol group in the amidine fragment with
a tolyl group in the case of NH2-derivatives (compare
NCS 834021 and 834020) gives a small positive effect, and
in the case of piperazine derivatives - negative (for
example, NCS 832693 and 832691).
It is worth noting for the most active NCS derivatives
834019, 832693, 834020 the tendency of inhibition mainly
of Colon Cancer and Leukemia lines.
Thus, further modifications of the basic structure should
be carried out in the direction of creating a greater variety of
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
18
N-methylpiperazine derivatives and amidines with the NH2
group due to variations of the Ar1–Ar3 substituents (in the
created library, the variations of these positions were
inferior to the number of variations of the amine fragment);
study of the influence of the latter on bioactivity; as well as
determination of other types of biological action of such
derivatives, in particular, antimicrobial.
Conclusions
In conclusion, we have developed an efficient protocol
for the rapid synthesis of N-(2,4-diarylthiazol-5-
yl)benzamidines, which provides easy variation of
substituents in four positions. In vitro studies of the
anticancer activity of 18 substances revealed only a
moderate anticancer effect of 3 of them and a weak effect of
another 3 derivatives. But the variety of possible
compounds of this class provides grounds for further
research in the direction of identifying substances with
more powerful activity.
Notes
Acknowledgments and finances. We would like to
thank US Public Health Service and National Cancer
Institute, USA, for in vitro evaluation of anticancer
activity (providing the NCI-60 cell testing) within
the framework of Developmental Therapeutic Program
(http://dtp.cancer.gov), and Enamine Ltd for the material
and technical support for the synthetic part of this work.
Disclaimer. This material should not be interpreted as
representing the viewpoint of the U.S. National Institutes of
Health, or the National Cancer Institute.
Author contributions. O. O. S.: synthesis of compo-
unds, Investigation, writing of abstract, writing
experimental section, editing. M. V. K.: synthesis of
compounds, analysis of bioactivity, formal analysis.
S. G. P.: synthesis of compounds, investigation, formal
analysis, editing. O. V. S.: formal analysis, writing
experimental section, editing. V. S. M.: investigation,
formal analysis, manuscript writing, editing. V. S. B.:
conceptualization, supervision, writing, review & editing.
Experimental section
The solvents were purified according to the standard
procedures. All materials were purchased from commercial
sources and used without further purification. The success
rate was calculated as the number of successful experiments
divided by the total number of experiments. 1H NMR
spectra were recorded on a Varian VXR-400 spectrometer
(400 MHz) and 13C NMR spectra were recorded at Bruker
170 spectrometer (126 MHz) spectra in DMSO-d6 or
CF3CO2D, or CDCl3 solution. Chemical shifts are reported
in ppm downfield from TMS as internal standards. Mass
spectra were recorded on an LC-MS instrument with
chemical ionization (CI). LC-MS data were acquired on an
Agilent 1200 HPLC system equipped with
DAD/ELSD/LCMS-6120 diode matrix and mass-selective
detector. Melting points were measured on a MPA100
OptiMelt automated melting point system. Combustion
elemental analysis was performed by hand in the
V.P. Kukhar Institute of Bioorganic Chemistry and
Petrochemistry analytical laboratory. The carbon and
hydrogen contents were determined using the Pregl
gravimetric method, nitrogen – using the Duma's
gasometrical micromethod, sulfur – by the Scheininger
titrimetric method.
A representative procedure for the synthesis of N'-(2,4-
diphenylthiazol-5-yl)benzimidamide (7{1-1-1-1}).
20.8 g (0.1 mol) of PCl5 was added to a solution of 35.6 g
(0.1 mol) of N-(2,4-diphenylthiazol-5-yl)benzamide (5) in
300 ml of benzene, and the solution was boiled with stirring
for 5 h and left for 10-12 hours at 20-25 ºC. An excess of
sulfur dioxide (SO2) gas was blown through the solution for
20-25 minutes, then the reaction mixture was left for 1 hour.
The solvent was evaporated in vacuo and formed solid
residue was treated with hexane, filtered and dried in vacuo.
The obtained N-(2,4-diphenylthiazol-5-yl)benzimidoyl
chloride (6) was used for further syntheses.
To a solution of 0.01 mol of imidoyl chloride in 50 ml of
anhydrous 1,4-dioxane, an excess of a saturated solution of
ammonia (NH3) in dioxane (5 ml) was added, and the
reaction mixture was left for 10-12 hours at 20-25 ºC. The
solvent was evaporated in vacuo, the formed solid residue
was treated with water, filtered, dried and purified by
crystallization from acetonitrile.
A solution of 0.01 mol of imidoyl chloride, 0.011 mol of
the corresponding secondary aliphatic amine and 0.011 mol
(1.55 ml) of Et3N was boiled with stirring for 5 hours, then
left for 12 hours at 20-25 °C. The solvent was evaporated in
vacuo, the formed solid residue was treated with water,
filtered, dried and purified by crystallization from acetonitrile
with the addition of a small amount of dimethylformamide.
Yield: 2.70 g, 76%. Colorless solid, mp 163-165 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J 7.7 Hz, 2H),
8.07 (br s, 2H), 7.94 (br d, J 7.0 Hz, 2H), 7.58-7.43 (m,
8H), 7.39 (t, J 7.7 Hz, 2H), 7.24 (t, J 7.3 Hz, 1H). 13C NMR
(126 MHz, DMSO-d6) δ 157.8, 156.1, 144.5, 140.3, 135.4,
134.6, 134.0, 130.9, 129.3, 129.1 2, 128.4 2, 128.1 2,
127.4 2, 126.9 2, 126.4, 125.4 2. IR (KBr) 3432,
3328, 3061, 3024, 1621 (vs), 1596 (s), 1563 (vs), 1504,
1478, 1443, 1377, 1340, 1311, 1207, 1071, 1046, 1025,
966, 917, 853, 774, 758, 692 (vs), 597, 558. HPLC (CI) m/z
(M+H)+ 354. Found, %: C, 74,62; H, 4,96;
N, 11,78; S, 9,00. C22H17N3S. Calculated, %: C, 74.34; H,
4.82; N, 11.82; S, 9.02.
N'-(2,4-Diphenylthiazol-5-yl)-4-methylbenzimidamide
(7{1-2-1-1}).
Yield: 3.00 g, 81.3%. Colorless solid, mp 149-151 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J 7.6 Hz, 2H),
8.02-7.86 (m, 4H), 7.57-7.41 (m, 5H), 7.39 (t, J 7.5 Hz,
2H), 7.32 (d, J 8.0 Hz, 2H), 7.24 (t, J 7.5 Hz, 1H), 2.39 (s,
3H). 13C NMR (126 MHz, DMSO-d6) δ 157.8, 144.5, 141.1,
135.2, 134.5, 133.9, 131.4, 129.4, 129.1 2, 129.0 2,
O.O. Severin, M.V. Kachaeva et al.
19
128.1 2, 127.9 2, 127.5, 126.9, 126.5 2, 125.4 2,
21.00. IR (KBr) 3362, 3297, 3158, 3054, 1634 (s), 1581,
1556 (vs), 1510 (s), 1477, 1436, 1396, 1335, 1305, 1285,
1203, 1177, 1062, 1025, 975, 914, 893, 862, 828, 758 (s),
722, 692 (s), 672, 621, 534. HPLC (CI) m/z (M+H)+ 370.
Found, %: C, 74.92; H, 5.39; N, 11.39; S, 8.69. C23H19N3S.
Calculated, %: C, 74.77; H, 5.18; N, 11.37; S, 8.68.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-methylpiperazin-1-yl)-
1-phenylmethanimine (7{1-1-1-2}).
Yield: 3.47 g, 79%. Colorless solid, mp 161-163 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J 7.8 Hz, 2H),
7.60 (d, J 7.2 Hz, 2H), 7.56-7.47 (m, 3H), 7.47-7.30 (m,
5H), 7.30-7.22 (m, 3H), 4.04-3.78 (br s, 4H with other
signals), 3.28-3.01 (br s, 4H, with other signals), 2.22 (s,
3H). 13C NMR (126 MHz, DMSO-d6) δ 157.8, 156.1, 144.5,
140.3, 141.1, 135.4, 134.6, 134.0, 129.4, 291.0 2, 129.0
2, 128.4 2, 128.4, 128.1 2, 126.9 2, 126.4 2, 124.9,
52.1, 49.7, 11.9. IR (KBr) 3052, 2939, 2883, 2841, 2803,
1603, 1575 (vs), 1498, 1445, 1418 (s), 1362, 1341, 1292,
1279, 1254, 1134, 1104, 1073, 999, 979, 928, 890, 841,
781, 755, 687 (s), 654, 598. HPLC (CI) m/z (M+H)+ 439.
Found, %: C, 74.21; H, 6.13; N, 12,71; S, 7.29. C27H26N4S.
Calculated, %: C, 73.94; H, 5.98; N, 12.77; S, 7.31.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-ethylpiperazin-1-yl)-1-
phenylmethanimine (7{1-1-1-3}).
Yield: 3.44 g, 80%. Colorless solid, mp 161-163 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J 7.7 Hz, 2H),
7.60 (d, J 7.4 Hz, 2H), 7.54-7.46 (m, 3H), 7.43 (t, J 7.6 Hz,
2H), 7.36 (p, J 6.3 Hz, 3H), 7.25 (d, J 8.1 Hz, 3H), 3.91 (s,
1H), 3.33-3.15 (br s, 4H with other signals), 2.37 (br s, 4H
with other signals), 1.03 (q, J 8.5, 7.2 Hz, 3H). 13C NMR
(126 MHz, DMSO-d6) δ 157.8, 156.1, 144.5, 140.3, 135.4,
134.6, 134.0, 130.3, 129.4, 129.0 2, 128.5 2, 128.0 2,
127.4 2, 126.9 2, 126.3, 125.4 2, 52.1 2, 51.5 2,
48.7, 11.9. IR (KBr) 3047, 2973, 2887, 2850, 2808, 1569
(vs), 1497, 1443, 1420 (s), 1366, 1342, 1311, 1259 (s),
1152, 1123, 1015, 979, 940, 887, 840, 763, 687 (s), 650,
600, 546. HPLC (CI) m/z (M+H)+ 453.2. Found, %:
C, 74.42; H, 6.36; N, 12.35; S, 7.06. C28H28N4S. Calculated,
%: C, 74.30; H, 6.24; N, 12.38; S, 7.08.
1-(4-Allylpiperazin-1-yl)-N-(2,4-diphenylthiazol-5-yl)-1-
phenylmethanimine (7{1-1-1-4}).
Yield: 3.57 g, 77%. Colorless solid, mp 143-145 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J 7.5 Hz, 2H),
7.60 (d, J 7.2 Hz, 2H), 7.43-7.11 (m, 11H), 3.13 (s, 2H),
2.38 (s, 3H), 1.88 (s, 2H), 1.63 (s, 4H), 1.45 (s, 1H), 0.97
(d, J 72.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ
160.8, 155.0, 144.7, 140.5, 135.6, 135.1, 133.7, 131.3,
130.3, 129.4, 129.1, 129.0 2, 128.4 2, 128.0 2, 127.4
2, 126.3 2, 125.0 2, 118.0, 60.7, 53.4 2, 50.1 2. IR
(KBr) 3059, 3041, 2978, 2932, 2914, 2886, 2844, 2811,
2762, 1573 (vs), 1495 (s), 1444 (s), 1418 (s), 1364, 1344
(s), 1306, 1259 (s), 1218, 1140, 1089, 999 (s), 977, 921,
891, 842, 813, 752 (s), 696 (s), 598, 545. HPLC (CI) m/z
(M+H)+ 465. Found, %: C, 75.13; H, 6.16; N, 12.03; S,
6.87. C29H28N4S. Calculated, %: C 74.97; H 6.07; N 12.06;
S 6.90.
N-(2,4-Diphenylthiazol-5-yl)-1-phenyl-1-(4-phenylpipe-
razin-1-yl)methanimine (7{1-1-1-6}).
Yield: 3.90 g, 78%. Colorless solid, mp 195-197 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J 7.8 Hz, 2H),
7.61 (d, J 7.4 Hz, 2H), 7.54 (d, J 6.6 Hz, 3H), 7.46-7.31 (m,
7H), 7.25 (t, J 7.4 Hz, 3H), 6.99 (d, J 7.9 Hz, 2H), 6.82 (t, J
7.4 Hz, 1H), 4.06 (br s, 4H with other signals), 3.16-3.03
(br s, 4H, with other signals). 13C NMR (126 MHz, DMSO-
d6) δ 157.8, 156.1, 144.5, 140.3, 135.4, 134.6, 134.0, 130.9,
129.5, 129.3, 129.0 2, 128.6 2, 128.1 2, 128.0, 127.5,
127.4 2, 126.9 2, 126.4, 126.2, 125.4, 125.0, 115.8 2,
56.4 2, 52.3 2. IR (KBr) 3060, 3019, 2895, 2814,
1579, 1551 (vs), 1497 (s), 1448, 1422 (s), 1376, 1337 (s),
1307, 1269, 1223 (s), 1141, 1101, 1070, 1011, 975, 930,
876, 847, 754 (s), 691 (s), 517. HPLC (CI) m/z (M+H)+
501.2. Found, %: C, 76.89; H, 5.73; N, 11.17; S, 6.39.
C32H28N4S. Calculated, %: C, 76.77; H, 5.64; N, 11.19; S,
6.40.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-(4-methoxyphenyl)-
piperazin-1-yl)-1-phenylmethanimine (7{1-1-1-7}).
Yield: 4.13 g, 78%. Colorless solid, mp 177-179 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J 7.8 Hz, 2H),
7.61 (d, J 7.3 Hz, 2H), 7.53 (q, J 6.3 Hz, 3H), 7.43 (t, J 7.6
Hz, 2H), 7.40-7.25 (m, 6H), 6.94 (d, J 9.0 Hz, 2H), 6.84 (d,
J 9.0 Hz, 2H), 4.06 (br s, 4H with other signals), 3.69 (s,
3H), 3.23-3.05 (br s, 4H with other signals). 13C NMR
(126 MHz, DMSO-d6) δ 157.8, 156.1, 144.5, 140.3, 135.4,
134.6, 134.0, 130.9, 129.5, 129.3, 129.0 2, 128.6 2,
128.1 2, 128.0, 127.5, 127.4 2, 126.9 2, 126.4, 126.2,
125.4, 125.0, 115.8 2, 56.4 2, 52.3 2, 56.8. IR (KBr)
3058, 2986, 2901, 2811, 1556 (vs), 1507 (s), 1449, 1423 (s),
1379, 1337, 1306, 1266, 1243 (s), 1223, 1180, 1144, 1099,
1039, 1014, 971, 929, 825, 758 (s), 713, 692 (s), 631, 609,
532. HPLC (CI) m/z (M+H)+ 533. Found, %: C, 74.82; H,
5.79; N, 10.54; S, 6.03. C33H30N4OS. Calculated, %:
C, 74.69; H, 5.70; N, 10.56; S, 6.04.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-(4-fluorophenyl)-
piperazin-1-yl)-1-phenylmethanimine (7{1-1-1-8}).
Yield: 4.20 g, 81%. Colorless solid, mp 213-215 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J 7.8 Hz, 2H),
7.61 (d, J 7.4 Hz, 2H), 7.53 (q, J 6.6 Hz, 3H), 7.44 (t, J 7.6
Hz, 2H), 7.34 (ddt, J 22.0, 15.7, 7.2 Hz, 6H), 7.08 (t, J 8.7
Hz, 2H), 7.00 (dd, J 9.1, 4.6 Hz, 2H), 4.06 (br s, 4H with
other signals), 3.09 (br s, 4H with other signals). 13C NMR
(126 MHz, DMSO-d6) δ 160.7, 155.1, 147.6, 144.5, 140.8,
135.6, 133.7, 131.2, 130.4, 129.5, 129.0 2, 128.6 2,
128.1 2, 128.0, 127.5, 127.4 2, 126.9 2, 126.4, 125.0,
117.7, 115.5, 115.3 2, 56.4 2, 52.3 2. IR (KBr)
3047, 3017, 2906, 2822, 1550 (vs), 1503 (vs), 1448, 1423
(s), 1379, 1337, 1307, 1286, 1266, 1230 (s), 1156, 1141,
1099, 1070, 1013, 974, 931, 815, 755, 693 (s), 632, 600,
517. HPLC (CI) m/z (M+H)+ 519.2. Found, %: C, 74.23; H,
5.29; N, 10.76; S, 6.15. C32H27FN4S. Calculated, %:
C, 74.11; H, 5.25; F, 3.66; N, 10.80; S, 6.18.
N-(2,4-Diphenylthiazol-5-yl)-1-(3-methylpiperidin-1-yl)-
1-(p-tolyl)methanimine (7{1-2-1-15}).
Yield: 3.79 g, 84%. Colorless solid, mp 198-200 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 7.70-7.53
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
20
(m, 2H), 7.44-7.24 (m, 8H), 7.18-7.05 (m, 2H), 2.98 (d, J
13.4 Hz, 2H), 2.39 (s, 3H), 2.33 (d, J 13.8 Hz, 3H), 1.49 (d,
J 169.2 Hz, 3H), 1.00-0.90 (m, 3H). 13C NMR (126 MHz,
DMSO-d6) δ 157.8, 144.5, 141.1, 135.2, 134.5, 133.9,
131.4, 129.4, 129.1 2, 129.0 2, 128.1 2, 127.9 2,
127.5, 126.9, 126.5 2, 125.4 2, 21.00, 53.1, 45.7, 31.2,
29.1, 23.4, 18.0. IR (KBr) 2939, 2919, 2844, 1556 (vs),
1501, 1423, 1368, 1345, 1258, 1118, 1084, 967, 903, 851,
829, 756, 685, 598, 550. HPLC (CI) m/z (M+H)+ 452.2.
Found, %: C, 77.25; H, 6.56; N, 9.26; S, 7.08. C29H29N3S.
Calculated, %: C, 77.12; H, 6.47; N, 9.30; S, 7.10.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-methylpiperidin-1-yl)-
1-(p-tolyl)methanimine (7{1-2-1-16}).
Yield: 3.62 g, 80%. Colorless solid, mp 165-167 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 7.70-7.53
(m, 2H), 7.44-7.24 (m, 8H), 7.18-7.05 (m, 2H), 2.98 (d, J
13.4 Hz, 2H), 2.39 (s, 3H), 2.33 (d, J 13.8 Hz, 3H), 1.49 (d,
J 169.2 Hz, 3H), 1.20-1.05 (m, 3H). 13C NMR (126 MHz,
DMSO-d6) δ 157.8, 144.5, 141.1, 135.2, 134.5, 133.9,
131.4, 129.4, 129.1 2, 129.0 2, 128.1 2, 127.9 2,
127.5, 126.9, 126.5 2, 125.4 2, 21.00, 45.2 2, 34.7
2, 32.2, 20.6. IR (KBr) 3055, 3040, 2954, 2920, 2853,
1573 (vs), 1502, 1446, 1408 (s), 1372, 1344, 1310, 1252 (s),
1218, 1121, 1088, 965, 911, 883, 826, 803, 758 (s), 717,
690 (s), 650, 598, 542. HPLC (CI) m/z (M+H)+ 452.2.
Found, %: C, 77.22; H, 6.53; N, 9.28; S, 7.11. C29H29N3S.
Calculated, %: C, 77.12; H, 6.47; N, 9.30; S, 7.10.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-ethylpiperazin-1-yl)-1-
(p-tolyl)methanimine (7{1-2-1-3}).
Yield: 3.70 g, 79%. Colorless solid, mp 165-167 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J 7.6 Hz, 2H),
7.62 (d, J 7.2 Hz, 2H), 7.47 7.32 (m, 5H), 7.32 7.23 (m,
3H), 7.13 (d, J 7.2 Hz, 2H), 4.04 3.76 (br. s, 2H, NCH2),
3.25-3.03 (br s, 4H with other signals), 2.50 (br s, 4H with
other signals), 2.37 (d, J 17.4 Hz, 5H), 1.02 (t, J 6.6 Hz).
13C NMR (126 MHz, DMSO-d6) δ 157.8, 144.5, 141.1,
135.2, 134.5, 133.9, 131.4, 129.4, 129.1 2, 129.0 2,
128.1 2, 127.9 2, 127.5, 126.9, 126.5 2, 125.4 2,
57.3 2, 50.2 2, 48.4, 21.00, 12.1. IR (KBr) 3049,
3032, 2972, 2923, 2883, 2848, 2812, 1567 (vs), 1503, 1442,
1421 (s), 1368, 1344, 1309, 1287, 1258, 1156, 1122, 1069,
1015, 977, 946, 891, 824, 776, 759, 688, 648, 598, 547.
HPLC (CI) m/z (M+H)+ 467. Found, %: C, 74.82; H, 6.54;
N, 12.02; S, 6.85. C29H30N4S. Calculated, %: C, 74.64;
H, 6.48; N, 12.01; S, 6.87.
1-(4-Allylpiperazin-1-yl)-N-(2,4-diphenylthiazol-5-yl)-1-(p-
tolyl)methanimine (7{1-2-1-4}).
Yield: 3.88 g, 81%. Colorless solid, mp 138-140 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J 7.7 Hz, 2H),
7.60 (d, J 7.4 Hz, 2H), 7.54-7.47 (m, 3H), 7.43 (t, J 7.6 Hz,
2H), 7.36 (p, J 7.1, 6.5 Hz, 3H), 7.25 (d, J 8.1 Hz, 2H), 5.91
(s, 1H), 5.18 (s, 2H), 3.43 (br s, 2H with other signals), 3.15
(d, 2H), 2.37 (t, J 7.3 Hz, 4H), 1.02 (t, J 7.2 Hz, 3H).
13C NMR (126 MHz, DMSO-d6) δ 161.1, 154.9, 145.0,
140.2, 139.9, 135.6, 135.1, 133.8, 129.8 2, 129.0, 128.9
2, 128.3 2, 128.2, 127.9 2, 127.3 2, 126.2, 125.0
2, 117.8, 60.6, 52.9 2, 55.6 2, 21.0. IR (KBr) , 1643,
1558 (vs), 1503 (s), 1479, 1426 (s), 1367, 1339 (s), 1289,
1242, 1209, 1150, 1126, 1079, 1030, 1001 (s), 971, 931,
915, 858, 817, 757 (s), 692 (s), 663, 595, 550. HPLC (CI)
m/z (M+H)+ 479.2. Found, %: C, 75.36; H, 6.39; N, 11.70;
S, 6.69. C30H30N4S. Calculated, %: C, 75.28; H, 6.32;
N, 11.71; S, 6.70.
Ethyl 4-(((2,4-diphenylthiazol-5-yl)imino)(p-tolyl)-
methyl)piperazine-1-carboxylate (7{1-2-1-5}).
Yield: 4.24 g, 83%. Colorless solid, mp 156-158 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J 7.6 Hz, 2H),
7.62 (d, J 7.0 Hz, 2H), 7.44 (t, J 7.6 Hz, 2H), 7.41-7.23 (m,
6H), 7.17 (d, J 7.8 Hz, 2H), 4.08 (q, J 7.0 Hz, 2H), 4.02-
3.72 (br s, 2H), 3.71-3.36 (br s, 4H), 3.28-3.01 (br s, 2H),
2.35 (s, 3H), 1.20 (t, J 6.9 Hz, 3H). 13C NMR (126 MHz,
DMSO-d6) δ 161.2, 155.2, 154.6, 144.6, 140.6, 140.1,
135.5, 133.7, 130.0 2, 129.1, 129.0 2, 128.5 2, 128.0
3, 127.4 2, 126.3, 125.0 2, 61.0, 47.1 2, 43.2 2,
21.0, 14.6. IR (KBr) 3049, 2987, 2917, 2854, 1706 (s),
1693 (s), 1567 (vs), 1506, 1467, 1422 (s), 1344, 1308, 1276,
1231 (s), 1168, 1141, 1102, 1069, 1005, 977, 893, 825, 761,
690, 596, 548. HPLC (CI) m/z (M+H)+ 511. Found, %:
C, 70.60; H, 5.98; N, 11.01; S, 6.26. C30H30N4O2S.
Calculated, %: C, 70.56; H, 5.92; N, 10.97; S, 6.28.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-phenylpiperazin-1-yl)-
1-(p-tolyl)methanimine (7{1-2-1-6}.
Yield: 4.33 g, 84%. Colorless solid, mp 202-204 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J 8.0 Hz, 2H),
7.63 (d, J 6.9 Hz, 2H), 7.44-7.32 (m, 7H), 7.28-7.19 (m,
5H), 6.98 (d, J 8.1 Hz, 2H), 6.82 (t, J 7.2 Hz, 1H), 4.05 (s,
4H), 3.53 (br s, 4H, with other signals), 2.37 (s, 3H).
13C NMR (126 MHz, DMSO-d6) δ 157.8, 144.5, 141.1,
135.2, 134.5, 133.9, 131.4, 129.9, 129.4, 129.1 2, 129.0
2, 128.5, 128.1 2, 128.0, 127.9 2, 127.4, 126.9, 126.5
2, 125.4 2, 125.0, 119.3, 115.8, 47.1 2, 43.2 2, 21.0.
IR (KBr) 3044, 2909, 2884, 2812, 1552 (vs), 1499, 1448
(s), 1421 (s), 1373, 1338, 1308, 1264, 1229, 1141, 1095,
1013, 973, 929, 825, 758, 692, 524. HPLC (CI) m/z (M+H)+
515.2. Found, %: C, 77.24; H, 5.92; N, 10.84; S, 6.21.
C33H30N4S. Calculated, %: C, 77.01; H, 5.88; N, 10.89;
S, 6.23.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-(4-methoxyphenyl)-
piperazin-1-yl)-1-(p-tolyl)methanimine (7{1-2-1-7}).
Yield: 4.47 g, 82%. Colorless solid, mp 187-189 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J 7.5 Hz, 2H),
7.63 (s, 2H), 7.47-7.29 (m, 8H), 7.20 (d, J 7.6 Hz, 2H), 6.90
(dd, J 35.5, 6.2 Hz, 4H), 4.07 (s, 2H), 3.70 (t, J 4.4 Hz, 4H),
3.02 (s, 2H), 2.37 (s, 3H). 13C NMR (126 MHz, DMSO-d6)
δ 170.8, 163.1, 161.1, 155.0, 153.3, 145.0, 144.8, 140.4,
140.0, 135.6 2, 133.7 2, 129.9 2, 129.0 2, 128.4,
128.1, 128.0 2, 127.4, 126.3, 125.0, 117.9 2, 114.3 2,
55.8, 55.1 2, 49.9 2, 21.0. IR (KBr) 3058, 2990, 2950,
2911, 2807, 1555 (vs), 1506 (vs), 1423 (s), 1378, 1339,
1308, 1288, 1268, 1245 (s), 1228, 1179, 1141, 1037, 1014,
973, 926, 825, 761, 693, 626, 597, 533. HPLC (CI) m/z
(M+H)+ 545. Found, %: C, 75.06; H, 6.03; N, 10.27;
S, 5.88. C34H32N4OS. Calculated, %: C, 74.97; H, 5.92; N,
10.29; S, 5.89.
N-(2,4-Diphenylthiazol-5-yl)-1-(4-(2-fluorophenyl)-
piperazin-1-yl)-1-(p-tolyl)methanimine (7{1-2-1-9}).
O.O. Severin, M.V. Kachaeva et al.
21
Yield: 4.26 g, 80%. Colorless solid, mp 158-160 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J 7.8 Hz, 2H),
7.63 (d, J 6.8 Hz, 2H), 7.44 (t, J 7.6 Hz, 2H), 7.41-6.96 (m,
12H), 4.06 (br s, 4H with other signals), 3.01 (br s, 4H with
other signals), 2.36 (d, J 2.9 Hz, 3H). 13C NMR (126 MHz,
DMSO-d6) δ 170.8, 163.1, 161.1, 156.0, 155.1, 154.0,
144.8, 140.5, 140.0, 139.4, 135.5 2, 133.7, 129.9, 129.0,
128.4, 128.0 2, 127.4, 126.3, 125.0, 124.9, 124.8, 122.9,
122.8, 119.7, 119.6, 116.1, 115.9, 47.1 2, 43.2 2, 21.0.
IR (KBr) 3048, 2999, 2972, 2916, 2888, 2847, 1576 (vs),
1500 (s), 1416 (s), 1368, 1342, 1310, 1269, 1235 (s), 1204,
1137, 1091, 1013, 977, 935, 884, 825, 747 (s), 720, 690 (s),
650, 596, 544. HPLC (CI) m/z (M+H)+ 533.4. Found, %:
C, 74.52; H, 5.58; N, 10.50; S, 6.02. C33H29FN4S.
Calculated, %: C, 74.41; H, 5.49; F, 3.57; N, 10.52; S, 6.02.
1-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-(2,4-diphenyl-
thiazol-5-yl)-1-(p-tolyl)methanimine (7{1-2-1-22}).
Yield: 3.94 g, 81%. Colorless solid, mp 165-167 °C.
1H NMR (400 MHz, CF3COOD) δ 8.32-7.35 (m, 18H), 5.72
(s, 1H), 5.05 (s, 1H), 4.71 (s, 1H), 4.23 (s, 1H), 3.78 (s, 1H),
3.44 (s, 1H) 2.89 (d, 3H). 13C NMR (126 MHz, DMSO-d6)
δ 171.3, 164.2, 159.8, 150.9, 142.4, 139.8, 134.1, 133.4,
131.5 2, 130.6 2, 129.2 4, 129.1 2, 128.7 2, 128.6,
127.5 2, 125.5, 125.4, 118.7, 116.3, 115.6, 43.2, 41.5,
21.8, 16.4. IR (KBr) 3063, 3031, 2927, 2844, 1592, 1559
(vs), 1502 (s), 1477, 1443, 1417 (s), 1364, 1341, 1297,
1278, 1243, 1218, 1189, 1133, 1099, 1043, 977, 915, 847,
825, 744, 684, 595. HPLC (CI) m/z (M+H)+ 486.2. Found,
%: C, 79.26; H, 5.68; N, 8.63; S, 6.57. C32H27N3S.
Calculated, %: C, 79.14; H, 5.60; N, 8.65; S, 6.60.
(N-Сyclohexyl-N'-(2,4-diphenylthiazol-5-yl)-N,4-
dimethylbenzimidamide (7{1-2-1-25}).
Yield: 3.73 g, 80%. Colorless solid, mp 181-183 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J 7.5 Hz, 2H),
7.60 (d, J 7.2 Hz, 2H), 7.43-7.30 (m, 8H), 7.14 (d, J 7.2 Hz,
2H), 3.42 (s, 3H), 3.13 (s, 2H), 2.66 (s, 1H), 2.38 (s, 3H),
1.75 (d, J 101.9 Hz, 8H). 13C NMR (126 MHz, DMSO-d6,
DMSO-d6) δ 170.8, 163.1, 160.1, 147.8, 143.2, 139.9,
133.3, 130.9 2, 130.3 2, 129.6 2, 129.3 2, 129.0 2,
128.6 2, 127.5 2, 125.6, 63.4, 34.1, 30.0 2, 25.7,
25.1 2, 21.8. IR (KBr) 3057, 3044, 3019, 2919, 2852,
1596, 1546 (vs), 1502 (s), 1448, 1397 (s), 1340, 1214, 1133,
1072, 1024, 1003, 980, 909, 889, 831, 813, 777, 758, 687,
598. HPLC (CI) m/z (M+H)+ 466.2. Found, %: C, 77.44;
H, 6.76; N, 9.03; S, 6.87. C30H31N3S. Calculated, %:
C, 77.38; H, 6.71; N, 9.02; S, 6.88.
Biological assay
The antiviral activity of synthesized compounds was
tested in the Department of Pediatrics, University of
Alabama, Birmingham; description of the technique see in
[11].
The anticancer activity of synthesized compounds was
tested according to the International Program of the
National Institutes of Health – DTP (Developmental
Therapeutic Program) of the National Cancer Institute
(NCI, Bethesda, Maryland, USA) on 60 cancer cell lines
[14]; a description of the technique is also given in [15].
References
1. Zhang T.Y. The Evolving Landscape of Heterocycles in Drugs and
Drug Candidates. Advances in Heterocyclic Chemistry. 2017, 121,
1-12.
2. Narasimhamurthy, K.H.; Sajith, A.M.; Joy, M.N.; Rangappa, K.S.
An Overview of Recent Developments in the Synthesis of
Substituted Thiazoles. Chemistry Select. 2020, 5, 5629-5656.
3. Zhang, Z.; Shu, B.; Zhang, Y.; Deora, G.S.; Li, Q.S. 2,4,5-
Trisubstituted Thiazole: A Privileged Scaffold in Drug Design and
Activity Improvement. Curr Top Med Chem. 2020, 20, 2535-2577.
4. Borcea, A.M.; Ionuț, I.; Crișan, O.; Oniga, O. An Overview of the
Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity
of Thiazole and Bisthiazole Derivatives. Molecules. 2021, 26, 624.
5. Scott, D.A.; Aquila, B.M.; Bebernitz, G.A.; Cook, D.J.; Dakin, L.A.;
Deegan, T.L.; Maureen, M.H.; Stephanos, I.; Paul, D.L.; Charles,
A.O.; Minwei, Y.; Zheng, X. Pyridyl and thiazolyl bisamide CSF-1R
inhibitors for the treatment of cancer. Bioorg. Med. Chem. Lett. 2008,
18, 4794-4797.
6. Vilain, A.C.; Pirotte, B.; Vergely, I.; Boggetto, N.; Masereel, B.;
Schynts, M.; Jacques, D.; Reboud-Ravaux, M. Evaluation of the
Inhibitory Activity on Serine and Aspartic Proteases of 4-Amino-4H-
1,2,4-triazole and 5-Aminothiazole Derivatives Structurally Related
to β-Lactam Antibiotics. J. Pharm. Pharmacol. 1993, 45, 466-472.
7. Uchikawa, O.; Fukatsu, K.; Suno, M.; Aono, T.; Doi, T. In vivo
Biological Activity of Antioxidative Aminothiazole Derivatives.
Chem. Pharm. Bull. 1996, 44, 2070-2077.
8. Heal, W.; Thompson, M.J.; Mutter, R.; Cope, H.; Louth, J.C.; Chen,
B. Library Synthesis and Screening: 2,4-Diphenylthiazoles and 2,4-
Diphenyloxazoles as Potential Novel Prion Disease Therapeutics. J.
Med. Chem. 2007, 50, 1347-1353.
9. Mauri, M.C.; Volonteri, L.S.; Colasanti, A.; Fiorentini, A., De
Gaspari, I.F.; Bareggi, S.R. Clinical pharmacokinetics of atypical
antipsychotics: a critical review of the relationship between plasma
concentrations and clinical response. Clin. Pharmacokinet. 2007, 46,
359-388.
10. Berlin, R.G.; Clineschmidt, B.V.; Majka, J.A. Famotidine: An
appraisal of its mode of action and safety. Am. J. Med. 1986, 81, 8-
12.
11. Maccallini, C.; Fantacuzzi, M.; Amoroso, R. Amidine-Based
Compounds Affecting L-Arginine Metabolism. In L-Arginine in
Clinical Nutrition. Nutrition and Health; Patel, V., Preedy, V.,
Rajendram, R., Eds.; Springer International Publishing Imprint:
Humana Press, Cham. 2017, pp 41-53.
12. Michelin, R.A.; Sgarbossa, P.; Mazzega, I.; Sbovata, S.; Gandin, V.;
Marzano, C.; Bertani, R. Chemistry and Biological Activity of
Platinum Amidine Complexes. Chem. Med. Chem. 2011, 6, 1172-
1183.
13. Sondhi, S.M.; Rani, R.; Roy, P.; Agrawal, S.K.; Saxena, A.K.
Conventional and microwave assisted synthesis of small molecule
based biologically active heterocyclic amidine derivatives. Eur. J.
Med. Chem. 2010, 45, 902-908.
14. Severin, A.O.; Pilyo, S.G.; Potikha, L.M.; Brovarets, V.S. Synthesis
and Antitumor Activity of 5-Phenyl-1,3-thiazole-4-sulfonamide
Derivatives. Rus. J. Gen. Chem. 2022, 92, 174-184.
15. Turov, K.V.; Mitiukhin, O.P.; Chumachenko, S.A.; Zyabrev, V.S.;
Brovarets, V.S. Anticancer evaluation of di- and trifunctional
substituted 1,3-thiazoles. Ukr. Bioorg. Acta. 2020, 15, 2-11.
16. Pat. 109165 UA, IPC C07D277/32, C07D417/04, A61P35/00, 2,4-
Disulfanyl-5-cycloamino substituted thiazoles and their using as
anticancer drugs / Zyabrev, V.S; Babiy, S.B; Turov, K.V; Vasilenko,
O.M; Vinogradova, T.K.; Brovarets, V.S.; Publ. 27.07.2015 (in
Ukrainian).
17. Drach, B.S.; Dolgodushina, I.Yu.; Kirsanov, A.V. Interaction of ω-
chloro-ω-acylamidoacetophenones with thioacetamide. Russ. J. Org.
Chem. 1973, 9, 414-419.
18. Belyuga, A.G.; Brovarets, V.S.; Chernega, A.N.; Drach, B.S.
Preparation of 6-aryl-5-acylaminoimidazo[2,1-b]thiazoles, as well as
their 1,3,4-thiadiazole analogues based on amidophenacylating
reagents. J. Org. Pharm. Chem. 2005, 3, 38-42.
19. Aly, A.A.; Brässe, S.; Gomaa, A.M. Amidines: their synthesis,
reactivity, and applications in heterocyclic synthesis. Arkivoc, 2018,
6, 85-138.
20. NCI-60 Human Tumor Cell Lines Screen. DTP Developmental
Therapeutics Program, NIH website [Internet]. Available from:
https://dtp.cancer.gov/discovery_development/nci-60/default.htm
(accessed on September 14, 2022).
https://dtp.cancer.gov/discovery_development/nci-60/default.htm
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
22
21. Velihina, Ye.S.; Pil'o, S.G.; Zyabrev, V.S.; Moskvina, V.S.;
Shablykina, O.V.; Brovarets, V.S. 2-(Dichloromethyl)pyrazolo[1,5-
a][1,3,5]triazines: synthesis and anticancer activity. Biopolym. Cell.
2020, 36, 61-74.
Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на
ріст ракових клітин
O.O. Северін1, М.В. Качаєва1, С.Г. Пільо1, О.В. Шабликіна1,2, В.С. Москвіна1,2*, В.С. Броварець1
1 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
2 Київський національний університет імені Тараса Шевченка, Київ, Україна
Резюме: Досліджено ефективний метод отримання бібліотеки N-(2,4-диарилтіазол-5-іл)бензамідинів. Створено бібліотеку з 25 похідних з
різними замісниками в чотирьох положеннях у ключовій структурі. Проаналізовано активність синтезованих похідних амідину “ in vitro” на 60
лініях ракових клітин та встановлено залежність «структура-активність». Виявлено, що зниження проліферації клітинних ліній раку товстої
кишки та лейкемії сполуками NCS 834019, 832693, 834020 більш ніж на половину.
Ключові слова: N-(2,4-діарилтіазол-5-іл)бензамідини; комбінаторна бібліотека; антиракова активність.
Experimental section
|
| id | oai:ojs2.bioorganica.com.ua:article-31 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:44Z |
| publishDate | 2022 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/bc/0ba076c4b3e34685e70697883c5dfdbc.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-312026-07-19T14:56:53Z The N-(2,4-diarylthiazol-5-yl)benzamidines library creation and the effect of this compounds on cancer cell growth Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин Severin, Oleksandr O. Kachaeva, Maryna V. Pilyo, Stepan G. Shablykina, Olga V. Moskvina, Viktoriia S. Brovarets, Volodymyr S. N-(2,4-diarylthiazol-5-yl)benzamidines combinatorial library anticancer activity N-(2,4-діарилтіазол-5-іл)бензамідини комбінаторна бібліотека антиракова активність A versatile and efficient protocol for the synthesis of library of N-(2,4-diarylthiazol-5-yl)benzamidines is described. We obtained a library of 25 diversity with different of substituents in four positions in key framework. The synthesized amidine derivatives were evaluated for their in vitro anticancer activity. Analysis of anticancer activity on 60 cancer cell lines showed a decrease of proliferation of Colon Cancer and Leukemia cell lines by more than half and allowed to establish the structure-activity relationship. Досліджено ефективний метод отримання бібліотеки N-(2,4-диарилтіазол-5-іл)бензамідинів. Створено бібліотеку з 25 похідних з різними замісниками в чотирьох положеннях у ключовій структурі. Проаналізовано активність синтезованих похідних амідину “in vitro” на 60 лініях ракових клітин та встановлено залежність «структура-активність». Виявлено, що зниження проліферації клітинних ліній раку товстої кишки та лейкемії сполуками NCS 834019, 832693, 834020 більш ніж на половину. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/31 10.15407/bioorganica2022.02.014 Ukrainica Bioorganica Acta; Vol. 17 No. 2 (2022): Ukrainica Bioorganica Acta; 14-22 Ukrainica Bioorganica Acta; Том 17 № 2 (2022): Ukrainica Bioorganica Acta; 14-22 1814-9766 1814-9758 10.15407/bioorganica2022.02 en https://bioorganica.com.ua/index.php/journal/article/view/31/62 Copyright (c) 2022 Oleksandr O. Severin, Maryna V. Kachaeva, Stepan G. Pilyo, Olga V. Shablykina, Viktoriia S. Moskvina, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | N-(2,4-діарилтіазол-5-іл)бензамідини комбінаторна бібліотека антиракова активність Severin, Oleksandr O. Kachaeva, Maryna V. Pilyo, Stepan G. Shablykina, Olga V. Moskvina, Viktoriia S. Brovarets, Volodymyr S. Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин |
| title | Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин |
| title_alt | The N-(2,4-diarylthiazol-5-yl)benzamidines library creation and the effect of this compounds on cancer cell growth |
| title_full | Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин |
| title_fullStr | Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин |
| title_full_unstemmed | Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин |
| title_short | Створення бібліотеки N-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин |
| title_sort | створення бібліотеки n-(2,4-діарилтіазол-5-іл)бензамідинів та вплив цих сполук на ріст ракових клітин |
| topic | N-(2,4-діарилтіазол-5-іл)бензамідини комбінаторна бібліотека антиракова активність |
| topic_facet | N-(2,4-diarylthiazol-5-yl)benzamidines combinatorial library anticancer activity N-(2,4-діарилтіазол-5-іл)бензамідини комбінаторна бібліотека антиракова активність |
| url | https://bioorganica.com.ua/index.php/journal/article/view/31 |
| work_keys_str_mv | AT severinoleksandro then24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT kachaevamarynav then24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT pilyostepang then24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT shablykinaolgav then24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT moskvinaviktoriias then24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT brovaretsvolodymyrs then24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT severinoleksandro stvorennâbíblíotekin24díariltíazol5ílbenzamídinívtavplivcihspoluknarístrakovihklítin AT kachaevamarynav stvorennâbíblíotekin24díariltíazol5ílbenzamídinívtavplivcihspoluknarístrakovihklítin AT pilyostepang stvorennâbíblíotekin24díariltíazol5ílbenzamídinívtavplivcihspoluknarístrakovihklítin AT shablykinaolgav stvorennâbíblíotekin24díariltíazol5ílbenzamídinívtavplivcihspoluknarístrakovihklítin AT moskvinaviktoriias stvorennâbíblíotekin24díariltíazol5ílbenzamídinívtavplivcihspoluknarístrakovihklítin AT brovaretsvolodymyrs stvorennâbíblíotekin24díariltíazol5ílbenzamídinívtavplivcihspoluknarístrakovihklítin AT severinoleksandro n24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT kachaevamarynav n24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT pilyostepang n24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT shablykinaolgav n24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT moskvinaviktoriias n24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth AT brovaretsvolodymyrs n24diarylthiazol5ylbenzamidineslibrarycreationandtheeffectofthiscompoundsoncancercellgrowth |