Synthesis of Novel 3-(Pyridin-4-yl)-1,2,4-Triazines, their Analogs and Study of the Activity Against Vaccinia Virus

Article abstract of DOI:10.1007/s10593-021-02924-4

[Figure not available: see fulltext.] Using atom-economical approaches, new representatives of 3-(pyridin-4-yl)-1,2,4-triazines and their 4-nitrophenyl analogs were obtained, and their activity in relation to the vaccinia virus was studied. The new compou

Full text of DOI:10.1007/s10593-021-02924-4

DOI 10.1007/s10593-021-02924-4
Chemistry of Heterocyclic Compounds 2021, 57(4), 462–466
Synthesis of novel 3-(pyridin-4-yl)-1,2,4-triazines, their analogs
and study of the activity against vaccinia virus
Olga V. Shabunina1, Yaroslav K. Shtaitz1, Dmitry S. Kopchuk1,2*, Alexey P. Krinochkin1,2,
Sougata Santra1, Grigory V. Zyryanov1,2, Zhuo Wang3, Vladimir L. Rusinov1,2, Oleg N. Chupakhin1,2
1 Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia; e-mail: dkopchuk@mail.ru
2 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 Sofyi Kovalevskoi St., Yekaterinburg 620108, Russia; e-mail: chupakhin@ios.uran.ru
3 Beijing University of Chemical Technology ,
Beijing 100029, China; e-mail: wangzhuo77@mail.buct.edu.cn
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2021, 57(4), 462–466
Submitted 30.11.2020
Accepted 31.03.2021
Using atom-economical approaches, new representatives of 3-(pyridin-4-yl)-1,2,4-triazines and their 4-nitrophenyl analogs were
obtained, and their activity in relation to the vaccinia virus was studied. The new compounds have shown promising characteristics, in
particular, in comparison to the antiviral drug Cidofovir.
Keywords: 1,2,4-triazines, antiviral activity, ipso substitution, nucleophilic hydrogen substitution, solvent-free reactions, vaccinia virus.
Since the early 1980s there is a steady increase in the
incidence of variola virus worldwide.1 However, the range
of medicines available for smallpox is very limited.2 In this
regard, the WHO Advisory Committee has published
recommendations that strongly advise to continue the
development of new antiviral drugs against orthopox-
viruses.3
1,2,4-Triazine derivatives are of significant interest due
to their biological activity,4–7 including the antiviral one.8–10
Previously, 3-(pyridin-4-yl)-1,2,4-triazines have also
shown various types of biological activity, in particular
antifungal,11 sedative-hypnotic,12 anti-inflammatory,13 anti-
proliferative.14 These compounds are also of interest as
herbicides15 and enzyme inhibitors.16 In this article, we
report the results of the biological activity study of the new
3-(pyridin-4-yl)-1,2,4-triazines and their analogs against
vaccinia virus.
acid hydrazides with subsequent interaction with
NH4OAc,19 as well as zinc-catalyzed hydrohydrazination of
propargylamides with BocNHNH2.20 Separately, a synthetic
approach based on isonitrosoacetophenone hydrazones by
their condensation with aldehydes followed by aroma-
tization of dihydro-1,2,4-triazines by the action of an
oxidizing agent to form 1,2,4-triazine 4-oxides21,22 or by
dehydration in boiling AcOH to form 1,2,4-triazine should
be noted.23,24
Within the framework of this work, we realized the first
method, as a result of which 1,2,4-triazine 4-oxides 3a–c
were obtained by condensation of isonitrosoacetophenone
hydrazones 1a,b followed by aromatization of
intermediates 2a–c (Scheme 1). Hydrogen nucleophilic
substitution reaction with acetone cyanhydrin in the pre-
sence of Et3N led to 1,2,4-triazine-5-carbonitriles 4a–c.25
Subsequent nucleophilic ipso substitution of the cyano
group at the C-5 atom, which is a convenient synthetic
method,26–28 led to the target compounds 5a–g containing
various amine fragments at the C-5 position. This step was
performed without the use of a solvent, as we recently
proposed.29 To compare the properties, in addition to
3-(pyridin-4-yl)-1,2,4-triazines, we obtained their analogs –
compounds 5f,g, containing 4-nitrophenyl fragment at the
To date, a number of synthetic approaches to 3-(pyridin-
4-yl)-1,2,4-triazines have been reported in the literature.
The following methods to obtain these heterocycles can be
noted – condensation of the corresponding amidrazones7 or
carboxylic acid hydrazides13 with 1,2-diones,
cross-
coupling reactions,18 intramolecular condensations,11
synthesis based on α-diazo-β-keto esters and carboxylic
0009-3122/21/57(4)-0462©2021 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2021, 57(4), 462–466
Scheme 1
Table 1. Biological activity of 1,2,4-triazines 5a–g and 6
C-3 position. All considered reactions proceeded in
accordance with the previously developed synthetic proto-
cols, without significant deviations, with yields cor-
responding to the expected, from moderate to good. The
total yields of compounds 5a–g relative to the starting
1,2,4-triazine 4-oxides 3a–c were 49–59%.
IC50**
TC50,* (vaccinia
mg/ml
Triazine
R
H
R1
R2
virus),
mg/ml
5-Unsubstituted 1,2,4-triazine 6 was obtained applying
another version of the 1,2,4-triazine ring aromatization as a
result of dehydration of intermediate 2b in boiling AcOH.
The structures of products 5a–g and 6 were confirmed
4-Py
>100
4.96
5а
N
H
H
4-Py
4-Py
>100
>100
9.40
3.41
5b
5c
1
based on the data of H, 13C NMR spectroscopy, mass
1
spectrometry, and elemental analysis. Thus, the Н NMR
spectra of 1,2,4-triazines 5a–g contain signals of the
protons of the aromatic substituent at the C-6 position, the
4-pyridyl fragment (or 4-nitrophenyl in the case of
compounds 5f,g), and the corresponding amine fragment in
aliphatic proton resonance regions. In the 1H NMR
spectrum of compound 6, the presence of a triazine proton
singlet at the С-5 position should be noted.
Cl
Cl
H
4-Py
4-Py
19.71
57.01
100
8.44
0.77
5d
5e
5f
H2NNH–
4-O2NC6H4
16.02
Antiviral activity of compounds 5a–g and 6 was tested,
and the results are presented in Table 1.
H
4-O2NC6H4
4-Py
>100
12.93
5g
According to Table 1, in many cases the new compounds
showed lower IC50 values in comparison to the known
antiviral drug Cidofovir. The lowest IC50 value has been
shown by 1,2,4-triazine 5e. However, as its disadvantage, a
relatively low TC50 value should be noted, which reduces
the potential for its further application. In general, the most
promising antiviral properties have been shown by 1,2,4-
triazine 6, without any substituents at the C-5 position, as
demonstrated by its relatively low IC50 value and high TC50
value.
The replacement of the pyridin-4-yl fragment at the C-3
position of 1,2,4-triazine by 4-nitrophenyl generally led to
the decrease in the antiviral activity. In particular, in the
case of 1,2,4-triazines 5c,f containing piperidine fragment
at the C-5 position, compound 5c shows lower IC50 value.
Thus, we have obtained new 3-(pyridin-4-yl)-1,2,4-tri-
azines, as well as their 4-nitrophenyl-substituted analogs,
using atom-economical approaches, that exclude the use of
catalysts, expensive reagents, and complex synthetic
procedures. The step of substitution of the cyano group by
the amine fragment was realized in the absence of a
Cl
H
>100
>100
0.95
6
Cidofovir
10.87
* TC50 – toxic concentration.
** IC50 – half maximal inhibitory concentration.
solvent, which is important in the light of reducing the
value of the E-factor of the reaction.30 The activity of the
new compounds against vaccinia virus was studied. The
obtained TC50 and IC50 values for a number of compounds
are more promising than those for the known antiviral drug
Cidofovir.
Experimental
1H and 13C NMR spectra were recorded on a Bruker
Avance II spectrometer (400 and 100 МHz, respectively) in
DMSO-d6 (unless stated otherwise), internal standard –
1
residual solvent signals (2.50 ppm for H nuclei, 39.5 ppm
for 13С nuclei). Mass spectra were recorded on a Bruker
Daltonics micrOTOF-Q II spectrometer, electrospray
463

Chemistry of Heterocyclic Compounds 2021, 57(4), 462–466
ionization. Elemental analysis was performed on a
8.35–8.39 (2Н, m, H Py); 8.84–8.88 (2Н, m, H Py).
13С NMR spectrum, δ, ppm: 115.1; 121.4; 129.3; 130.6;
131.0; 134.4; 136.9; 140.2; 151.2; 156.6; 159.5. Mass
spectrum, m/z (Irel, %): 294 [M+H]+ (100). Found, %:
C 61.47; H 2.79; N 23.99. C15H8ClN5. Calculated, %:
C 61.34; H 2.75; N 23.84.
PerkinElmer PE 2400 automatic CHN-analyzer, series II.
Reaction progress and purity of the obtained compounds
were monitored by TLC on Sigma-Aldrich 91835 plates.
Products were purified by column chromatography on
Sigma-Aldrich (230–400 mesh) silica gel.
All commercially available reagents were used without
preliminary purification. The starting isonitrosoaceto-
phenone hydrazones 1a,b31 and 1,2,4-triazine 4-oxide 3c32
were obtained according to the literature methods.
3-(4-Nitrophenyl)-6-phenyl-1,2,4-triazine-5-carbonitrile
(4с). Yield 455 mg (75%), yellow crystals, mp 140–142°С.
1Н NMR spectrum, δ, ppm: 7.65–7.71 (3Н, m, H Ph); 8.10–
8.15 (2Н, m, H Ph); 8.43–8.48 (2Н, m, H nitrophenyl);
8.76–8.81 (2Н, m, H nitrophenyl). 13С NMR spectrum,
δ, ppm: 115.2; 124.5; 129.1 (2C); 129.2; 129.3; 131.7;
134.1; 138.7; 149.8; 156.9; 159.3. Mass spectrum, m/z
(Irel, %): 304 [M+H]+ (100). Found, %: C 63.43; H 3.12;
N 23.22. C16H9N5O2. Calculated, %: C 63.37; H 2.99; N 23.09.
Synthesis of 5-amino-substituted 1,2,4-triazines 5a–g
(General method). The corresponding amine (0.44 mmol,
1.60 mmol in the case of hydrazine hydrate) was added to
1,2,4-triazine-5-carbonitrile 4a–c (0.40 mmol). The reaction
mixture was stirred without a solvent under argon
atmosphere at 150°С for 8 h. The residue was purified by
column chromatography on silica gel, eluent CH2Cl2,
Rf 0.3. Analytical samples were obtained by recrystalli-
zation from EtOH.
1-[6-Phenyl-3-(pyridin-4-yl)-1,2,4-triazin-5-yl]azepane
(5а). Yield 90 mg (68%), yellow crystals, mp 139–141°С.
1Н NMR spectrum, δ, ppm: 1.33–1.43 (4Н, m, СH2
azepane); 1.55–1.70 (4Н, m, СH2 azepane); 3.36–3.60 (4Н,
m, СH2 azepane); 7.46–7.56 (3Н, m, H Ph); 7.59–7.65 (2Н,
m, H Ph); 8.25–8.30 (2Н, m, H Py); 8.76–8.82 (2Н, m,
H Py). 13С NMR spectrum, δ, ppm: 26.1; 26.7; 49.7; 121.4;
127.7; 128.5; 128.9; 137.5; 143.0; 146.3; 150.4; 152.9;
156.3. Mass spectrum, m/z (Irel, %): 332 [M+H]+ (100).
Found, %: C 72.59; H 6.27; N 21.01. C20H21N5. Calculated, %:
C 72.48; H 6.39; N 21.13.
6-Phenyl-3-(pyridin-4-yl)-5-(pyrrolidin-1-yl)-1,2,4-tri-
azine (5b). Yield 75 mg (62%), yellow crystals, mp 189–
191°С. 1Н NMR spectrum, δ, ppm: 1.74–1.89 (4Н, m, СH2
pyrrolidine); 2.75–4.00 (4Н, m, СH2 pyrrolidine); 7.47–
7.56 (3Н, m, H Ph); 7.57–7.63 (2Н, m, H Ph); 8.27–8.32
(2Н, m, H Py); 8.76–8.81 (2Н, m, H Py). 13С NMR
spectrum, δ, ppm: 24.8; 49.4; 121.4; 128.1; 128.6; 128.9;
136.8; 143.1; 147.1; 150.4; 151.2; 157.0. Mass spectrum, m/z
(Irel, %): 304 [M+H]+ (100). Found, %: C 71.18; H 5.76;
N 23.22. C18H17N5. Calculated, %: C 71.27; H 5.65; N 23.09.
6-Phenyl-5-(piperidin-1-yl)-3-(pyridin-4-yl)-1,2,4-tri-
azine (5c). Yield 82 mg (64%), yellow crystals, mp 159–
161°С. 1Н NMR spectrum, δ, ppm: 1.44–1.53 (4Н, m, СH2
piperidine); 1.53–1.61 (2Н, m, СH2 piperidine); 3.41–3.51
(4Н, m, СH2 piperidine); 7.47–7.59 (3Н, m, H Ph); 8.25–
8.30 (2Н, m, H Ph); 8.25–8.30 (2Н, m, H Py); 8.76–8.81
(2Н, m, H Py). 13С NMR spectrum, δ, ppm: 23.5; 24.9;
47.2; 121.4; 127.0; 128.8; 129.3; 137.1; 142.8; 147.1;
150.4; 153.7; 156.7. Mass spectrum, m/z (Irel, %): 318
[M+H]+ (100). Found, %: C 71.79; H 6.16; N 22.30.
C19H19N5. Calculated, %: C 71.90; H 6.03; N 22.07.
Synthesis of 1,2,4-triazine 4-oxides 3a,b (General
method). Pyridine-4-carbaldehyde (3.00 mmol) was added to
a solution of the corresponding hydrazone 1a,b (3.00 mmol)
in EtOH (30 ml). The resulting mixture was kept at room
temperature for 12 h. The precipitate was filtered off,
washed with EtOH, and dried. The resulting residue was
suspended in glacial AcOH (10 ml), and Pb3O4 (2.07 g,
3.00 mmol) was added in portions while stirring at room
temperature for 1 h. Then, the mixture was kept at room
temperature for 15 min, and H2O (100 ml) was added. The
resulting precipitate was filtered off and washed with H2O.
Analytical samples were obtained by recrystallization from
PhMe.
6-Phenyl-3-(pyridin-4-yl)-1,2,4-triazine 4-oxide (3а).
Yield 300 mg (40%), light-brown crystals, mp 204–206°С.
1Н NMR spectrum, δ, ppm: 7.54–7.62 (3H, m, H Ph); 8.22–
8.30 (4Н, m, H Py); 8.76–8.81 (2H, m, H Ph); 9.37 (1Н, s,
Н-5). Mass spectrum, m/z (Irel, %): 251 [M+H]+ (100). Found,
%: C 67.03; H 3.88; N 22.50. C14H10N4O. Calculated, %:
C 67.19; H 4.03; N 22.39.
6-(4-Chlorophenyl)-3-(pyridin-4-yl)-1,2,4-triazine 4-oxide
(3b). Yield 370 mg (43%), light-brown crystals, mp 220–
1
222°С. Н NMR spectrum, δ, ppm: 7.57–7.62 (2H, m,
H chlorophenyl); 8.23–8.26 (2H, m, H Py); 8.27–8.31 (2H,
m, H chlorophenyl); 8.77–8.80 (2H, m, H Py); 9.44 (1Н, s,
Н-5). Mass spectrum, m/z (Irel, %): 285 [M+H]+ (100).
Found, %: C 58.90; H 3.26; N 19.77. C14H9ClN4O.
Calculated, %: C 59.06; H 3.19; N 19.68.
Synthesis of 1,2,4-triazine-5-carbonitriles 4a–c (General
method). Acetone cyanohydrin (0.27 ml, 3.00 mmol) and
Et3N (0.13 ml, 1.0 mmol) were added to a suspension of
1,2,4-triazine 4-oxide 3a–c (2.0 mmol) in 1,2-dichloro-
ethane (50 ml). The resulting mixture was stirred at 50°С
for 1 h. The solvent was evaporated under reduced
pressure, and the residue was purified by column
chromatography on silica gel, eluent CH2Cl2, Rf 0.5.
Analytical samples were obtained by recrystallization from
PhMe.
6-Phenyl-3-(pyridin-4-yl)-1,2,4-triazine-5-carbonitrile
(4а). Yield 408 mg (79%), yellow crystals, mp 182–184°С.
1Н NMR spectrum, δ, ppm: 7.64–7.72 (3Н, m, H Ph); 8.08–
8.14 (2Н, m, H Ph); 8.36–8.41 (2Н, m, H Py); 8.84–8.89
(2Н, m, H Py). Mass spectrum, m/z (Irel, %): 260 [M+H]+
(100). Found, %: C 69.34; H 3.63; N 27.16. C15H9N5.
Calculated, %: C 69.49; H 3.50; N 27.01.
6-(4-Chlorophenyl)-3-(pyridin-4-yl)-1,2,4-triazine-
5-carbonitrile (4b). Yield 450 mg (77%), yellow crystals,
mp 187–189°С. 1Н NMR spectrum, δ, ppm: 7.67–7.72 (2Н,
m, H chlorophenyl); 8.10–8.14 (2Н, m, H chlorophenyl);
6-(4-Chlorophenyl)-3-(pyridin-4-yl)-5-(thiomorpholin-
4-yl)-1,2,4-triazine (5d). Yield 92 mg (62%), yellow
1
crystals, mp 194–196°С. Н NMR spectrum, δ, ppm: 2.62–
464

Chemistry of Heterocyclic Compounds 2021, 57(4), 462–466
2.71 (4Н, m, СH2 thiomorpholine); 3.71–3.81 (4Н, m, СH2
155.0; 160.3. Mass spectrum, m/z (Irel, %): 269 [M+H]+
(100). Found, %: C 62.46; H 3.27; N 20.76. C14H9ClN4.
Calculated, %: C 62.58; H 3.38; N 20.85.
Study of the antiviral activity of compounds 5a–g
and 6 was carried out on a Vero cell culture against
vaccinia virus (LIVP strain) according to the literature
method.33
thiomorpholine); 7.60–7.65 (2Н, m, H chlorophenyl); 7.78–
7.84 (2Н, m, H chlorophenyl); 8.26–8.30 (2Н, m, H Py);
8.78–8.82 (2Н, m, H Py). 13С NMR spectrum, δ, ppm:
25.7; 49.0; 121.4; 129.0; 129.1; 134.2; 135.6; 142.5; 146.5;
150.5; 154.2; 156.9. Mass spectrum, m/z (Irel, %): 370
[M+H]+ (100). Found, %: C 58.49; H 4.30; N 18.99.
C18H16ClN5S. Calculated, %: C 58.45; H 4.36; N 18.93.
6-(4-Chlorophenyl)-5-hydrazinyl-3-(pyridin-4-yl)-
1,2,4-triazine (5e). Yield 92 mg (77%), yellow crystals,
The work was carried out with financial support from
Russian Science Foundation (grant 19-73-10144), as well
as Russian Foundation for Basic Research (grant 19-53-
55002).
Zhuo Wang thanks National Natural Science Foundation
of China (grant 81961138011) and Beijing Natural Science
Foundation (grant 7192106).
1
mp 239–241°С. Н NMR spectrum, δ, ppm: 4.23 (2Н, br. s,
NH2); 6.80 (1Н, br. s, NH); 7.56–7.62 (2Н, m,
H chlorophenyl); 7.70–7.75 (2Н, m, H chlorophenyl); 8.37–
8.42 (2Н, m, H Py); 8.81–8.86 (2Н, m, H Py). 13С NMR
spectrum (CDCl3), δ, ppm: 121.8; 129.5; 129.9; 130.9;
137.0; 142.8; 146.1; 150.5; 154.3; 159.3. Mass spectrum, m/z
(Irel, %): 299 [M+H]+ (100). Found, %: C 56.14; H 3.76;
N 28.22. C14H11ClN6. Calculated, %: C 56.29; H 3.71; N 28.13.
3-(4-Nitrophenyl)-6-phenyl-5-(piperidin-1-yl)-1,2,4-tri-
azine (5f). Yield 100 mg (69%), yellow crystals, mp 169–
171°С. 1Н NMR spectrum, δ, ppm: 1.46–1.56 (4Н, m, СH2
piperidine); 1.56–1.65 (2Н, m, СH2 piperidine); 3.42–3.55
(4Н, m, СH2 piperidine); 7.47–7.61 (3Н, m, H Ph); 7.71–
7.80 (2Н, m, H Ph); 8.45–8.44 (2Н, m, H nitrophenyl);
8.59–8.68 (2Н, m, H nitrophenyl). 13С NMR spectrum,
δ, ppm: 23.5; 24.7; 47.3; 123.8; 127.0; 128.7; 128.8; 129.3;
137.1; 141.6; 146.7; 149.0; 154.7; 156.7. Mass spectrum,
m/z (Irel, %): 362 [M+H]+ (100). Found, %: C 66.42;
H 5.27; N 19.32. C20H19N5O2. Calculated, %: C 66.47;
H 5.30; N 19.38.
Authors thank Evgeny F. Belanov (Novosibirsk) for
performing biological tests of the synthesized compounds.
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N-(Furan-2-ylmethyl)-3-(4-nitrophenyl)-6-phenyl-
1,2,4-triazin-5-amine (5g). Yield 101 mg (68%), yellow
crystals, mp >250°С. Н NMR spectrum, δ, ppm (J, Hz):
4.71 (2H, d, J = 5.6, CH2); 6.43–6.47 (2H, m, NH, H-3
furan); 7.56–7.64 (4Н, m, Н Ph, H-5 furan); 7.69–7.75 (2H,
m, H Ph); 8.19 (1H, dd, J = 5.6, J = 5.6, H-4 furan); 8.37–
1
8.42 (2Н, m,
H nitrophenyl); 8.61–8.67 (2Н, m,
H nitrophenyl). 13С NMR spectrum, δ, ppm: 37.0; 107.4;
110.5; 123.8; 128.5; 128.7; 129.0; 129.8; 133.4; 141.7;
142.1; 147.7; 148.9; 151.6; 152.6; 158.1. Mass spectrum, m/z
(Irel, %): 374 [M+H]+ (100). Found, %: C 64.46; H 3.97;
N 18.61. C20H15N5O3. Calculated, %: C 64.34; H 4.05; N 18.76.
6-(4-Chlorophenyl)-3-(pyridin-4-yl)-1,2,4-triazine (6).
Pyridine-4-carbaldehyde (0.24 ml, 2.53 mmol) was added to
a solution of hydrazone 1b (500 mg, 2.53 mmol) in EtOH
(30 ml). The resulting mixture was kept at room tempe-
rature for 12 h. The precipitate was filtered off, washed
with EtOH, and dried. The residue was then suspended in
glacial AcOH (30 ml), and the resulting mixture was heated
to reflux 2 times. The solvent was evaporated under
reduced pressure. EtOH (30 ml) was added to the resulting
residue, the crystals formed were filtered off, washed with
EtOH, and dried. An analytical sample was obtained by
recrystallization from EtOH. Yield 490 mg (72%), yellow
crystals, mp 182–184°С. 1Н NMR spectrum, δ, ppm: 7.67–
7.73 (2Н, m, H chlorophenyl); 8.29–8.34 (2Н, m, H chloro-
phenyl); 8.34–8.40 (2Н, m, H-3,5 Py); 8.84–8.89 (2Н, m,
H-2,6 Py); 9.57 (1H, s, Н-5). 13С NMR spectrum, δ, ppm:
121.3; 128.8; 129.4; 131.7; 136.4; 141.7; 147.9; 150.8;
465

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