Design, synthesis, and bioactivity of nortopsentin analogues containing 1,2,4-triazole moieties

Article abstract of DOI:10.1002/jhet.3817

Plant diseases are serious and difficult to control. Novel and efficient pesticides are urgently needed. A series of nortopsentin analogues were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities. Compound 3g wit

Full text of DOI:10.1002/jhet.3817

Received: 17 August 2019
DOI: 10.1002/jhet.3817
Revised: 5 September 2019
Accepted: 23 October 2019
A R T I C L E
Design, synthesis, and bioactivity of nortopsentin analogues
containing 1,2,4‐triazole moieties
Xinyu Zhao1 | Ancai Liao1 | Fan Zhang1 | Qi Zhao1 | Lijia Zhou1 | Jingjing Fan1 |
Zheng Zhang1 | Ziwen Wang1
| Qingmin Wang2
1 Tianjin Key Laboratory of Structure and
Abstract
Performance for Functional Molecules,
MOE Key Laboratory of Inorganic–
Organic Hybrid Functional Material
Chemistry, College of Chemistry, Tianjin
Normal University, Tianjin, China
Plant diseases are serious and difficult to control. Novel and efficient pesticides
are urgently needed. A series of nortopsentin analogues were designed, synthe-
sized, and evaluated for their antiviral activities and fungicidal activities. Com-
pound 3g with higher antiviral activity than nortopsentin D and ribavirin
emerged as new antiviral lead compound. Further fungicidal activity tests
revealed that nortopsentin analogues displayed broad‐spectrum fungicidal
activities. Compounds 3a, 3d, and 3f displayed higher antifungal activities
against Cercospora arachidicola Hori than commercial fungicides carbendazim
and chlorothalonil. Current research has laid a foundation for the application
of nortopsentin analogues in plant protection.
2 State Key Laboratory of Elemento‐
Organic Chemistry, Research Institute of
Elemento‐Organic Chemistry, College of
Chemistry, Collaborative Innovation
Center of Chemical Science and
Engineering (Tianjin), Nankai University,
Tianjin, China
Correspondence
Ziwen Wang, Tianjin Key Laboratory of
Structure and Performance for Functional
Molecules, MOE Key Laboratory of
Inorganic–Organic Hybrid Functional
Material Chemistry, College of Chemistry,
Tianjin Normal University, Tianjin
300387, China.
Email: hxxywzw@tjnu.edu.cn
Qingmin Wang, State Key Laboratory of
Elemento‐Organic Chemistry, Research
Institute of Elemento‐Organic Chemistry,
College of Chemistry, Collaborative
Innovation Center of Chemical Science
and Engineering (Tianjin), Nankai
University, Tianjin, China
Email: wangqm@nankai.edu.cn
Funding information
Natural Science Fund of China, Grant/
Award Numbers: 21772145, 21732002 and
21672117; Training Program of Outstand-
ing Youth Innovation Team of Tianjin
Normal University and the Program for
Innovative Research Team in University
of Tianjin, Grant/Award Number: TD13‐
5074; Foundation of Development Pro-
gram of Future Expert in Tianjin Normal
University, Grant/Award Number:
WLQR201802
J Heterocyclic Chem. 2019;1–7.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
ZHAO ET AL.
oxadiazoles.[21] In the previous work, we found that
nortopsentin alkaloids had good antiviral activities
against plant viruses for the first time.[22] On the other
hand, 1,2,4‐triazole ring system is an important five‐
membered heterocycle ring found in many molecules
with significant biological activity.[23–25] Considering the
above findings, we designed and synthesized a series of
nortopsentin analogues containing 1,2,4‐triazole ring sys-
tem (Figure 2). The antiviral activities, fungicidal activi-
ties, and structure‐activity relationships were evaluated
systematically.
1 | INTRODUCTION
Viral diseases are the second most serious plant diseases
after fungi in agricultural production, and most crops
around the world are harmed to varying degrees. Plant
viruses are absolutely parasitic in plant cells, and the
materials, energy, and sites required for their replication
are provided by host cells. Because plants do not have a
complete immune system, it is difficult to control plant
viral diseases, which has always been a difficult and hot
issue in plant diseases and virology research.[1–3] Tobacco
mosaic virus (TMV), named for its first discovery in
tobacco, is the earliest discovered and most studied virus.
It is often used as a model virus in the development of
antiviral agents. Besides harming tobacco, TMV can also
infect more than 400 crops such as tomato, eggplant,
potato, pepper, and Solanum nigrum.[4,5] The existing
antiviral agents can only give moderate control effect
(antiviral agent ribavirin in Figure 1: less than 50% anti‐
TMV effect at 500 μg/mL), and the treatment effect is
poor. The prevention and treatment of viral diseases has
a long way to go.[6]
Natural products are the source of pesticide discovery.
However, the probability that a natural product directly
isolated from organisms can be directly used as a pesti-
cide for treating diseases is very low. Using these “basic
molecules” as structures to synthesize variants of active
molecules is an absolutely feasible way to develop pesti-
cides because of their immense structural diversity and
wide variety of biological activities.[7–10]
Bisindole alkaloids are a family of very important
natural products isolated from marine organisms.
Nortopsentins A to D (Figure 1) are one of the important
marine alkaloids. Biological activity research revealed
that nortopsentins A to D displayed interesting biological
activities such as cytotoxicity against P388 cells and anti-
fungal activity against Candida albicans.[11–13] A series of
nortopsentin analogues were reported in which the
central imidazole ring was replaced by several five‐
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
According to previous structure‐activity relationships,[22]
nortopsentin analogues 3a‐3j were designed and obtained
by one‐step condensation reaction (Scheme 1) of com-
mercially available 1H‐indole‐3‐carbonitrile and corre-
sponding
acylhydrazines
2a‐2j.
As
previously
reported,[26] some 1,2,4‐triazoles also exhibit tautomerism
(Figure 3). 1H NMR spectrum of nortopsentin 3b showed
a splitting of all signals, which could be suppressed by the
addition of 1% of CF3COOH into the deuterated solvent.
2.2 | Phytotoxic activity
The phytotoxic‐activity tests showed that the
nortopsentin analogues 3a‐3j were safe for testing on
plants at 500 μg/mL. The detailed test procedures can
be seen in the Supporting Information.
2.3 | Antiviral activity in vivo
The results of the anti‐TMV activities of the nortopsentin
analogues 3a‐3j are listed in Table 1 with nortopsentin D
and the commercial plant virucide ribavirin as the con-
trols. The inactive activities of all compounds listed in
Table 1 at 500 μg/mL were first tested, and the curative
activities and protective activities of compounds with
good inactive activities (inactive effect: less than 40%)
were further tested.
membered
heterocycles
such
as
bis‐indolyl‐
thiophenes,[14] ‐pyrazole,[15] ‐oxazoles,[16] ‐isoxazoles,[17]
‐furans,[17] ‐pyrroles,[18] ‐thiazoles,[19,20] and ‐1,2,4‐
As depicted in Table 1, the nortopsentin analogues 3a‐
3j containing 1,2,4‐triazole showed good antiviral activi-
ties in vivo. Compound 3e showed the same level of bio-
logical activity as nortopsentin D but higher than
ribavirin. Among these compounds, compound 3g
displayed the best antiviral activity, which is higher than
that of nortopsentin D and ribavirin. Compared with
nortopsentin D, 3a exhibited relatively low activity. The
FIGURE 1 Structures of ribavirin and nortopsentins A to D

ZHAO ET AL.
3
FIGURE 2 Design of nortopsentin analogues [Color figure can be viewed at wileyonlinelibrary.com]
SCHEME 1 Synthesis of 3a‐3j
substitution of benzene ring for indole ring is beneficial
to the improvement of biological activity (inhibitory
effect: 3b > 3a). The introduction of fluorine atom in
the ortho‐ and meta‐position of benzene ring would lead
to a sharp decrease in activity (inhibitory effect:
3b > 3c, 3d), and the introduction of fluorine atom in
the para‐position would be beneficial to the improvement
of activity (inhibitory effect: 3e > 3b). The introduction of
trifluoromethyl at the ortho‐position of benzene ring
FIGURE 3 Tautomerization of 1,2,4‐triazole
TABLE 1 In vivo antiviral activities of compounds 3a−3j,
nortopsentin D and ribavirin against TMV.
leads to
a decrease in activity (inhibitory effect:
Compd
Concn
(μg/mL)
Inactive
Curative
Protective
effect (%)a
effect (%)a
effect (%)a
3b > 3f), while the introduction of trifluoromethyl at
the para‐position is beneficial to the improvement of
activity (inhibitory effect: 3g > 3b). Compounds 3h‐3j
displayed lower antiviral activities than 3b, which indi-
cated that the introduction of chlorine atom and methoxy
group are bad for activity. From the above structure‐
activity relationship, it can be seen that the 1,2,4‐triazole
ring and benzene ring regions are very sensitive, and
minor changes will have a great impact on the activity.
3a
3b
500
28 3
—
—
500
100
40 1
10 1
32 3
6 2
36 2
10 1
3c
3d
3e
500
500
14 3
10 3
—
—
—
—
500
100
45 4
19 1
42 3
17 2
39 1
11 3
3f
500
23 1
—
—
3g
500
100
48
23
1
2
42
20
2
1
45
22
3
1
2.3.1 | In vitro fungicidal activity
3h
3i
500
500
500
9 3
—
—
Nortopsentin analogues 3a‐3j were also evaluated for
their fungicidal activities with nortopsentin D and com-
mercial fungicides carbendazim and chlorothalonil as
controls.
The fungicidal activities of 3a‐3j were evaluated in
mycelial growth tests[27] conducted in artificial media
against 14 plant pathogens at a rate of 50 μg/mL. The
results showed that these compounds also exhibited
broad‐spectrum fungicidal activities (Table 2). Com-
pounds 3a‐3j displayed higher antifungal activities than
8 2
—
—
—
—
3j
33 3
Nortopsentin 500
D
45 2
20 2
40 3
17 2
37 1
12 1
100
Ribavirin
500
100
38 1
12 1
36 2
11 1
37 2
9 2
Abbreviation: TMV, tobacco mosaic virus. Activity data with prominent were
presented in bold.
aAverage of three replicates; All results are expressed as mean SD.

4
ZHAO ET AL.
TABLE 2 In vitro fungicidal activities of compounds 3a‐3j, nortopsentin D, carbendazim, and chlorothalonil against 14 kinds of fungi
Fungicidal Activities (%)a/50 μg/mL
Compound
F.C
C.H
P.P
R.C
B.M
W.A
F.M
A.S
F.G
P.I
P.C
S.S
R.S
B.C
3a
3b
3c
3d
3e
3f
16 2 60 1 35
3
33
3
1
2
14 2 24
25 1 47
14 2 12
1
2
3
2
1
13 1 48
33 2 48
3
2
1
3
2
3
1
1
2
2
1
2
16
37
8
1
2
1
2
1
2
3
2
1
16
32
13
36
23
1
2
1
2
1
20
47
10
43
27
2
1
2
1
2
3
2
1
2
1
1
46
53
41
73
43
75
64
66
48
52
39
1
2
1
2
3
2
1
1
2
2
2
56
47
38
56
38
59
41
50
38
38
14
100
2
3
2
3
2
3
2
1
2
1
1
13
49
14
71
51
59
51
61
23
44
7
1
2
1
2
1
2
1
2
1
2
1
1
28 1 48
16 1 28
3
2
83 2 46
23 24
1
8
1 15
38 3 68 1 63 1 71 1 28 3 44
42 2 59
13 1 26
33
14
35
37
43
39
0
28 2 32
1
21
2
1
2
42
1 17 2 27
31 1 72 3 56
65 2 50 1 62 2 54 1 56
61 3 43
3g
3h
3i
19 2 48
28 1 52
21 2 27
19 1 36
1
2
1
2
2
2
2
4
38
2
3
3
1
2
2
1
22 1 24
33 2 47
23 1 30
1
2
3
2
2
1
1
33 2 41
33 1 48
24 2 45
17 1 26
23
36
2
1
2
1
2
1
17
47
16
17
3
88 3 53
37
15
58
54
96
2
1
1
1
2
46
30
26
78
98
27
3j
14
2
9
16
Nortopsentin D 26 1 29
Carbendazimb 77 2 58
Chlorothalonilb 97 1 11
21 1 42
72 2 90
97 2 97
9
1 33
10
88
1
2
16
84 1 56
83
90 2 100
55 2 100
96
79 2 56 1 100
100
27 1 100
Abbreviations: A.S, Alternaria solani; B.C, Botrytis cinerea; B.M, Bipolaris maydis; C.H, Cercospora arachidicola Hori; F.C, Fusarium oxysporum f. sp. cucumeris;
F.G, Fusarium graminearum; F.M, Fusarium moniliforme; P.C, Phytophthora capsici; P.I, Phytophthora infestans; P.P, Physalospora piricola; R.C, Rhizoctonia
cerealis; R.S, Rhizoctonia solani; S.S, Sclerotinia sclerotiorum; W.A, Watermelon anthracnose. Activity data with prominent were presented in bold.
aAverage of three replicates; all results are expressed as mean SD.
bThe commercial agricultural fungicides were used for comparison of antifungal activity.
nortopsentin D against most of the 14 plant pathogens.
Compounds 3a, 3d, and 3f displayed higher antifungal
activities against Cercospora arachidicola Hori than
commercial fungicides carbendazim and chlorothalonil.
Compounds 3b, 3d, and 3h showed higher antifungal
activities against Physalospora piricola than commercial
fungicide carbendazim. Different from the rule of antivi-
ral activity, m‐fluorobenzene ring compound 3d and
o‐trifluoromethyl compound 3f displayed relatively
higher antifungal activities against most of the 14 plant
pathogens (inhibitory effect: 3d > 3c, 3e; 3f > 3g).
3 | EXPERIMENTAL
3.1 | Chemistry
The reagents were purchased from commercial sources
and were used as received. All anhydrous solvents were
dried and purified by standard techniques prior to use.
The melting points of the compounds were tested on an
X‐4 binocular microscope (Beijing Tech Instruments
Company). NMR spectra were obtained with a Bruker
AV 400 spectrometer (Bruker Co., Fallanden, Switzer-
land) with either CDCl3 or DMSO‐d6 as the solvent.
High‐resolution mass spectra were obtained with an
FT‐ICR mass spectrometer (Ionspec, 7.0 T, Kuala
Lumpur, Malaysia).
In summary, nortopsentin analogues 3a‐3j were
designed, synthesized, and evaluated for their antiviral
activities and fungicidal activities. Compound 3e showed
the same level of biological activity as nortopsentin D but
higher than ribavirin. Compound 3g with higher antiviral
activity than nortopsentin D and ribavirin emerged as
new antiviral lead compound. Further fungicidal test
reveal that these compounds displayed broad‐spectrum
fungicidal activities against 14 kinds of plant fungi at
50 μg/mL. Compounds 3a‐3j displayed higher antifungal
activities than nortopsentin D against most of the 14
plant pathogens. Compounds 3a, 3d, and 3f displayed
higher antifungal activities against Cercospora
3.1.1 | General procedures for the prepa-
ration of compounds 3a‐3j
The mixture of 1H‐indole‐3‐carbonitrile (1, 1 g, 7 mmol),
corresponding acylhydrazines 2a‐2j (3.5 mmol) and
K2CO3 (0.48 g, 3.5 mmol) in n‐BuOH (10 mL) was stirred
at 160°C for 8 hours. Then, the mixture was allowed to
reach room temperature and taken into water (50 mL).
The resulting solution was extracted with ethyl acetate
(3 × 50 mL). The combined organic phases were washed
with brine (100 mL), dried over anhydrous Na2SO4,
arachidicola
Hori
than
commercial
fungicides
carbendazim and chlorothalonil. Current research has
laid a foundation for the application of nortopsentin ana-
logues in plant protection.

ZHAO ET AL.
5
filtered, and concentrated in vacuo. The residue was puri-
fied by flash chromatography on a silica gel using petro-
leum ether and ethyl acetate (2:1, v/v) as the eluent to
give 3a‐3j.
DMSO‐d6) isomers δ 163.6, 161.2, 136.3, 130.9, 130.8,
130.4, 130.3, 125.8, 124.6, 123.6, 122.3, 121.9, 120.7,
120.4, 118.2, 118.0, 114.35, 114.29, 114.12, 114.07, 112.0,
103.2. C16H12FN4 [M + H]+ 279.1041, found (ESI+)
279.1043.
3,5‐Di(1H‐indol‐3‐yl)‐4H‐1,2,4‐triazole (3a)
Yellow solid; yield 77%; mp 217°C to 219°C; H NMR
1
3‐(5‐(4‐Fluorophenyl)‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indole
(400 MHz, DMSO‐d6) isomers δ 13.70 (s, 0.38H, NH),
11.69 and 11.63 (s, 1H, NH), 11.52 and 11.39 (s, 1H,
NH), 11.09 (s, 0.52H, NH), 8.55‐7.79 (m, 4H, Ar‐H),
7.45‐7.50 (m, 2H, Ar‐H), 7.16‐7.21 (m, 4H, Ar‐H); 13C
NMR (100 MHz, DMSO‐d6) isomers δ 162.4, 137.5,
136.9, 130.0, 129.9, 125.6, 125.4, 123.0, 122.5, 121.0,
120.7, 112.3. C18H14N5 [M + H]+ 300.1244, found (ESI+)
300.1249.
(3e)
1
Brown solid; yield 52%; mp 262°C to 264°C; H NMR
(400 MHz, DMSO‐d6) δ 12.21 (s, 1H, NH), 11.91 (s, 1H,
NH), 8.46 (s, 1H, Ar‐H), 8.26 (d, J = 2.0 Hz, 1H, Ar‐H),
7.99‐8.03 (m, 2H, Ar‐H), 7.80 (dd, J = 5.9, 8.2 Hz, 1H,
Ar‐H), 7.64 (d, J = 7.7 Hz, 1H, Ar‐H), 7.56 (d,
J = 7.9 Hz, 1H, Ar‐H), 7.24‐7.40 (m, 2H, Ar‐H); 13C
NMR (100 MHz, DMSO‐d6) isomers δ 162.5, 147.2,
135.7, 134.9, 131.3, 130.9, 130.8, 130.7, 130.6, 129.8,
129.7, 127.2, 123.8, 122.1, 118.9, 116.8, 116.4, 116.3,
116.1, 116.0, 115.9, 115.8, 113.4. C16H12FN4 [M + H]+
279.1041, found (ESI+) 279.1046.
3‐(5‐Phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indole (3b)
1
Brick red solid; yield 58%; mp 151°C to 152°C; H NMR
(400 MHz, DMSO‐d6) isomers δ 14.25 and 13.98 (s, 1H,
NH), 11.68 and 11.43 (s, 1H, NH), 8.38 and 8.31 (d,
J = 6.1 Hz, 1H, Ar‐H), 7.87‐8.16 (m, 4H, Ar‐H), 7.43‐
3‐(5‐(2‐(Trifluoromethyl)phenyl)‐4H‐1,2,4‐triazol‐3‐yl)‐
1H‐indole (3f)
Yellow solid; yield 45%; mp 253°C to 254°C; H NMR
1
7.57 (m, 3H, Ar‐H), 7.16‐7.22 (m, 2H, Ar‐H); H NMR
1
(400 MHz, DMSO‐d6, 1% TFA) δ 11.66 (s, 1H, NH),
8.36 (d, J = 7.1 Hz, 1H, Ar‐H), 8.14 (d, J = 7.3 Hz,
2H, Ar‐H), 8.05 (d, J = 2.0 Hz, 1H, NH), 7.88 (d,
J = 7.3 Hz, 1H, Ar‐H),7.46‐7.56 (m, 4H, Ar‐H), 7.20‐
7.23 (m, 2H, Ar‐H); 13C NMR (100 MHz, DMSO‐d6,
1% TFA) δ 167.8, 136.3, 131.2, 129.21, 129.19, 128.8,
128.2, 127.4, 125.9, 125.7, 124.7, 122.1, 120.8, 120.2,
111.9. C16H13N4 [M + H]+ 261.1135, found (ESI+)
261.1131.
(400 MHz, DMSO‐d6) δ 14.20 (s, 1H, NH), 11.71 (s, 1H,
NH), 8.33 (d, J = 7.7 Hz, 1H, Ar‐H), 8.05 (d, J = 2.5 Hz,
1H, Ar‐H), 8.01 (d, J = 7.6 Hz, 1H, Ar‐H), 7.90 (d,
J = 7.8 Hz, 1H, Ar‐H), 7.80 (t, J = 7.2 Hz, 1H, Ar‐H),
7.68 (d, J = 7.6 Hz, 1H, Ar‐H), 7.52 (d, J = 7.9 Hz, 1H,
Ar‐H), 7.16‐7.25 (m, 2H, Ar‐H); 13C NMR (100 MHz,
DMSO‐d6) δ 160.3, 152.4, 136.8, 132.7, 132.2, 129.6,
127.01, 127.00, 126.1, 125.2, 122.8, 121.1, 120.8, 112.5,
103.7. C17H12F3N4 [M + H]+ 329.1009, found (ESI+)
329.1015.
3‐(5‐(2‐Fluorophenyl)‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indole
(3c)
1
Brown solid; yield 65%; mp 165°C to 167°C; H NMR
3‐(5‐(4‐(Trifluoromethyl)phenyl)‐4H‐1,2,4‐triazol‐3‐yl)‐
1H‐indole (3g)
Yellow solid; yield 57%; mp 157°C to 158°C; H NMR
(400 MHz, DMSO‐d6) isomers δ 14.13 and 14.10 (s, 1H,
NH), 11.71 and 11.46 (s, 1H, NH), 8.36 (d, J = 8.7 Hz,
1H, Ar‐H), 8.17‐8.21 (m, 1H, Ar‐H), 8.07 and 7.97 (s,
1H, Ar‐H), 7.67‐7.73 (m, 1H, Ar‐H), 7.48‐7.54 (m, 2H,
Ar‐H), 7.37 (d, J = 7.5 Hz, 1H, Ar‐H), 7.21‐7.28 (m, 2H,
Ar‐H); 13C NMR (100 MHz, DMSO‐d6) δ 168.7, 130.4,
130.2, 130.0, 125.7, 125.0, 124.5, 124.4, 122.3, 120.7,
120.4, 116.6, 116.3, 112.0, 103.2. C16H12FN4 [M + H]+
279.1041, found (ESI+) 279.1037.
1
(400 MHz, DMSO‐d6) δ 14.24 (s, 1H, NH), 11.73 (s,
1H, NH), 8.36‐8.42 (m, 2H, Ar‐H), 8.08‐8.17 (m, 2H,
Ar‐H), 7.84‐7.90 (m, 3H, Ar‐H), 7.52‐7.74 (m, 1H, Ar‐
H), 7.24 (t, J = 3.7 Hz, 1H, Ar‐H); 13C NMR
(100 MHz, DMSO‐d6) isomers δ 166.9, 166.2, 136.3,
134.7, 131.7, 131.5, 130.1, 128.6, 128.3, 126.4, 125.8,
125.7, 125.6, 125.5, 125.23, 125.20, 124.7, 122.2, 120.7,
120.3, 112.0. C17H12F3N4 [M + H]+ 329.1009, found
(ESI+) 329.1011.
3‐(5‐(3‐Fluorophenyl)‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indole
(3d)
1
Brown solid; yield 72%; mp 156°C to 157°C; H NMR
3‐(5‐(4‐Methoxyphenyl)‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indole
(400 MHz, DMSO‐d6) δ 14.13 (s, 1H, NH), 11.72 (s,
1H, NH), 8.38 (s, 1H, Ar‐H), 8.07 (s, 1H, Ar‐H), 8.00
(d, J = 7.4 Hz, 1H, Ar‐H), 7.87 (d, J = 9.8 Hz, 1H, Ar‐
H), 7.67‐7.82 (m, 1H, Ar‐H), 7.47‐7.62 (m, 2H, Ar‐H),
7.20‐7.29 (m, 2H, Ar‐H); 13C NMR (100 MHz,
(3h)
1
Yellow solid; yield 74%; mp 183°C to 185°C; H NMR
(400 MHz, DMSO‐d6) δ 13.87 (s, 1H, NH), 11.54 (s, 1H,
NH), 8.37 (d, J = 6.5 Hz, 1H, Ar‐H), 8.02‐8.08 (m, 2H,
Ar‐H), 7.86‐7.94 (m, 1H, Ar‐H), 7.42‐7.51 (m, 1H, Ar‐H),

6
ZHAO ET AL.
7.21 (d, J = 5.4 Hz, 1H, Ar‐H), 6.97‐7.17 (m, 3H, Ar‐H),
3.83 (s, 3H, OCH3); 13C NMR (100 MHz, DMSO‐d6) iso-
mers δ 167.0, 166.5, 165.4, 162.8, 162.0, 136.3, 136.2,
131.3, 129.3, 128.4, 127.4, 126.2, 124.8, 121.7, 121.1,
120.9, 120.3, 114.1, 113.8, 113.7, 113.3, 111.8, 111.7, 55.4,
55.2. C17H15N4O [M + H]+ 291.1240, found (ESI+)
291.1246.
CONFLICT OF INTEREST
The authors declare no competing financial interest.
ORCID
Ziwen Wang https://orcid.org/0000-0001-9798-7021
3‐(5‐(3,4,5‐Trimethoxyphenyl)‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐
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1
Yellow solid; yield 63%; mp 242°C to 243°C; H NMR
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(400 MHz, DMSO‐d6) δ 11.52 (s, 2H, NH), 8.13 (d,
J = 7.7 Hz, 2H, Ar‐H), 8.01 (d, J = 2.9 Hz, 2H, Ar‐H),
7.41 (d, J = 7.9 Hz, 2H, Ar‐H), 7.23 (s, 1H, Ar‐H), 3.82
(s, 6H, OCH3), 3.72 (s, 3H, OCH3); 13C NMR (100 MHz,
DMSO‐d6) isomers δ 167.4, 167.1, 153.1, 141.8, 136.7,
132.0, 129.1, 128.9, 126.7, 126.4, 122.3, 121.5, 120.8,
112.2, 110.9, 107.0, 65.5, 60.6, 56.4. C19H19N4O3
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Brown solid; yield 68%; mp 246°C to 248°C; H NMR
4180.
(400 MHz, DMSO‐d6) δ 14.28 (s, 1H, NH), 11.74 (s, 1H,
NH), 8.36‐8.38 (m, 1H, Ar‐H), 8.05‐8.11 (m, 3H, Ar‐H),
7.70 (s, 1H, Ar‐H), 7.48‐7.55 (m, 1H, Ar‐H), 7.23 (t,
J = 3.6 Hz, 2H, Ar‐H); 13C NMR (100 MHz, DMSO‐d6)
δ 163.1, 136.3, 135.3, 134.6, 131.5, 128.1, 126.3, 125.9,
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This study was supported by Natural Science Fund of
China (21772145, 21732002, 21672117), Training Program
of Outstanding Youth Innovation Team of Tianjin Nor-
mal University and the Program for Innovative Research
Team in University of Tianjin (TD13‐5074), and the
Foundation of Development Program of Future Expert
in Tianjin Normal University (WLQR201802).
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How to cite this article: Zhao X, Liao A, Zhang
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