Synthesis and biological activity of acyl thiourea containing difluoromethyl pyrazole motif

Article abstract of DOI:10.1080/10426507.2019.1633530

A series of new acyl thiourea derivatives containing difluoromethyl pyrazole moiety were designed and synthesized. Their structures were confirmed by ¹H NMR, ³¹C NMR, MS and HRMS. The bioassay results showed that some of title compounds exhibited good in vivo fungicidal activity against Botrytis cinerea and Fusarium oxysporum and good antibacterial activity against Pseudomonas syringae pv. Lachrymans at 50 mg/L respectively.

Full text of DOI:10.1080/10426507.2019.1633530

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis and biological activity of acyl thiourea
containing difluoromethyl pyrazole motif
Li-Jing Min, Zhi-Wen Zhai, Yan-Xia Shi, Liang Han, Cheng-Xia Tan, Jian-Quan
Weng, Bao-Ju Li, Yong-Gang Zhang & Xing-Hai Liu
To cite this article: Li-Jing Min, Zhi-Wen Zhai, Yan-Xia Shi, Liang Han, Cheng-Xia Tan, Jian-Quan
Weng, Bao-Ju Li, Yong-Gang Zhang & Xing-Hai Liu (2019): Synthesis and biological activity of acyl
thiourea containing difluoromethyl pyrazole motif, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2019.1633530
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1633530
Synthesis and biological activity of acyl thiourea containing difluoromethyl
pyrazole motif
a
b
c
b
b
b
c
Li-Jing Min , Zhi-Wen Zhai , Yan-Xia Shi , Liang Han , Cheng-Xia Tan , Jian-Quan Weng , Bao-Ju Li ,
d
b
Yong-Gang Zhang , and Xing-Hai Liu
a
b
College of Life Science, Huzhou University, Huzhou, Zhejiang, China; College of Chemical Engineering, Zhejiang University of Technology,
c
d
Hangzhou, China; Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China; Biology Institute, Qilu
University of Technology (Shandong Academy of Sciences), Jinan, Shandong, China
ABSTRACT
ARTICLE HISTORY
A series of new acyl thiourea derivatives containing difluoromethyl pyrazole moiety were designed
Received 5 September 2018
Accepted 14 June 2019
1
31
and synthesized. Their structures were confirmed by H NMR, C NMR, MS and HRMS. The bio-
assay results showed that some of title compounds exhibited good in vivo fungicidal activity
against Botrytis cinerea and Fusarium oxysporum and good antibacterial activity against
Pseudomonas syringae pv. Lachrymans at 50 mg/L respectively.
KEYWORDS
Pyrazole; synthesis;
thiourea; fungicidal activity
GRAPHICAL ABSTRACT
Introduction
replaced by CHF group on the pyrazole ring, because many
2
commercial SDHI contain CHF group on the pyrazole ring.
Our original strategy is depicted in Scheme 2.
2
Pyrazole is an important five-member heterocycle, which can be
[1–4]
[5–9]
found in many drugs
or pesticides.
For example, many
succinate dehydrogenase inhibitors (SDHI) contain pyrazole
[10–14]
motif,
such as penthiopyrad, sedaxane, pydiflumetofen, Results and discussion
bixafen, fluxapyroxad, isopyrazam and benzovindiflupyr. On the
other hand, the thiourea structure also is an important bioactive
substructure in various biomolecules. These compounds have
also displayed various biological activities, such as antiviral activ-
The synthetic route is shown in Scheme 3. The pyrazole
ring is a key intermediate in the synthetic route. Many refer-
[40–42]
ences
reported the synthesis methods of pyrazole ring.
[15]
[16]
[17]
In this paper, the pyrazole ring was synthesized from ethyl
4,4-difluoro-3-oxobutanoate and triethyl orthoformate as
starting materials via two steps. Then the pyrazole acyl
chloride was given also via two steps from the intermediate
ity,
anticancer activity,
fungicidal activity,
anti HIV-1
[18]
[19]
activity, cholinesterases inhibitory activity, anti-inflamma-
tory activity and antitubercular activity.
[20]
[21]
In recent years, phase transfer catalysis (PTC) has been
shown as a powerful and efficient technique which can pro-
mote a variety of reactions under mild conditions and thus it
[
43,44]
2.
At last, difluoromethyl pyrazole acyl thiourea deriva-
tives were successfully synthesized using PEG-600 as solid-
[
45]
[
22,23]
[25]
liquid phase transfer catalyst.
The phase transfer catalyst
has attracted increased attention.
work
From our previous
[
24]
and the reported reference,
a reaction mechanism PEG-600 is indispensable for this reaction. This procedure is
convenient and facile. In addition, PEG-600 is relatively
In line with our work on bioactive heterocyclic com- nontoxic, highly stable, inexpensive, and readily available.
catalyzed by PEG can be prepared and is shown in Scheme 1.
[
26–38]
pounds,
zole
the thiourea containing trifluoromethyl pyra-
The structures of the target compounds were confirmed
[
39]
[17]
1
or methyl pyrazole
motifs were synthesized. In by H NMR, MS and HRMS. Taking compound 6a as
1
order to find higher fungicidal activity in thiourea com- example, in the H NMR spectra, the CHF
proton signal
2
pounds with pyrazole motif, the CF3 or CH3 group was (6.97 ppm) was triple peak with the coupling constant 54 Hz
CONTACT Xing-Hai Liu
China; Yong-Gang Zhang
xhliu@zjut.edu.cn
zhangyg@sdas.org
College of Chemical Engineering, Zhejiang University of Technology, Chaowang Road 18, Hangzhou 310014,
Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Keyuan Road 19, Jinan,
Jinan, Shandong 250014, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1633530.
ß 2019 Taylor & Francis Group, LLC

2
L.-J. MIN ET AL.
Table 1. The in vivo biological activity of some compounds at 50 ppm
%, inhibitory).
(
Control effective %
No
CM
PS
FO
BC
6
6
6c
a
b
ꢂ22.52 ± 1.06
ꢂ52.67 ± 2.24
ꢂ33.71 ± 1.55
ꢂ26.21 ± 0.98
ꢂ54.35 ± 2.21
ꢂ49.87 ± 2.11
ꢂ31.27 ± 1.24
ꢂ44.96 ± 1.65
ꢂ23.62 ± 0.58
ꢂ46.01 ± 1.44
ꢂ38.89 ± 1.12
ꢂ51.35 ± 2.34
74.09 ± 2.23
44.55 ± 1.74
47.67 ± 1.45
65.86 ± 1.76
75.74 ± 2.34
69.36 ± 2.06
60.17 ± 1.11
63.89 ± 1.54
70.43 ± 2.31
54.78 ± 2.66
54.17 ± 2.11
53.35 ± 2.41
53.53 ± 2.33
52.55 ± 2.24
ꢂ0.86 ± 0.00
ꢂ7.82 ± 0.45
ꢂ9.56 ± 0.90
10.44 ± 1.01
37.40 ± 2.01
ꢂ18.25 ± 0.98
23.48 ± 1.12
53.92 ± 2.31
33.05 ± 1.14
39.13 ± 1.23
53.05 ± 2.34
46.09 ± 2.41
71.30 ± 3.01
69.09 ± 1.75
86.36 ± 1.23
41.82 ± 0.99
30.00 ± 0.00
ꢂ38.18 ± 1.02
34.54 ± 1.12
ꢂ20.00 ± 0.00
11.82 ± 1.02
68.18 ± 1.23
4.54 ± 0.09
Scheme 1. The proposed mechanism by PEG catalyzed.
6
6
6
6
6
6
6
6
6
d
e
f
g
h
i
j
k
l
24.54 ± 2.00
20.00 ± 0.00
67.27 ± 1.21
YCK
Scheme 2. The design strategy of title compounds.
Note: CM(Corynespora mazei), PS(Pseudomonas syringae pv. lachrymans),
BC(Botrytis cinerea), FO(Fusarium oxysporum) , YCK(Fluxapyroxad).
that of the control. The activity of the other compounds is
the same as the control. From Table 1, the preliminary struc-
ture and activity relationship (SAR) analysis indicated that
substitution on the phenyl ring can influence fungicidal activ-
ity. For example, for the Botrytis cinerea, if the substitution is
F on the 3-position of phenyl ring, then high activity (86%)
was exhibited when the substitution is F on the 2-position of
phenyl ring, the fungicidal activity decreases ( ꢀ 60%), such as
Scheme 3. The synthetic route of title compounds.
6
a and 6i. It is the same as the control. If the OCF group is
3
at the 2-position of phenyl ring, the fungicidal activity also
decreases. Generally, the activity is higher when the electron
due to the influence of F atom. The two NH protons of
thiourea bridge can be found at 9.28 and 12.54 ppm as sin-
gle peak respectively. The appearance of signal at 4.03 ppm withdrawing group is on the phenyl ring.
belongs to the methyl protons of pyrazole ring. The
8
.10 ppm was recognized as CH of pyrazole ring. The ben-
Experimental
13
zene proton are at 7.17 to 7.27. The C NMR spectrum of
6a showed 20 distinct peaks that confirmed the proposed Instrument and materials
structure. Two peaks at d ¼ 160.81 and 178.60 ppm corre-
sponded to C ¼ O and C ¼ S carbon atoms, respectively. The
peak at d ¼ 39.95 ppm connected to the methyl carbon
Melting points were determined by an X-4 apparatus and
uncorrected. H NMR spectra were measured on a Bruker
AV- 400 or 500 MHz instrument using TMS as an internal
1
atom. The carbon bearing the CHF group was easily identi-
2
standard and CDCl as the solvent. HRMS was determined
3
fied as triple peaks by carbon–fluorine coupling with the
on a JOEL AccuTOF (JMS-T 100LC) instrument equipped
with electrospray ionization (ESI) ion source. The
coupling constant about 234 Hz. The title compounds exhib-
þ
ited the M þ H peak in the ESI-MS and HR-ESI-
1
13
Supplemental Materials contains sample H and C NMR
MS results.
and mass spectra of the products, 6 (Figures S1 – S48).
The in vivo fungicidal activity against Corynespora mazei,
Pseudomonas syringae pv. lachrymans, Botrytis cinerea,
Fusarium oxysporum were determined at 50 ppm and
Fluxapyroxad as control. The results are listed in Table 1.
General procedure
Unfortunately, all of thiourea compounds displayed no activ- Ethyl-2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate
ity against Corynespora mazei at 50mg/L. Surprisingly, they (1) (38)
increase the fungal Corynespora mazei grow at 50mg/L. For In a 500 mL four-necked flask, ethyl 4,4-difluoro-3-oxobuta-
the Fusarium oxysporum, compounds 6a, 6 b, 6c and 6f also
can increase fungal growth, and compound 6 h and 6k exhib-
ited moderate (about 50%) fungicidal activity against
Fusarium oxysporum. Among them, compound 6 b exhibited
the best fungicidal activity (86%) against Botrytis cinerea at
noate (16.6 g, 100 mmol), triethyl orthoformate (44.46 g,
3
00 mmol) and acetic anhydride (61.25 g, 600 mmol) were
ꢁ
added and heated at 120 C for 6 h. The solvent was
removed and the product was then distilled under vacuum
over a column to give a colorless liquid, yield 90%.
50 ppm. Furthermore, compounds 6a and 6i also exhibited
good activity against Botrytis cinerea, which is the same as
the control. For the Pseudomonas syringae pv. Lachrymans, Ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxyl-
all the title compounds exhibited good activities. For example, ate (2) (38)
compound 6c, 6d, 6e and 6 h displayed good activity against To a solution of methyl hydrazine(1.9g, 0.041 mol) in ethyl
Pseudomonas syringae pv. Lachrymans, and are higher than acetate, was added ethyl-2-(ethoxymethylene)-4,4-difluoro-3-

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
þ
oxobutanoate (9.1 g, 0.041 mol) dropwise. The mixture was [M þ H] ; HRMS (ESI) m/z: Calculated, 329.0678, Found,
ꢁ
þ
stirred under 5 C for 1 h, then further stirred at reflux tem- 329.0680 [M þ H] .
perature for 3 h. After the reaction was complete, the mix-
ture was cooled and concentrated. The residue was
recrystallized with a yield of 85%, m. p. 62-63 C, H NMR
ꢁ
1
3-(Difluoromethyl)-N-((3-fluorophenyl)carbamothioyl)-1-
methyl-1H-pyrazole-4-carboxamide 6b
(
400 MHz, CDCl ), d1.32-1.38 (m, 3 H, -COCH CH ), 1.44-
3 2 3
ꢁ
1
Light yellow solid, yield 83.3%, m.p. 145 ꢀ 146 C, H NMR
1
.49 (m, 3 H, -COOCH CH ), 4.22-4.41 (m, 4 H,
2 3
(
400 MHz, CDCl ) d: 4.02 (s, 3 H, CH ), 6.83-7.10 (m, 2 H,
-
¼
OCH CH ), 6.26-6.60 (m, 1 H, ¼CH), 7.91 (t, J
3
3
2
3
H-F
CHF þPh), 7.37-7.40 (m, 2 H, Ph), 7.74 (d, J ¼ 10.4 Hz, 1 H,
52.00 Hz, 1 H, -CHF ).
2
2
Ph), 8.08 (s, 1 H, CH), 9.21 (s, 1 H, NH), 12.56 (s, 1 H, NH);
1
1
3
C NMR (125 MHz, CDCl ) d: 39.94(N-CH ), 110.64(t,
3
3
3
-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
JC,F¼235.0 Hz, CHF ), 111.17, 111.37, 113.56, 113.72, 114.15,
2
(3) (38)
1
19.45, 129.99, 130.06, 135.24, 138.96, 139.04, 144.89(t,
2
A solution of NaOH (1.2 g, 30 mmol) in water (50 mL) was
added to ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-
carboxylate (5.1 g, 25 mmol). The mixture was stirred for
overnight, then the mixture was acidified by using HCl, to
afford the white solid 3-(difluoromethyl)-1-methyl-1H-pyra-
JC,F¼27.8 Hz, Pyrazole-C), 160.98, 161.55, 163.50(C ¼ O),
þ
1
78.25(C ¼ S); MS(ESI) m/z: 329 [M þ H] ; HRMS (ESI) m/z:
þ
Calculated, 329.0678, Found, 329.0670 [M þ H] .
zole-4-carboxylic acid after filtration and drying with a yield 3-(Difluoromethyl)-N-((3,4-difluorophenyl)carbamothioyl)-
ꢁ
ꢁ
1
of 95%, m. p. 204 C ꢀ 205 C, H NMR (400 MHz, CDCl ), 1-methyl-1H-pyrazole-4-carboxamide 6c
3
ꢁ
1
d 3.91 (s, 3 H, N-CH ), 7.19 (t, J
.31 (s, 1 H, pyrazolyl-H), 12.73 (s, 1 H, -COOH).
¼54.20 Hz, 1 H, -CHF ), Light yellow solid, yield 84.6%, m.p. 137 ꢀ 138 C, H NMR
3
H-F
2
8
(400 MHz, CDCl ) d: 4.03 (s, 3 H, CH ), 6.95 (t, J ¼ 54 Hz,
3
3
1
7
1
H, CHF ), 7.18-7.23 (m, 1 H, Ph), 7.21-7.33 (m, 1 H, Ph),
2
.79-7.83 (m, 1 H, Ph), 8.08 (s, 1 H, CH), 9.24 (s, 1 H, NH),
3
-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chlor-
13
2.46 (s, 1 H, NH); C NMR (125 MHz, CDCl3) d: 39.96(N-
ide (4) (38)
1
CH ), 110.77(t, JC,F¼235.2 Hz, CHF ), 113.79, 113.94,
3
2
A mixture of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-
carboxylic acid 3 (1.45 g, 7.50 mmol) and thionyl chloride
3.57 g, 30 mmol) was refluxed for 4 h. After the reaction
was completed, the excess thionyl chloride was removed.
The yellow liquid acyl chloride 4 was given and used for
next step without further purification.
1
1
1
1
14.15, 117.20, 117.32, 120.32, 133.91, 133.94, 133.97,
35.42, 144.70(t, J ¼28.0 Hz, Pyrazole-C), 147.81, 147.88,
C,F
2
(
48.98,
149.07,
149.45,
149.53,
150.63,
150.72,
þ
60.96(C ¼ O), 178.68(C ¼ S); MS(ESI) m/z: 347 [M þ H] ;
HRMS (ESI) m/z: Calculated, 347.0584, Found,
þ
3
47.0573 [M þ H] .
General procedure for the preparation of title com-
pounds 6a–6l
A mixture of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-
3
1
-(Difluoromethyl)-N-((2,6-difluorophenyl)carbamothioyl)-
-methyl-1H-pyrazole-4-carboxamide 6d
ꢁ
1
Light yellow solid, yield 87.8%, m.p. 177 ꢀ 178 C, H NMR
carbonyl chloride 4 (10 mmol), NH SCN (0.99 g, 13 mmol)
4
(500 MHz, CDCl ) d: 4.03 (s, 3 H, CH ), 6.95-7.05 (m, 3 H,
3
3
and PEG-600 (0.1 mL) in dry CH COCH3 (20 mL) were
3
CHF þPh), 7.33-7.39 (m, 1 H, Ph), 8.11 (s, 1 H, CH), 9.49
2
stirred at room temperature for 1 h. The color of mixture
was red. When the color of the solution was changed to yel-
low, the reaction complete and further stirred for 1 h. The
mixture was filterated and the solvent was removed to give
yellow solid 5 was prepared without further purification.
Then, the solution of substituted aniline (2 mmol) in dry
13
(s, 1 H, NH), 11.68 (s, 1 H, NH); C NMR (125 MHz,
1
CDCl ) d:39.97(N-CH ), 110.59(t, JC,F¼239.2 Hz, CHF ),
3
3
2
1
1
1
10.91, 111.50, 111.89, 111.92, 112.07, 112.91, 113.08,
14.16, 129.42, 129.50, 135.29, 137.64, 160.94(C ¼ O),
þ
81.57(C ¼ S); MS(ESI) m/z: 347 [M þ H] ; HRMS (ESI) m/
þ
z: Calculated, 347.0584, Found, 347.0561 [M þ H] .
CH CN (15 mL) was dropwised into the mixture. The target
3
compounds were given by filteration. (Scheme 2).
3
-(Difluoromethyl)-N-(mesitylcarbamothioyl)-1-methyl-1H-
pyrazole-4-carboxamide 6e
3
-(Difluoromethyl)-N-((2-fluorophenyl)carbamothioyl)-1-
ꢁ
1
Light yellow solid, yield 91%, m.p. 188 ꢀ 189 C, H NMR
methyl-1H-pyrazole-4-carboxamide 6a
ꢁ
1
(500 MHz, CDCl ) d: 2.27 (s, 6 H, 2CH ), 2.32 (s, 3 H, CH ),
Light yellow solid, yield 93.3%, m.p. 162 ꢀ 163 C, H NMR
3
3
2
4
.01 (s, 3 H, CH ), 6.96 (s, 2 H, Ph), 7.00 (t, J ¼ 54 Hz, 1 H,
(
400 MHz, CDCl ) d: 4.03 (s, 3 H, CH ), 6.97 (t, J ¼ 54 Hz,
3
3
3
CHF ), 8.08 (s, 1 H, CH), 9.35 (s, 1 H, NH), 11.62 (s, 1 H,
1
7
9
H, CHF ), 7.17-7.20 (m, 1 H, Ph) , 7.22 (s, 1 H, Ph), 7.24-
2
2
13
.27 (m, 1 H, Ph) , 8.10 (s, 1 H, CH) , 8.40-8.44 (m, 1 H, Ph), NH); C NMR (125 MHz, CDCl
.28 (s, 1 H, NH), 12.54 (s, 1 H, NH); C NMR (500 MHz, CH
) d: 18.06, 21.01, 39.83(N-
3
13
1
), 110.17(t,
J
C,F¼235.7 Hz, CHF ), 114.18, 128.99,
3
2
1
2
CDCl3) d: 39.95(N-CH ), 110.78(t, JC,F¼233.2 Hz, CHF ), 132.78, 134.84, 134.91, 137.86, 145.65(t,
J
C,F¼26.8 Hz,
3
2
1
1
1
14.30, 115.55, 115.67, 124.05, 125.46, 125.92, 125.99, 127.70, Pyrazole-C), 161.40(C ¼ O), 180.36(C ¼ S); MS(ESI) m/z:
2
þ
27.75, 135.56, 144.60(t, J ¼28.0 Hz, Pyrazole-C), 154.23, 353 [M þ H] ; HRMS (ESI) m/z: Calculated, 353.1242,
C,F
þ
55.88, 160.81(C ¼ O), 178.60(C ¼ S); MS(ESI) m/z: 329 Found, 353.1244 [M þ H] .

4
L.-J. MIN ET AL.
3
-(Difluoromethyl)-1-methyl-N-((2-(trifluoromethoxy)phe-
3-(Difluoromethyl)-N-((4-ethylphenyl)carbamothioyl)-1-
methyl-1H-pyrazole-4-carboxamide 6j
nyl)carbamothioyl)-1H-pyrazole-4-carboxamide 6f
ꢁ
1
ꢁ
1
Light yellow solid, yield 82.6%, m.p. 128 ꢀ 129 C, H NMR Light yellow solid, yield 74.2%, m.p. 134 ꢀ 135 C, H NMR
(
400 MHz, CDCl ) d: 4.02 (s, 3 H, CH ), 6.96 (t, J ¼ 53.6 Hz, (400 MHz, CDCl
3
) d: 1.27 (t, J ¼ 7.6 Hz, 3 H, CH
), 2.66-2.72
3
), 6.98 (t, J ¼ 53.6 Hz, 1 H,
3
3
1
8
1
H, CHF ), 7.30-7.33 (m, 1 H, Ph), 7.37-7.41 (m, 2 H, Ph), (m, 2 H, CH
2
), 4.02 (s, 3 H, CH
3
2
CHF ), 7.26 (d, J ¼ 8.4 Hz, 2 H,Ph), 7.59 (d, J ¼ 8.4 Hz, 2 H,
.13 (s, 1 H, CH), 8.65-8.67 (m, 1 H, Ph), 9.30 (s, 1 H, NH),
2.78 (s, 1 H, NH); C NMR (125 MHz, CDCl ) d: 39.91(N-
2
1
3
Ph), 8.08 (s, 1 H, CH), 9.18 (s, 1 H, NH), 12.34 (s, 1 H, NH);
3
1
3
1
C NMR (125 MHz, CDCl ) d: 15.39, 28.46, 39.92(N-CH ),
CH ), 110.90(t, JC,F¼234.9 Hz, CHF ), 114.32, 121.05,
3
3
3
2
1
1
10.50(t, JC,F¼235.6 Hz, CHF ), 114.32, 124.26, 128.29,
2
1
25.43, 126.89, 127.14, 130.76, 135.91, 141.13, 144.36(t,
2
128.38, 130.31, 134.92, 135.10, 135.18, 143.18, 145.09(t,
JC,F¼28.3 Hz, Pyrazole-C), 160.74(C ¼ O), 178.43(C ¼ S);
2
þ
JC,F¼27.6 Hz, Pyrazole-C), 160.94(C ¼ O), 178.39(C ¼ S);
MS(ESI) m/z: 395 [M þ H] ; HRMS (ESI) m/z: Calculated,
þ
þ
MS(ESI) m/z: 339 [M þ H] ; HRMS (ESI) m/z: Calculated,
3
95.0596, Found, 395.0604 [M þ H] .
þ
3
39.1086, Found, 339.1104 [M þ H] .
N-((2,6-diethylphenyl)carbamothioyl)-3-(difluoromethyl)-1-
methyl-1H-pyrazole-4-carboxamide 6k
N-((2-chlorophenyl)carbamothioyl)-3-(difluoromethyl)-1-
methyl-1H-pyrazole-4-carboxamide 6g
Light yellow solid, yield 86.3%, m.p. 166 ꢀ 167 C, H NMR
ꢁ
1
ꢁ
1
Light yellow solid, yield 89%, m.p. 152 ꢀ 153 C, H NMR
(
2
500 MHz, d -DMSO) d: 1.15 (t, J ¼ 7.5 Hz, 6 H, 2CH ),
6
3
(
1
7
500 MHz, CDCl ) d: 4.02 (s, 3 H, CH ), 6.98 (t, J ¼ 54 Hz,
3
3
.53 ꢀ 2.59 (m, 4 H, 2CH ), 3.97 (s, 3 H, CH ), 7.16 (d,
2
3
H, CHF ), 7.23-7.25 (m, 1 H, Ph), 7.34-7.37 (m, 1 H, Ph),
2
J ¼ 7.5 Hz, 2 H,Ph), 7.28 (t, J ¼ 54Hz, 1 H, CHF ), 7.26 (t,
2
.48-7.79 (m, 1 H, Ph), 8.11 (s, 1 H, CH), 8.39-8.41 (m, 1 H,
J ¼ 7.5 Hz, 1 H, Ph), 8.83 (s, 1 H, CH), 11.53 (s, 1 H, NH),
13
Ph), 9.33 (s, 1 H, NH), 12.58 (s, 1 H, NH); C NMR
125 MHz, CDCl3) d: 39.94(N-CH3), 110.78(t,
13
1
1.83 (s, 1 H, NH);
C NMR (125 MHz, CDCl ) d:
3
(
1
2.63(CH3),
22.66(CH2),
37.75(N-CH3),
107.64(t,
1
JC,F¼235.0 Hz, CHF ), 114.31, 126.34, 126.91, 127.71,
1
2
JC,F¼238.3 Hz, CHF ), 111.75, 124.41, 126.41, 133.23,
2
2
1
28.02, 129.65, 135.16, 135.64, 144.57(t,
J
¼28.4 Hz,
2
C,F
1
1
39.96, 145.00(t, J ¼28.4 Hz, Pyrazole-C), 160.93(C ¼ O),
C,F
Pyrazole-C), 160.64(C ¼ O), 178.72(C ¼ S); MS(ESI) m/z:
þ
79.54(C ¼ S); MS(ESI) m/z: 367 [M þ H] ; HRMS (ESI) m/
þ
3
45 [M þ H] ; HRMS (ESI) m/z: Calculated, 345.0383,
þ
z: Calculated, 367.1399, Found, 367.1395 [M þ H] .
þ
Found, 345.0376 [M þ H] .
N-((4-(tert-butyl)phenyl)carbamothioyl)-3-(difluoromethyl)-
1
-methyl-1H-pyrazole-4-carboxamide 6l
3
1
-(Difluoromethyl)-N-((3,5-dimethylphenyl)carbamothioyl)-
-methyl-1H-pyrazole-4-carboxamide 6h
ꢁ
1
Light yellow solid, yield 85%, m.p.157 ꢀ 158 C, H NMR
(500 MHz, CDCl ) d: 1.34 (s, 9 H, 3CH ), 4.02 (s, 3 H, CH ),
3 3 3
ꢁ
1
Light yellow solid, yield 82.3%, m.p. 135 ꢀ 137 C, H NMR
6
.98 (t, J ¼ 54 Hz, 1 H, CHF ), 7.44 (d, J ¼ 9.0 Hz, 2 H, Ph),
2
(400 MHz, CDCl ) d: 2.36 (s, 6 H, 2CH ), 4.03 (s, 3 H, CH ),
3 3 3
7.62 (d, J ¼ 8.5 Hz, 2 H, Ph), 8.07 (s, 1 H, CH), 9.18 (s, 1 H,
13
6
2
.94 (s, 1 H, Ph), 6.98 (t, J ¼ 53.6 Hz, 1 H, CHF ), 7.31 (s,
2
NH), 12.36 (s, 1 H, NH); C NMR (125 MHz, CDCl ) d:
3
1
H, Ph), 8.06 (s, 1 H, CH), 9.14 (s, 1 H, NH), 12.31 (s, 1 H, 31.30, 34.63, 39.92(N-CH ), 110.53(t, J ¼235.2 Hz, CHF ),
3
C,F
2
1
3
NH); C NMR (125 MHz, CDCl ) d: 21.29, 39.91(N-CH ), 114.35, 123.74, 125.55, 125.80, 125.88, 127.81, 134.91,
3
3
1
2
1
10.43(t, JC,F¼235.6 Hz, CHF ), 114.33, 121.94, 128.73, 134.97, 135.12, 145.04(t, J ¼27.3 Hz, Pyrazole-C), 149.98,
2
C,F
2
þ
1
34.82, 135.04, 137.36, 138.68, 145.23(t,
J
¼26.8 Hz, 160.92(C ¼ O), 178.18(C ¼ S); MS(ESI) m/z: 367 [M þ H] ;
C,F
Pyrazole-C), 160.96(C ¼ O), 178.28(C ¼ S); MS(ESI) m/z: HRMS (ESI) m/z: Calculated, 367.1399, Found,
þ
þ
3
39 [M þ H] ; HRMS (ESI) m/z: Calculated, 339.1086, 367.1398 [M þ H] .
þ
Found, 339.1094 [M þ H] .
Greenhouse in vivo biological evaluation
The biological activity of compounds 6a ꢀ 6l against
3
-(Difluoromethyl)-1-methyl-N-((2,3,4-trifluorophenyl)car-
Fusarium oxysporum, Corynespora mazei, Pseudomonas
bamothioyl)-1H-pyrazole-4-carboxamide 6i
syringae pv. lachrymans and Botrytis cinerea was evaluated
ꢁ
1
Light yellow solid, yield 59.6%, m.p. 127 ꢀ 128 C, H NMR
[46–50]
according to reference.
A potted plant test method was
(
1
8
400 MHz, CDCl ) d: 4.03 (s, 3 H, CH ), 6.96 (t, J ¼ 54 Hz,
3
3
adopted. Germination was induced by soaking cucumber
H, CHF ), 7.01-7.09 (m, 1 H, Ph), 7.94-8.00 (m, 1 H, Ph),
ꢁ
2
seeds in water for 2 h at 50 C and then keeping the seeds
13
.12 (s, 1 H, CH), 9.38 (s, 1 H, NH), 12.42 (s, 1 H, NH) .
C
ꢁ
moist for 24 h at 28 C in an incubator. When the radicles
NMR (125 MHz, CDCl3) d: 39.96(N-CH3), 110.81(t,
were 0.5 cm, the seeds were grown in plastic pots containing
a 1:1 (v/v) mixture of vermiculite and peat. Cucumber plants
1
JC,F¼234.6 Hz, CHF ), 111.28, 111.42, 112.36, 120.33,
2
1
20.36, 123.36, 123.42, 135.18, 135.77, 144.46(t, used for inoculations were at the stage of two cotyledons.
2
JC,F¼27.9 Hz, Pyrazole-C), 161.05(C ¼ O), 179.76(C ¼ S); Tested compounds and commercial fungicide were sprayed
þ
MS(ESI) m/z: 365 [M þ H] ; HRMS (ESI) m/z: Calculated, with a hand sprayer on the surface of the leaves and on a
þ
3
65.0490, Found, 365.0495 [M þ H] .
fine morning, at the standard concentration of 50 lg/mL,

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
each plant was sprayed with compounds and commercial
fungicides fluxapyroxad was used as controls. After 2 h,
inoculations of Fusarium oxysporum, Corynespora mazei,
Pseudomonas syringae pv. lachrymans and Botrytis cinerea
DFT Calculations and Biological Activity of 2-(3-Methyl-5-
Pyridin-2’-yl)-1H-Pyrazol-1-yl) Ethanol. Molecules 2016, 21,
020. DOI: 10.3390/molecules21081020.
(
1
[
[
4] Gomha, S. M.; Abdel-Aziz, H. M.; El-Reedy, A. A. M. Facile
Synthesis of Pyrazolo[3,4-c ]Pyrazoles Bearing Coumarine Ring
as Anticancer Agents. J. Heterocyclic Chem. 2018, 55,
1960–1965. DOI: 10.1002/jhet.3235.
5] Sun, N. B.; Zhai, Z. W.; Shen, Z. H.; Weng, J. Q.; Tan, C. X.;
Liu, X. H.; Han, L. Synthesis, Crystal Structure and Antifungal
Activity of N-((2,6-Difluorophenyl)carbamoyl)1,3-dimethyl-1H-
pyrazole-4-carboxamide. Chin. J. Struct. Chem 2017, 36,
were carried out by spraying fungal spore suspension with
4
1
ꢃ 10 spore/mL, which was smashed with a T10 basic
V
R
ULTRA-TURRAX (IKA, Guangzhou, China). Each kind of
inoculum was sprayed at 300 lL/plant. Each treatment was
replicated four times. After inoculation, the plants were
ꢁ
ꢁ
maintained at 18–30 C (mean temperature of 24 C and
above 80% relative humidity (RH)). The antifungal activity
was evaluated when the non-treated plant (blank) fully
developed symptoms. The area of inoculated treated leaves
covered by disease symptoms was assessed and compared to
that of non-treated ones to determine the average disease
index. The relative control efficacy of compounds compared
to the blank assay was calculated via the following equation:
1667–1672. DOI: 10.14102/j.cnki.0254-5861.2011-1582.
[6] Cheng, L.; Zhao, W.; Shen, Z. H.; Xu, T. M.; Wu, H. K.; Peng,
W. L.; Liu, X. H. Synthesis, Nematicidal Activity and Docking
Study of Novel Pyrazole-4-Carboxamide Derivatives against
Meloidogyne Incognita. Lett. Drug Des. Discov. 2019, 16, 29–35.
DOI: 10.2174/1570180815666180326150827.
[
[
[
7] Cheng, L.; Shen, Z. H.; Xu, T. M.; Tan, C. X.; Weng, J. Q.;
Han, L.; Peng, W. L.; Liu, X. H. Synthesis and Nematocidal
Activity
of
N-Substituted
3-Methyl-1 H
-Pyrazole-4-
Carboxamide Derivatives against Meloidogyne Incognita. J.
Heterocyclic Chem. 2018, 55, 946–950. DOI: 10.1002/jhet.3123.
8] Zhao, W.; Xing, J. H.; Xu, T. M.; Peng, W. L.; Liu, X. H.
Synthesis and in Vivo Nematocidal Evaluation of Novel 3-
relative control efficacy ð%Þ ¼ ðCK ꢂ PTÞ=CK ꢃ 100%
where CK is the average disease index during the blank
assay and PT is the average disease index after treatment
during testing. All experiments were replicated three times.
(
Trifluoromethyl)-1H-Pyrazole-4-Carboxamide
Front. Chem. Sci. Eng. 2017, 11, 363–368. DOI: 10.1007/s11705-
16-1595-x.
Derivatives.
0
9] Zhao, W.; Shen, Z. H.; Xu, T. M.; Peng, W. L.; Liu, X. H.
Synthesis, Nematocidal Activity and Docking Study of Novel
Conclusions
Chiral
Pyrazole-4-Carboxamide Derivatives. J. Heterocyclic Chem.
017, 54, 1751–1756. DOI: 10.1002/jhet.2753.
1-(3-Chloropyridin-2-yl)-3-(Difluoromethyl)-1 H
To explore higher active thiourea compounds with fungi-
cidal and antibacterial activity, some new thiourea deriva-
-
2
tives containing difluoromethyl pyrazole motif were [10] Zhao, W.; Shen, Z. H.; Xing, J. H.; Yang, G.; Xu, T. M.; Peng,
W. L.; Liu, X. H. Synthesis and Nematocidal Activity of Novel
designed and synthesized. Most of the title compounds pos-
1
-(3-Chloropyridin-2-yl)-3-(Trifluoromethyl)-1H-Pyrazole-4-
Carboxamide Derivatives. Chem. Pap. 2017, 71, 921–928. DOI:
0.1007/s11696-016-0012-8.
sessed good antibacterial activity against Pseudomonas syrin-
gae pv. lachrymans. The structure can be recognized as new
lead antibacterial compounds with further structural
modifications.
1
[
11] Zhao, W.; Shen, Z. H.; Xing, J. H.; Xu, T. M.; Peng, W. L.; Liu,
X. H. Synthesis, Characterization, Nematocidal Activity and
Docking Study of Novel Pyrazole-4-carboxamide Derivatives.
Chin. J. Struct. Chem 2017, 36, 423–428. DOI: 10.14102/j.cnki.
0254-5861.2011-1353.
12] Li, W.; Li, J. H.; Shen, H. F.; Cheng, J. G.; Li, Z.; Xu, X. Y.
Synthesis, Nematicidal Activity and Docking Study of Novel
Chromone Derivatives Containing Substituted Pyrazole. Chin.
Chem. Lett 2018, 29, 911–914. DOI: 10.1016/j.cclet.2017.10.011.
13] Cheng, L.; Cai, P. P.; Zhang, R. R.; Han, L.; Tan, C. X.; Weng,
J. Q.; Xu, T. M.; Liu, X. H. Synthesis and Insecticidal Activity
of New Quinoline Derivatives Containing Perfluoropropanyl
Moiety. J. Heterocycl. Chem 2019, 56(4), 1312–1317. DOI: 10.
Disclosure statement
[
No potential conflict of interest was reported by the authors.
Funding
[
This work was funded by Zhejiang Provincial Natural Science
Foundation of China (No. LY19C140002), Research Fund of
Department of Education of Zhejiang Province (Y201840646) and
Open Fund of Collaborative Innovation Center of Zhejiang Province
Green Pesticide (LSNY201805).
1002/jhet.3502.
[
[
14] Liu, X. H.; Zhao, W.; Shen, Z. H.; Xing, J. H.; Yuan, J.; Yang,
G.; Xu, T. M.; Peng, W. L. Synthesis, Nematocidal Activity and
Docking Study of Novel Chiral 1-(3-Chloropyridin-2-yl)-3-
(
Trifluoromethyl)-1H-Pyrazole-4-Carboxamide
Derivatives.
Bioorg. Med. Chem. Lett 2016, 26, 3626–3628. DOI: 10.1016/j.
bmcl.2016.06.004.
References
15] Osman, H.; Yusufzai, S. K.; Khan, M. S.; Abd Razik, B. M.;
Sulaiman, O.; Mohamad, S.; Gansau, J. A.; Ezzat, M. O.;
Parumasivam, T.; Hassan, M. Z. New Thiazolyl-Coumarin
Hybrids: Design, Synthesis, Characterization, X-Ray Crystal
Structure, Antibacterial and Antiviral Evaluation. J. Mol. Struct
2018, 1166, 147–154. DOI: 10.1016/j.molstruc.2018.04.031.
[
[
[
1] Dai, H.; Ge, S. S.; Guo, J.; Chen, S.; Huang, M. L.; Yang, J. Y.;
Sun, S. Y.; Ling, Y.; Shi, Y. Development of Novel Bis-Pyrazole
Derivatives as Antitumor Agents with Potent Apoptosis
Induction Effects and DNA Damage. Eur. J. Med. Chem. 2018,
143, 1066–1076. DOI: 10.1016/j.ejmech.2017.11.098.
2] Padalkar, V. S.; Borse, B. N.; Gupta, V. D.; Phatangare, K. R.;
Patil, V. S.; Sekar, N. Synthesis and Antimicrobial Activities of [16] Karakus, S.; Tok, F.; Turk, S.; Salva, E.; Tatar, G.; Taskin-Tok,
Novel
Benzoxazoles, and Benzimidazoles. J. Heterocyclic Chem. 2016,
3, 1347–1355. DOI: 10.1002/jhet.1506.
2-[Substituted-1 H
-Pyrazol-4-yl]
Benzothiazoles,
T.; Kocyigit-Kaymakcioglu, B. Synthesis, Anticancer Activity
and ADMET Studies of N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-
5
[(3-substituted)Ureido/Thioureido]
Benzenesulfonamide
3] Radi, S.; Attayibat, A.; El-Massaoudi, M.; Salhi, A.; Eddike, D.;
Tillard, M.; Mabkhot, Y. N. X-Ray Single Crystal Structure,
Derivatives. Phosphorus Sulfur Silicon Relat. Elem 2018, 193,
528–534. DOI: 10.1080/10426507.2018.1452924.

6
L.-J. MIN ET AL.
[17] Sun, N. B.; Shen, Z. H.; Zhai, Z. W.; Han, L.; Weng, J. Q.; Tan, [31] Zhang, L. J.; Yang, M. Y.; Sun, Z. H.; Tan, C. X.; Weng, J. Q.;
C. X.; Liu, X. H. Design, Synthesis, Fungicidal Activity and
Docking Study of Acyl Thiourea Derivatives Containing
Pyrazole Moiety. Chin. J. Org. Chem. 2017, 37, 2705–2710.
DOI: 10.6023/cjoc201702003.
Wu, H. K.; Liu, X. H. Synthesis and Antifungal Activity of
1,3,4-Thiadiazole Derivatives Containing Pyridine Group. Lett.
Drug Des. Discov 2014, 11, 1107–1111. DOI: 10.2174/
1570180811666140610212731.
[18] Bielenica, A.; Stepien, K.; Sawczenko, A.; Lis, T.; Koziol, A. E.; [32] Liu, X. H.; Zhao, W.; Shen, Z. H.; Xing, J. H.; Xu, T. M.; Peng,
Madeddu, S.; Collu, D.; Iuliano, F.; Kosmider, A.; Struga, M.
Synthesis, Structural Studies and Biological Evaluation of
Halogen Derivatives of 1,3-Disubstituted Thiourea. Lett. Drug
W. L. Synthesis, Nematocidal Activity and SAR Study of Novel
Difluoromethylpyrazole Carboxamide Derivatives Containing
Flexible Alkyl Chain Moieties. Eur. J. Med. Chem. 2017, 125,
881–889. DOI: 10.1016/j.ejmech.2016.10.017.
Des.
Discov
2017,
14,
636–646.
DOI:
10.2174/
1570180814666170106121025.
[33] Sun, N. B.; Zhai, Z. W.; Tong, J. Y.; Cai, P. P.; He, F. Y.; Han,
L.; Liu, X. H. Synthesis, Crystal Structure and Fungicidal
Activity of3-(Difluoromethyl)-1-methyl-N-((2-(trifluoromethyl)-
phenyl)carbamoyl)-1H-pyrazole-4-carboxamide. Chin. J. Struct.
Chem 2019, 38, 706–712. DOI: 10.14102/j.cnki.0254-5861.2011-
[
[
19] Larik, F. A.; Shah, M. S.; Saeed, A.; Shah, H. S.; Channar, P. A.;
Bolte, M.; Iqbal, J. New Cholinesterase Inhibitors for
Alzheimer’s Disease: Structure Activity Relationship, Kinetics
and Molecular Docking Studies of 1–Butanoyl–3–Arylthiourea
Derivatives. Int. J. Biol. Macromol 2018, 116, 144–150. DOI: 10.
2
176.
34] Weng, J. Q.; Wang, L.; Liu, X. H. Synthesis, Crystal Structure
and Herbicidal Activity of 1, 2, 4-Triazol-5(4H)-One
Derivative. J. Chem. Soc. Pak 2012, 34, 1248–1252. DOI: 10.
155/2013/306361.
1016/j.ijbiomac.2018.05.001.
[
20] Sayed, M.; Kamal El-Dean, A. M.; Ahmed, M.; Hassanien, R.
Synthesis, Characterization, and Screening for anti-
Inflammatory and Antimicrobial Activity of Novel Indolyl
Chalcone Derivatives. J. Heterocyclic Chem. 2018, 55,
a
1
[
35] Liu, X. H.; Zhai, Z. W.; Xu, X. Y.; Yang, M. Y.; Sun, Z. H.;
Weng, J. Q.; Tan, C. X.; Chen, J. Facile and Efficient Synthesis
and Herbicidal Activity Determination of Novel 1,2,4-
Triazolo[4,3- a ]Pyridin-3(2 H )-One Derivatives via Microwave
Irradiation. Bioorg. Med. Chem. Lett. 2015, 25, 5524–5528. DOI:
1166–1175. DOI: 10.1002/jhet.3149.
[
21] Gundlewad, G. B.; Patil, B. R. Synthesis and Evaluation of
Some Novel 2-Amino-4-Aryl Thiazoles for Antitubercular
Activity. J. Heterocyclic Chem. 2018, 55, 769–774. DOI: 10.
1002/jhet.3098.
10.1016/j.bmcl.2015.10.064.
[
22] Xue, S. J.; Ke, S. Y.; Wei, T. B.; Duan, L. P.; Guo, Y. L.
Ultrasonic Irradiated Synthesis of N -(5-Aryl-2-Furoyl)Thiourea
Derivatives Containing Substituted Pyrimidine Ring under
Phase Transfer Catalysis. Jnl. Chinese Chemical Soc. 2004, 51,
[
36] Liu, X. H.; Xu, X. Y.; Tan, C. X.; Weng, J. Q.; Xin, J. H.; Chen,
J. Synthesis, Crystal Structure, Herbicidal Activities and 3D-
QSAR Study of Some Novel 1,2,4-Triazolo[4,3- a ]Pyridine
Derivatives. Pest Manag. Sci. 2015, 71, 292–301. DOI: 10.1002/
ps.3804.
1013–1018. DOI: 10.1002/jccs.200400151.
[
23] Wei, T. B.; Lin, Q.; Zhang, Y. M.; Wei, W. Microwave
[
[
37] Zhang, L. J.; Yang, M. Y.; Hu, B. Z.; Sun, Z. H.; Liu, X. H.;
Weng, J. Q.; Tan, C. X. Microwave-Assisted Synthesis of Novel
0
Promoted Efficient Synthesis of N-Aryl-N -Aroyl Thioureas
under Solvent-Free and Phase Transfer Catalysis Conditions.
Synth. Commun 2004, 34, 181–186. DOI: 10.1081/SCC-
8-Chloro-[1,2,4]Triazolo[4,3-$a$]Pyridine Derivatives. Turk. J.
Chem. 2015, 39, 867–873. DOI: 10.3906/kim-1408-78.
38] Yang, M. Y.; Zhao, W.; Sun, Z. H.; Tan, C. X.; Weng, J. Q.;
Liu, X. H. Synthesis and Biological Activity of Acylthiourea
Derivatives Contain 1,2,3-Thiadiazole and 1,3,4-Thiadiazole.
Lett. Drug Des. Discov 2015, 12, 314–318. DOI: 10.2174/
120027251.
[
24] Liu, X. H.; Tan, C. X.; Weng, J. Q. Phase Transfer–Catalyzed,
0
One-Pot Synthesis of Some Novel
N -Pyrimidinyl- N
-
Nicotinyl Thiourea Derivatives. Phosphorus Sulfur Silicon Relat.
Elem 2011, 186, 552–557. DOI: 10.1080/10426507.2010.508059f.
25] Wei, T. B.; Zhang, Y. M.; Wang, H.; Gao, L. M. Phase Transfer
Catalyzed Synthesis of Thiosemicarbazide and bis-
Thiosemicarbazide Derivatives of 2-Ethoxybenzoic Acid.
Phosphorus Sulfur Silicon Relat. Elem 2004, 179, 1539–1544.
DOI: 10.1080/10426500490464078.
26] Liu, X. H.; Wang, Q.; Sun, Z. H.; Wedge, D. E.; Becnel, J. J.;
Estep, A. S.; Tan, C. X.; Weng, J. Q. Synthesis and Insecticidal
Activity of Novel Pyrimidine Derivatives Containing Urea
Pharmacophore against Aedes Aegypti. Pest Manag. Sci. 2017,
1570180811666141010000435.
[
[
[
[
39] Wang, H.; Zhai, Z. W.; Shi, Y. X.; Tan, C. X.; Weng, J. Q.;
Han, L.; Li, B. J.; Liu, X. H. Novel Trifluoromethylpyrazole
Acyl Thiourea Derivatives: Synthesis, Antifungal Activity and
Docking Study. Lett. Drug Des. Discov 2019, 16, 785–791. DOI:
10.2174/1570180815666180704103047.
[
[
[
40] Wang, H.; Zhai, Z. W.; Shi, Y. X.; Tan, C. X.; Weng, J. Q.;
Han, L.; Li, B. J.; Liu, X. H. Novel Trifluoromethylpyrazole
Acyl Urea Derivatives: Synthesis, Crystal Structure, Fungicidal
Activity and Docking Study. J. Mol. Struct 2018, 1171, 631–638.
DOI: 10.1016/j.molstruc.2018.06.050.
7
3, 953–959. DOI: 10.1002/ps.4370.
27] Liu, X. H.; Weng, J. Q.; Wang, B. L.; Li, Y. H.; Tan, C. X.; Li,
Z. M. Microwave-Assisted Synthesis of Novel Fluorinated 1,2,4-
Triazole Derivatives, and Study of Their Biological Activity. Res.
Chem. Intermed. 2014, 40, 2605–2612. DOI: 10.1007/s11164-
41] Shen, Z. H.; Zhai, Z. W.; Sun, Z. H.; Weng, J. Q.; Tan, C. X.;
Liu, X. H. Synthesis,Crystal Structure and Biological Activity of
2
4
-Chloro-5-(((5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)thiazole. Chin. J.
013-1113-4.
Struct. Chem 2017, 36, 1137–1141. DOI: 10.14102/j.cnki.0254-
861.2011-1488.
28] Shen, Z. H.; Sun, Z. H.; Becnel, J. J.; Estep, A.; Wedge, D. E.;
Tan, C. X.; Weng, J. Q.; Han, L.; Liu, X. H. Synthesis and
Mosquiticidal Activity of Novel Hydrazone Containing
Pyrimidine Derivatives against Aedes Aegypti. Lett. Drug Des.
5
[
42] Zhao, W.; Shen, Z. H.; Xing, J. H.; Xu, T. M.; Peng, W. L.; Liu,
X. H. Synthesis and Nematocidal Activity of Novel Pyrazole
Carboxamide Derivatives against Meloidogyne Incognita. Lett.
Drug Des. Discov 2017, 14, 323–329. DOI: 10.2174/
1570180813666160930164327.
Discov
570180815666180102141640.
29] Liu, X. H.; Pan, L.; Weng, J. Q.; Tan, C. X.; Li, Y. H.; Wang,
2018,
15,
951–956.
DOI:
10.2174/
1
[
[
B. L.; Li, Z. M. Synthesis, Structure, and Biological Activity of [43] Jin, T.; Zhai, Z. W.; Han, L.; Weng, J. Q.; Tan, C. X.; Liu, X. H.
Novel (Oxdi/Tri)Azoles Derivatives Containing 1,2,3-
Thiadiazole or Methyl Moiety. Mol. Divers. 2012, 16, 251–260.
DOI: 10.1007/s11030-011-9352-z.
Synthesis, Crystal Structure, Docking and Antifungal Activity of
a New Pyrazole Acylurea Compound. Chin. J. Struct. Chem
2018, 37, 1259–1264. DOI: 10.14102/j.cnki.0254-5861.2011-
1919.
30] Tan, C. X.; Shi, Y. X.; Weng, J. Q.; Liu, X. H.; Li, B. J.; Zhao,
W.-G. Synthesis and Antifungal Activity of 1,2,4-triazole [44] Yan, S. L.; Yang, M. Y.; Sun, Z. H.; Min, L. J.; Tan, C. X.;
Derivatives Containing Cyclopropane Moiety. Lett. Drug Des.
Discov. 2012, 9, 431–435.
Weng, J. Q.; Wu, H. K.; Liu, X. H. Synthesis and Antifungal
Activity of 1,2,3-Thiadiazole Derivatives Containing 1,3,4-

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Thiadiazole Moiety. Lett. Drug Des. Discov 2014, 11, 940–943. [48] Fang, Y. M.; Zhang, R. R.; Shen, Z. H.; Tan, C. X.; Weng, J. Q.;
DOI: 10.2174/1570180811666140423222141.
45] Liu, X. H.; Tan, C. X.; Weng, J. Q. Synthesis, Dimeric Crystal
Structure, and Fungicidal Activity of 1-(4-Methylphenyl)-2-(5-
Xu, T. M.; Liu, X. H.; Huang, H. Y.; Wu, H. K. Synthesis and
Antifungal Activity of Some 6-Tert-Butyl-8-Chloro-2,
[
[
[
3
-Dimethylquinolin-4-ol Derivatives against Pyricularia Oryae.
Lett. Drug Des. Discov 2018, 15, 1314–1318. DOI: 10.2174/
570180815666180313121735.
(
(3,5-Dimethyl-1H-Pyrazol-1-yl)Methyl)-4-Phenyl-4H-1,2,4-
Triazol-3-Ylthio)Ethanone. Phosphorus Sulfur Silicon Relat.
Elem 2011, 186, 558–564. DOI: 10.1080/10426507.2010.508060.
46] Cheng, L.; Zhang, R. R.; Wu, H. K.; Xu, T. M.; Liu, X. H. The
1
[
[
49] Fang, Y. M.; Zhang, R. R.; Shen, Z. H.; Wu, H. K.; Tan, C. X.;
Weng, J. Q.; Xu, T. M.; Liu, X. H. Synthesis, Antifungal
Activity, and SAR Study of Some New 6-Perfluoropropanyl
Quinoline Derivatives. J. Heterocyclic Chem. 2018, 55, 240–245.
DOI: 10.1002/jhet.3031.
50] Zhai, Z. W.; Wang, Q.; Shen, Z. H.; Tan, C. X.; Weng, J. Q.;
Liu, X. H. Synthesis and Biological Activity of 1,2,4-Triazole
Thioether Derivatives Containing Pyrazole Moiety. Chin. J. Org.
Chem. 2017, 37, 232–236. DOI: 10.6023/cjoc201607031.
Synthesis
of
6-(tertbutyl)-8-fluoro-2,3-dimethylquinoline
Carbonate Derivatives and their Antifungal Activity Against.
Pyricularia oryzae. Front. Chem. Sci. Eng 2019, 13, 369–376.
DOI: 10.1007/s11705-018-1734-7.
47] Liu, X. H.; Fang, Y. M.; Xie, F.; Zhang, R. R.; Shen, Z. H.; Tan, C. X.;
Weng, J. Q.; Xu, T. M.; Huang, H. Y. Synthesis and in Vivo
Fungicidal Activity of Some New Quinoline Derivatives against Rice
Blast. Pest Manag. Sci. 2017, 73, 1900–1907. DOI: 10.1002/ps.4556.