Design, synthesis and insecticidal activities of novel 1-substituted-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives

Article abstract of DOI:10.1016/j.cclet.2016.06.010

A series of novel 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives (6a–6n, 7a, 7b, and 8a-8f) were synthesised by placing the amide bond at the 4-position of the pyrazole ring. These derivatives differed from the structure of chlorantraniliprole analogues with the amide bond at the 5-position of the pyrazole ring. Preliminary bioassay results revealed that a few title compounds exhibited good insecticidal activities against lepidopteran pests, such as Plutella xylostella, Mythimna separate, Heliothis armigera, and Ostrinia nubilalis. Some title compounds also elicited broad-spectrum insecticidal activities against dipterous insects including Culex pipiens pallens after altering the amide position. Similar to pyrazole-5-carboxamide analogues, compounds 6b and 6e showed 100% insecticidal activity against P. xylostella, C. pipiens pallens, and M. separate at concentrations of 200, 2, and 200?μg/mL, respectively. This finding suggested that 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives are potential alternative insecticides for management of agriculture pests.

Full text of DOI:10.1016/j.cclet.2016.06.010

G Model
CCLET 3730 1–5
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Design, synthesis and insecticidal activities of novel 1-substituted-
5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives
Q1 Zhi-Bing Wu a, Xiang Zhou a, Yi-Qiang Ye a, Pei-Yi Wang a, Song Yang a,b,
*
5
6
7
8
a State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Research and Development Center for Fine Chemicals, Guizhou University, Guiyang 550025, China
b College of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of novel 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives (6a–6n, 7a, 7b, and 8a-8f)
were synthesised by placing the amide bond at the 4-position of the pyrazole ring. These derivatives
differed from the structure of chlorantraniliprole analogues with the amide bond at the 5-position of the
pyrazole ring. Preliminary bioassay results revealed that a few title compounds exhibited good
insecticidal activities against lepidopteran pests, such as Plutella xylostella, Mythimna separate, Heliothis
armigera, and Ostrinia nubilalis. Some title compounds also elicited broad-spectrum insecticidal activities
against dipterous insects including Culex pipiens pallens after altering the amide position. Similar to
pyrazole-5-carboxamide analogues, compounds 6b and 6e showed 100% insecticidal activity against
Received 6 April 2016
Received in revised form 19 May 2016
Accepted 20 May 2016
Available online xxx
Keywords:
5-(Trifluoromethyl)-1H-pyrazole-4-
carboxamide
P. xylostella, C. pipiens pallens, and M. separate at concentrations of 200, 2, and 200
mg/mL, respectively.
Insecticidal activities
Chlorantraniliprole
Ryanodine receptors
This finding suggested that 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives are potential
alternative insecticides for management of agriculture pests.
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
9
10
1. Introduction
[8] and the change of diamide to diphenic amide [9]. To date, 26
numerous pyrazole-5-carboxamide analogues were designed and 27
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Agricultural pests, one of the most serious threats in crop
production, have caused huge economic losses annually. Chemical
control is used for crop protection because of its high efficiency and
accessibility. The pyrazole-5-carboxamide compound chlorantra-
niliprole exhibits excellent insecticidal activities against lepidop-
teran pests and has been successfully commercialised. Studies
showed that chlorantraniliprole acts on ryanodine receptors
(RyRs) [1–3]. Numerous researchers have focused on research
and development of alternative insecticides based on the structure
of chlorantraniliprole because of its effective bioactivity towards
insects. Fig. 1 shows that the structure chlorantraniliprole is
modified and optimised based on the following three aspects: part
A, substituted benzene ring or heterocyclic ring [4,5]; part B,
different substituent instead of amines [6]; part C, bridging group
instead of amide [7], the modification of pyridyl pyrazole moiety
reported with satisfactory insecticidal activities. However, resis- 28
tance risks have gradually emerged as a consequence of continuous 29
application of this pesticide [10,11]. Therefore, research and 30
development of alternative insecticide agents to reduce resistance 31
risks remains a challenging task in pesticide science. Among all 32
chlorantraniliprole derivatives reported, most of the amide bond 33
linked to the pyrazole ring are found on the 5-position; however, 34
pyrazole-4-carboxamide derivatives have been rarely investigated 35
[12].
36
In this study, a series of novel 5-(trifluoromethyl)-1H-pyrazole- 37
4-carboxamide derivatives were designed and synthesised with 38
the amide bond at the 4-position of the 5-trifluoromethyl-1H- 39
pyrazole ring to analyse insecticidal activity (Fig. 1). Within these 40
molecules, the trifluoromethyl group and 2-chloropyridine moiety 41
(or phenyl ring) are settled at the 5-position and 1-position of the 42
pyrazole ring, respectively. Acylhydrazone sub-structure (B2) was 43
introduced for comparison of amide moiety (B1) and embedded 44
into the structure of chlorantraniliprole to extend molecular scope 45
and obtain highly efficient target molecules. All target compounds 46
were bioassayed against Plutella xylostella, Culex pipiens pallens, 47
Mythimna separata, Heliothis armigera, and Ostrinia nubilalis. 48
Preliminary insecticidal bioassay results showed that a few 49
*
Corresponding author at: State Key Laboratory Breeding Base of Green Pesticide
and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Research and Development Center for Fine
Chemicals, Guizhou University, Guiyang, China. .
Q2
E-mail address: jhzx.msm@gmail.com (S. Yang).
http://dx.doi.org/10.1016/j.cclet.2016.06.010
1001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Z.-B. Wu, et al., Design, synthesis and insecticidal activities of novel 1-substituted-5-
(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.010

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Z.-B. Wu et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Fig. 1. Structure of modified and optimised chlorantraniliprole.
50
51
compounds exerted good activities against P. xylostella, C. pipiens
pallens, and M. separate.
N-(4-chloro-2-(isopropylcarbamoyl)-6-methylphenyl)-1-(3-c-
hloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxam-
ide (6e):
94
95
96
97
White solid, yield 47%, m.p. 234ꢀ235 8C; 1H NMR (500 MHz,
52
2. Experimental
DMSO-d6):
d
10.17 (s, 1H, NH), 8.66 (d, 1H, J = 4.6 Hz, pyridine H),
98
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
Melting points of the compounds were determined on a XT-4
binocular microscope (Beijing Tech Instrument Co., China) and
were not corrected. 1 H NMR and 13 C NMR spectra were recorded
on JEOL-ECX-500 spectrometer. Chemical shifts were reported in
parts per million (ppm) down field from TMS with the solvent
resonance as internal standard. Coupling constants (J) were
reported in Hz and referred to apparent peak multiplications.
Mass spectral studies were conducted on an Agilent 5973 organic
mass spectrometer. Elemental analysis was performed using
Vario-III CHN analyser. IR spectra were recorded on a Bruker
VECTOR 22 spectrometer.
The synthesis route for title compounds 6a–6n, 7a, 7b and 8a–8f
is shown in Scheme 1. Intermediates 1 to 3 were prepared through
previously reported procedure using ethyl 4,4,4-trifluoro-3-oxobu-
tanoate [13–15]. Key intermediates 4 were prepared by cyclisation
reaction from 3 and 2-amino-5-chloro-3-methylbenzoic acid in the
presence of pyridine and methylsufonyl chloride [3]. Intermediates
5 were prepared by treating intermediates 4 with 80% hydrazine
hydrate according to the reported method [16].
8.46 (s, 1H, pyrazole H), 8.39 (d, 1H, J = 8.0 Hz, benzene H), 8.23 (d,
1H, J = 7.5 Hz, pyridine H), 7.82-7.79 (m, 1H, pyridine H), 7.53 (s,
1H, benzene H), 7.35 (s, 1H, NH), 3.99-3.93 (m, 1H, CH), 2.27 (s, 3H,
PhCH3), 1.08 (s, 3H, CH3), 1.07 (s, 3H, CH3); 13C NMR (125 MHz,
99
100
101
102
103
104
105
106
107
108
109
DMSO-d6):
132.6, 132.0, 131.7, 131.3, 128.6, 128.4, 126.0, 122.8, 120.8,
120.6,118.5, 41.4, 22.6, 18.2; IR (KBr, cm-1):
3244.2, 3066.8,
d 165.5, 158.8, 148.3, 147.9, 141.4, 140.9, 139.3, 137.4,
n
2974.2, 2931.8, 1662.6, 1635.6, 1558.4, 1506.4, 1436.9, 1157.2,
867.9; MS (ESI): m/z 500 [M+H]+, 522 [M+Na]+; Anal. Calcd
(C21H18Cl2F3N5O2): C, 50.41; H, 3.63; N, 14.00. Found: C, 50.25; H,
3.52; N, 13.87.
2.4. Insecticidal test
110
All bioassays were performed on test organisms reared in the
laboratory and repeated at 25W1 8C according to statistical
requirements. Mortalities were corrected using Abbott’s formula.
Evaluations were based on a percentage scale (0 = no activity and
100 = complete eradication) at intervals of 5% [17–22].
111
112
113
114
115
72
2.1. General procedure for preparation of 6a–6n
3. Results and discussion
116
117
73
74
75
76
77
Substituted amine was added into a solution of intermediate 4
(0.68 mmol) in 5 mL of acetonitrile. The mixture was stirred at
room temperature, and TLC was used to monitor the reaction.
Finally, pure compounds (6a–6n) were obtained by recrystallising
the crude products in ethanol.
3.1. Synthesis
As shown in Scheme 1, compound 4 is the key intermediate for
the synthesis of title compounds and was prepared by 3 and
2-amino-5-chloro-3-methylbenzoic acid in the presence of pyri-
dine and methylsufonyl chloride. An 89% yield could be obtained
with the temperature at -5 8C. Then the reaction of 4 with
substituted amines gave target compounds 6a–6n with yields of
47% to 93%. Compounds 7a and 7b were synthesised by refluxing 4
and 40% methyl hydrazine. Compounds 8a–8f containing the
acylhydrazone sub-structure were prepared via the reaction of
intermediate 5 and ketones, aldehydes or hemiacetal in ethanol,
with the yield ranging from 70% to 90%.
118
119
120
121
122
123
124
125
126
127
128
78
2.2. General procedure for preparation of 7a and 7b
79
80
81
82
83
84
A mixture of 40% methyl hydrazine (9.9 mmol) in THF (10 mL)
was added gradually into the solution of intermediate
(4.9 mmol), dissolved in THF (10 mL) and then stirred at room
temperature for 2 h. TLC was used to monitor the reaction. The
mixture was filtered and recrystallised in ethanol to obtain title
compounds 7a and 7b.
4
3.2. Insecticidal activity
129
85
2.3. General procedure for preparation of title compounds 8a–8f
Preliminary insecticidal activity of the title compounds against
five kinds of pests is shown in Table 1. Commercial insecticides
such as chlorantraniliprole, avermectin or hexaflumuron were
selected as positive controls. As indicated in Table 1, most of the
target compounds exhibited good insecticidal activities against
130
131
132
133
134
135
136
137
138
86
87
88
89
90
91
92
93
Different ketone and aldehyde (or hemiacetal) (1.5 mmol) was
added to a stirred solution of intermediate 5 (1.0 mmol) in 5 mL of
ethanol. The mixture was refluxed for 30 min, filtered and
recrystallised in a mixture of ethanol and DMF (1:1 in volume)
to obtain pure compounds 8a–8f.
Physical and spectroscopic characterisation data for title
compounds 6a–6n, 7a, 7b and 8a–8f can be found in Supporting
information, and the representative data for 6e are shown below.
P. xylostella at 500
avermectin under the same conditions, compounds 6a, 6b and 8a
showed 100% activity against P. xylostella at 200 g/mL. Similar to
hexaflumuron, all the tested compounds exhibited 100% activity at
mg/mL. Similar to chlorantraniliprole and
m
Please cite this article in press as: Z.-B. Wu, et al., Design, synthesis and insecticidal activities of novel 1-substituted-5-
(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.010

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Z.-B. Wu et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
3
Scheme 1. Synthesis route for compounds 6a–6n, 7a, 7b and 8a–8f.
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
10
6b, 6e and 6l exhibited 100% activity at 2
As shown in Table 1, compounds 6a, 6b, 6d, 6e and 6h exhibited
100% insecticidal activity against M. separate at 600 g/mL; similar
to chlorantraniliprole and avermectin under the same concentra-
tion, 6b and 6e also showed 100% activity at 200 g/mL. Most
compounds exhibited moderate activities against H. armigera and
O. nubilalis at 600 g/mL except for compound 6b, which showed
m
g/mL against C. pipiens pallens. Among the said compounds,
Compound 6e was selected to dock with RyRs (PDB: 5C30) to 157
elucidate differences between the designed compounds and 158
chlorantraniliprole activity [23]. As shown in Fig. 2, the results 159
revealed that the molecular configuration and action sites of 6e 160
evidently differed from chlorantraniliprole when the ‘‘amide 161
bond’’ linked to the pyrazole ring changed from the 5-position 162
to the 4-position. Chlorantraniliprole interacted with amino acid 163
residues, namely, Leu977 and Thr982 (Fig. 2a); conversely, for 6e, 164
the related amino acid residues are Arg1036, Leu977, and Arg1044 165
(Fig. 2b). For chlorantraniliprole, the distances of O atom of the 166
pyrazole carbonyl group in chlorantraniliprole to the N atom in 167
m
g/mL.
m
m
m
100% activity against O. nubilalis.
Analysis of preliminary structure–activity relationships (SAR)
of compounds 6c–6m and 6e–6l showed that insecticidal activity
slightly decreased when 2-chloropyridine was replaced by
phenyl on the 1-position of the pyrazole ring. For compounds
6b to 8b and 6i to 8f, target compounds containing amide at part B
exhibited improved activities than those containing acylhydra-
zone. Compounds 6b and 6e exhibited improved insecticidal
activities against the five kinds of pests than the other title
compounds.
˚
˚
Leu977 and the O atom in Thr982 were 2.79 A and 2.73 AA/, 168
respectively. For 6e, the distance between pyrazole 1-N atom in 6e 169
˚
to the N atom in Arg1036 was 2.95 A. The distances of O atom of 170
phenyl carbonyl group in 6e to the N atom in Leu977 and Arg1044 171
˚
˚
were 3.06 A and 2.76 A, respectively. The difference of action sites 172
with ligands may facilitate the development of novel insecticides 173
promoted by different binding mode with RyRs.
174
Please cite this article in press as: Z.-B. Wu, et al., Design, synthesis and insecticidal activities of novel 1-substituted-5-
(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.010

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Z.-B. Wu et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Table 1
Insecticidal activity of title compounds against five kinds of pests at different concentrations.
Compound
Insecticidal activity (%)
Mythimna separate
Plutella xylostella
g/mL)
Culex pipiens pallens
g/mL)
Heliothis armigera
g/mL)
Ostrinia nubilalis
(mg/mL)
(
m
(
m
(
mg/mL)
(
m
500
200
100
10
5
2
1
600
200
100
60
600
600
6a
100
100
85
100
100
70
80
85
45
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
10
/
100
100
70
60
/
75
60
80
70
85
7
60
100
40
45
65
55
75
25
25
30
80
60
65
5
6b
100
60
100
6c
/
/
/
/
/
/
/
/
6d
80
50
/
/
/
100
100
100
40
30
100
30
100
100
60
40
6e
100
100
45
80
65
70
30
100
40
6f
85
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
6g
/
40
60
30
20
40
35
30
30
0
6h
100
100
80
90
90
45
80
70
65
100
100
100
60
40
40
30
100
80
40
6i
/
/
/
/
/
/
/
/
6j
60
6k
100
30
65
60
6l
/
/
/
/
/
/
/
100
20
100
10
80
6m
30
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
25
6n
90
60
20
10
7a
0
/
60
45
30
40
50
50
7b
70
40
100
55
40
40
8a
100
80
70
50
/
/
8b
/
/
100
100
100
100
100
0
70
40
10
40
30
0
60
40
/
/
/
/
/
/
/
/
/
/
50
35
40
20
40
0
20
60
25
55
25
0
8c
55
/
8d
100
55
70
15
8e
/
/
/
/
50
8f
55
30
Blank
0
0
100
100
0
100
100
0
0
0
0
100
100
0
100
100
Chlorantraniliprole
Avermectin
Hexaflumuron
100
100
/
/
/
/
/
/
/
/
100
100
100
100
/
/
/
/
/
100
100
100
100
/
/
/
100
100
‘‘/’’ not test
Fig. 2. (a) Zoomed-in view of the interaction between chlorantraniliprole and amino acids from the active site of the ryanodine receptor (PDB: 5C30); (b) Zoomed-in view of
the interaction between 6e and amino acids from the active site of the ryanodine receptor (PDB: 5C30).
175
4. Conclusion
receptor amino acid residues. These results can be used for further
studies on new pesticide development.
191
192
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
A series of novel 5-(trifluoromethyl)-1H-pyrazole-4-carboxa-
mide derivatives (6a-6n, 7a, 7b, and 8a–8f) were designed and
synthesised via settling the amide bond at the 4-position of the
pyrazole ring. Preliminary bioassay results indicated that some
title compounds exhibited good activities against lepidopteran
pests, such as P. xylostella, M. separate, H. armigera, and O. nubilalis.
Furthermore, some title compounds exhibited broad-spectrum
insecticidal activities against dipterous insects, including C. pipiens
pallens, when the 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide
moiety was introduced into the skeleton structure of chloran-
traniliprole. Among title compounds, 6b and 6e showed 100%
insecticidal activity against P. xylostella, C. pipiens pallens, and M.
Acknowledgments
193
The authors acknowledge Professor Qingmin Wang, State Key
laboratory of Elemento-Organic Chemistry, Nankai University, for
his help during insecticidal activity bioassay. This work was
financially supported by the Key Technologies R&D Program (No.
2014BAD23B01), and National Natural Science Foundation of
China (Nos. 21202025, 21372052).
194
195
196
197
198
199
Appendix A. Supplementary data
200
separate at concentrations of 200, 2, and 200
m
g/mL, respectively.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.cclet.2016.06.
010.
201
202
203
Molecular docking with RyRs revealed that the title compounds
and chlorantraniliprole contain different acting sites with the
Please cite this article in press as: Z.-B. Wu, et al., Design, synthesis and insecticidal activities of novel 1-substituted-5-
(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.010

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Z.-B. Wu et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
5
[12] X.L. Zhang, B.L. Wang, M.Z. Mao, et al., Synthesis and insecticidal activity of 237
5-chloro-N-[4-chloro-2-(substituted carbamoyl)-6-methylpheyl]-1-ary-3-(tri- 238
fluoromethyl)-1H-pyrazole-4-carboxamide, Chem. J. China Univ. 34 (2013) 239
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Please cite this article in press as: Z.-B. Wu, et al., Design, synthesis and insecticidal activities of novel 1-substituted-5-
(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.010