Synthesis and Insecticidal Evaluation of Novel Anthranilic Diamides Derivatives Containing 4-Chlorine Substituted N-Pyridylpyrazole

Article abstract of DOI:10.1002/cjoc.202000013

To search for potent insecticides targeting at ryanodine receptors (RyRs), a series of novel anthranilic diamides analogs containing 4-chlorine N-pyridylpyrazole were designed and synthesized. Their insecticidal activities were evaluated and the preliminary structure-activity relationships (SARs) were discussed. The insecticidal results showed that some of the compounds (8a—8h, 8m, 8n) exhibited good larvicidal activities against oriental armyworm at 2.5 mg·L^–1, and compound 8m possessed 60% insecticidal activity at 0.5 mg·L^–1. For diamondback moth, 8m exhibited better activity than Chlorantraniliprole at a hundred fold preference. The calcium imaging technique experiment results suggested that compound 8m could increase the intracellular [Ca²⁺]_i. With the neurons preincubated experiment, the results confirmed that the target of this series of compounds could be RyRs in the central larvae neurons of oriental armyworm. The results indicated that compound 8m could respond as a potential modulator of the insect ryanodine receptor.

Full text of DOI:10.1002/cjoc.202000013

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Synthesis and Insecticidal Evaluation of Novel Anthranilic Diamides
Derivatives Containing 4-Chlorine Substituted N-Pyridylpyrazole
Authors: Huangong Li, Yangyang Zhao, Pengwei Sun, Li Gao, Yuxin Li, Lixia Xiong ,
Na Yang, Sha Zhou* and Zhengming Li*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000013.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000013.
ISSN 1001-604X • CN 31-1547/O6
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Chinese Journal
of Chemistry
synthesis design, anthranilic diamides, insecticidal activity, RyRs,
Structure–activity relationships
Report
CJC
中
国 化 学 - An International Journal
Synthesis and Insecticidal Evaluation of Novel Anthranilic Diamides
Derivatives Containing 4-Chlorine Substituted N-Pyridylpyrazole
Huangong Li , Yangyang Zhao , Pengwei Sun, Li Gao, Yuxin Li, Lixia Xiong , Na Yang, Sha Zhou* and Zhengming Li *
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Cite this paper: Chin. J. Chem. 2020, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion To search for potent insecticides targeting at ryanodine receptors (RyRs), a series of novel anthranilic
diamides analogs containing 4-chlorine N-pyridylpyrazole were designed and synthesized. Their insecticidal activities were evaluated and the preliminary
structure-activity relationships (SARs) were discussed. The insecticidal results showed that some of the compounds（8a-8h,8m,8n）exhibited good larvicidal
activities against oriental armyworm at 2.5 mg·L-1 , and compound 8m possessed 60 % insecticidal activity at 0.5 mg·L-1. For diamondback moth, 8m
exhibited better activity than Chlorantraniliprole at a hundred fold preference. The calcium imaging technique experiment results suggested that compound
8m could increase the intracellular [Ca2+]i, and with the neurons preincubated experiment, the results confirmed that the target of this series of compounds
could be RyRs in the central larvae neurons of oriental armyworm. The results indicated that compound 8m could respond as a potential modulator of the
insect ryanodine receptor.
modifications were mainly aimed at the following three parts: the
Background and Originality Content
aliphatic amide moiety 1,[11-14]] the amide bridge moiety 2[15-18] and
The frequent application of traditional insecticides has
generated growing concern over a series of problems, such as
resistance,[1] environmental pollution and health risks.[2] To tackle
these problems, there is an urgent requirement to develop broad-
spectra and ultra efficient insecticidal compounds for pest
managements which could guarantee natural and harmonious
development.[3] It was reported that pyrazole-related
compounds[4,5] played a critical role in the pesticide field. And as
the representative of pyrazole-related compounds, diamide
insecticides, act selectively on insect ryanodine receptors,[6-8]
leading to the intermittent release of Ca2+ and finally causing
insects starving to death, such as Chlorantraniliprole (Fig. 1, A) and
Cyantraniliprole,[9,10] (Fig. 1, B). Therefore, it is regarded as a
promising target for ryanodine receptors in the design of
environment-friendly pesticides in the future.
the N-pyridylpyrazole moiety 3.[19-23] (Fig 2, C)
It is well
acknowledged that the introduction of halogens into molecule has
been regarded as the effective method for pesticide designs due to
their chemical and biological characteristics.[24,25] For example, Xu
et al. reported that 3,4-dihalopyrazole amide structure possessed
a slightly higher insecticidal activity against diamondback moth
than Chlorantraniliprole,[26] indicating that the 4-position of
pyrazole moiety substituted with chlorine group could improve the
bioactivity against diamondback moth. Tetrachlorantraniliprole
(SYP-9080), a novel anthranilic diamides insecticide, were launched
in 2014 which had extra chlorine substituted in the benzene ring.[27]
Besides, some molecules bearing fluorine and fluorinated
functional groups have been widely applied in pharmaceutical and
agrochemical chemistry.[28,29] The introduction of trifluoromethyl
substituent is often considered as an efficient strategy in the design
of bioactive chemicals owing to great changes in their
physicochemical and biological properties, such as enhancement of
binding affinity, lipophilicity and so on.[30-32] For example,
penthiopyrad,[33] as a novel fungicide, has a positive effect on the
botrytis cinereal and powdery mildew, in addition to basidiomycete.
Celecoxib[34] acts as an anti-inflammatory as well as antibacterial
agent. Given the above facts, trifluoromethyl and chlorine group
were brought into the pyrazole moiety to develop highly effective
pesticides.
Br
N
Br
N
O
O
N
N
Cl
Cl
NH
NH
N
N
O
O
Cl
NC
HN
HN
A
B
Chlorantraniliprole
Cyantraniliprole
In this paper, a series of novel 3-(trifluoromethyl)-1H-pyrazole-5-
carboxamide derivatives (Figure 2, 8a-8n) were synthesized with
the chlorine at the 4-position and their insecticidal activities were
evaluated. Meanwhile, the preliminary structure-activity
relationships (SARs) was explored, and the mode of action was
Figure 1. The structure of Chlorantraniliprole and Cyantraniliprole
Many research groups have devoted considerable efforts to a
number of structural modifications since the introduction of
diamide insecticides into the world market to date. Most of the
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differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000013
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Novel Anthranilic Diamides Derivatives Containing 4-Chlorine Substituted N-Pyridylpyrazole
Chin. J. Chem.
conducted.
CF3
NH2
Cl
Cl
HN
N
N
O
N
Cl
.
KMnO4
Cl
NH2NH2 H2O
1c
N
N
Br
N
1
Acetone:H2O=1:1
EtOH
AcOH, 110
3
℃
HN
O
R3
R3
H
N
R3=H or
R3
Cl
N
Cl
2a, 2b
3a, 3b
Cl
4a, 4b
O
N
R
2
CF3
CF3
C
HO
N
structures
N
Chemical
of
HO
NaClO
AcOH
DMF
,
N
1) (COCl)2
N
anthranilic diamides.
O
Cl
Cl
O
N,
2) N-diisopropylethylamine
N
N
NH2 O
R1
HN
Br
N
CF3
N
HN
O
NH
R1
R3
5a, 5b
R3
X
Cl
O
O
Cl
O
H
HN
X=Cl,Br
N
H
N
6a, 6b
H
N
R2
N
N
Cl
N
N
CF3
to
7a 7f
O
Cl
Cl
N
Cl
R
8a, R1 Me, R =Cl, R
8b, R1 Et, R2=Cl, R
Cl 8c, R1 i-Pr, R
8i, R1 Me, R =Cl, R =Cl
2
2
3
3=H
=
R2
.
=
O
N
N
R
N
R1 Et, R2=Cl, R3=Cl
=
3=H
3=H
=
O
8j,
N
D
E
8a-8n
work
2
2
=
=
R3
=Cl,
R
8k, R1 i-Pr, R
=Cl, =Cl
R3
NH
This
8d, R1
R2=Cl, R
3=H
=
3=H
8l, R1
N
cyclopropyl,
2
R2=Cl, R3=Cl,
R2=Cl, R3=H,
3=H
=
=
O
8e, R1 Me, R =Br, R
cyclopropyl,
R2
R2=Br or
8f, R1 Et, R2=Br, R
R1 i-Pr, R =Br, R
=
3=H
3=H
8m, R1 -CH2CF
Figure 2. Design of the title compounds
=
R3
2H,
,
HN
Cl
2
R1
R1
R2
=
=
8n,
-CH2CF3
=Cl,
R
8g,
8h, R1
R2=Br, R
=
3=H
cyclopropyl,
to
8a 8n
Results and Discussion
Synthesis
Scheme 2. Synthesis of compounds 8a-8n
From Scheme 1, compound 1c was synthesized by the
condensation
of
ethyl
trifluoroacetate(1a)
with
2-
Structure-activity relationship (SAR)
acetylfuran(1b).[35] The synthetic route for the title compounds 8a–
8n was shown in Scheme 2.[36-38] The final products were prepared
by a simple and convenient method, provoking the substitution
reaction of 2, 3-dichloropyridine with hydrazinium hydroxide to get
3a. By treating the intermediate 3a and compound 1c in acetic acid
compound 4a was prepared, which was used directly into the next
step to gain the key intermediate 5a. Compound 5a was added to
NaClO in AcOH with the reported method in previous literature [39]
to yield 6a. The title compounds were obtained by the
condensation reaction of compounds 6a(6b) with7a-7f.[40]
Larvicidal activity against Mythimna separata (M. separata)
The oriental armyworm, M. separata, is an economically
important and common Lepidopteran pest of cereal crops. The
larvicidal activities of target compounds 8a-8n and
Chlorantraniliprole against M. separata were shown in Table 1. The
results indicated that most of the title compounds exhibited good
insecticidal activity (100 %) at 2.5 mg·L-1. When the concentration
was reduced to 1 mg·L-1, compounds 8a, 8b, 8c and 8h showed
similar lethal rates–80 %, 85 %, 80 % and 80 %, respectively. It was
noted that compound 8m still had 100% larvicidal activity at 1 mg·L-
1. Furthermore, compound 8m possessed inhibitive capacity (60 %
pesticidal activity) at 0.5 mg·L-1.
O
O
O
O
O
Et
EtONa, 2O
ONa
CF3
+
F
3C
O
As seen from different alkyl groups in R1 from Table 1, the
sequence on larvicidal activity was CH2CF2H > Et ≈ i-Pr ≈ cyclopropyl
≈ Me. The activity of compound 8m with fluorine atom in R1 group
was increased compared with title compound 8b. It was speculated
that R1 group containing fluorinated substituents could be essential
for the improvement of the larvicidal activity. Compounds 8a-8d
(8e-8f) had similar activities, which indicated that electronic effects
of different groups at R1 site had little influence on the insecticidal
activity. To explore the effect of the R2 group in the benzene on
the pesticidal activities, compounds 8a, 8b, 8e and 8f were
synthesized and evaluated for their insecticidal activity. The
bioassay results manifested that the general sequence of the
larvicidal activity was Cl ≈ Br (8a vs 8e, 8b vs 8f, 8c vs 8g, 8d vs 8h).
The investigation of Cl group in R3 site impact on the larvicidal
activity was also conducted. The bioactivities of compounds 8i-8l
declined sharply in comparison with the corresponding compounds
8a-d (8a vs 8i, 8b vs 8j, 8c vs 8k, 8d vs 8l). These observations
revealed that R3 groups in the pyridine ring could have an
important influence on the larvicidal activity, which was speculated
that the introduction of Cl group might decrease insecticidal
1a
1c
1b
Scheme 1. Synthesis of compound 1c
Initially, when sulfuryl chloride (SO2Cl2) was used, the desired
compound 6 could not be obtained. It was postulated that the
heterocyclic ring of 3-(trifluoromethyl)-1H-pyrazole was lack of
electrons, which resulted in the failure of the attack of chloride
cation. Later, by using the sodium hypochlorite in AcOH, compound
6 was gained with good yields.
In the 1H NMR spectra, the active proton signals of the amide
moieties Ph-NH-CO- were observed at δ 10.49-10.55 in DMSO-d6
and δ 9.95-9.99 in CDCl3 and -Ph-CONH- at δ 8.29-8.56 in DMSO-d6
and δ 8.46 in CDCl3. In the 13C NMR spectra, the signals of
trifluoromethyl group appeared approximately at 120 ppm with
quartet.
Chin. J. Chem. 2020, 37, XXX－XXX© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimwww.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Novel Anthranilic Diamides Derivatives Containing 4-Chlorine Substituted N-Pyridylpyrazole
Chin. J. Chem.
bioactivity with the steric hindrance.
excellent insecticidal activities. When the concentration of the
tested compounds was at 0.01 mg·L-1, the title compounds 8a, 8c,
8e, 8m and 8n had similar larvicidal activities, equal to that of
Chlorantraniliprole. Moreover, compound 8a and 8m possessed 95 %
and 100 % bioassay activity at 5×10-4 mg·L-1, respectively, indicating
that their bioactivities were comparable to that of
Chlorantraniliprole. It was observed that 8m still gave a death rate
of 80 % at the lower concentration of 5×10-6 mg·L-1, which
surpassed that of Chlorantraniliprole.
In Table 3, the LC50 value of 8m was 0.3360 mg·L-1, which
indicated that the larvicidal activity of 8m was slightly lower than
that of Chlorantraniliprole(0.1254 mg·L-1).
Table 1. Insecticidal activities of title compounds 8a-8n and
Chlorantraniliprole against M. separata
larvicidal activity (%) at conc. (mg·L-1)
When the R3 group was H, the general insecticidal trend was Cl >
Br (8a vs 8e, 8b vs 8f, 8c vs 8g, 8d vs 8h). From table 2, it was found
that the activity of compound 8m was higher than that of 8b when
the R2 and R3 was fixed. In Table 4, the LC50 values of 8a and 8m
against P. xylostella correspondingly were 1.8×10-5 mg·L-1 and
3.7×10-6 mg·L-1, lower than that of Chlorantraniliprole (LC50, 1.0×10-
4 mg·L-1), implying that the larvicidal activity of the two compounds
surpassed the bioactivity of Chlorantraniliprole.
For the P. xylostella, the pesticidal activity of compound 8i-8l
declined obviously compared with compound 8a-8d at 2 mg·L-1,
and it was hypothesized that the introduction of the Cl group in the
pyridine could probably decrease the electron density of the
pyridine ring, causing a poor binding at the RyRs. When the R2 site
was substituted by Br or Cl group, the bioactivity results were
similar, which demonstrated that the electronic effects on the
improvement of bioactivity was slight.
Compd.
25
10
5
2.5
1
0.5
8a
8b
8c
8d
8e
8f
100 100
100 100
100 100
100 100
100 100
100 100
100 100
100 100
60
100 100
100 100
100 100
100 100
100 100
100 100
100 100
100 100
80
85
80
50
50
65
75
80
8g
8h
8i
8j
100 100
100 100
100
100
8k
8l
100
30
8m
8n
100 100
100 100
100 100
100 100
100
45
60
Table 3. LC50 values of compound 8m and chlorantraniliprole against M.
separata
Control
100 100
100 100
100 100
Compd.
8m
chlorantraniliprole
y = a + bx
y=6.3521+2.8547x
y=8.1189+3.4587x
R
LC50(mg/L)
0.3360
0.1254
Control= Chlorantraniliprole.
0.9844
0.9655
Table 2. Insecticidal activities of title compounds 8a-8n and
Chlorantraniliprole against P. xylostella
Table 4. LC50 values of compound 8a, 8m and chlorantraniliprole against P.
xylostella
larvicidal activity (%) at conc. (mg·L-1)
Compd.
10-2
100
10-3
100
5×10-4
95
5×10-5
82
5×10-6
40
Compd.
8a
8m
Chlorantra-
niliprole
y = a + bx
R
LC50(mg/L)
1.8×10-5
3.7×10-6
1.0×10-4
2
0.1
y = 12.8964 + 1.6597x
y = 14.0628 + 1.6694x
y = 11.2915 + 1.5391x
0.9911
0.9895
0.9673
8a
8b
8c
8d
8e
8f
100
90
100
100
90
100
100
94
100
100
85
88
97
70
70
85
43
100
90
Mode of action
To explore the mechanism of the title compounds, we studied
the impact of compound 8m on the free Ca2+ concentration in the
central neurons of third larva of M. separata. Figure 3 presented
the elevation of [Ca2+]i versus recording time when the fluorescent
loaded central neurons were treated with compound 8m. No
obvious change was observed for [Ca2+]i in the cytoplasmic of
central neurons after applying 8m at 0.5 ppm. However, when the
terminal concentration of 8m was increased from 0.5 ppm to 5 ppm,
[Ca2+]i in the cytoplasmic domain increased to 103.65 ± 1.46 (n =
13), and these results indicated that the change elevation of [Ca2+]i
was in a concentration dependent manner(Figure 3A). Further
experiments were also carried out to test the target. After the
neurons were preincubated with 1µM Ryanodine about 5min, the
[Ca2+]i in the cytoplasmic kept being released for a long time (n=7)
(Figure 3B). The results strongly suggested that the target of
compound 8m could be RyR in the test insect.
8g
8h
8i
100
90
70
8j
70
8k
8l
100
30
8m
8n
100
100
100
100
100
100
100
90
100
80
100
80
Control
100
100
100
95
75
Control= Chlorantraniliprole
Larvicidal activity against Plutella xylostella (P. xylostella)
To better study the insecticidal spectrums of these compounds,
the larvicidal results of title compounds(8a-8n) for P. xylostella
were summarized in Table 2. Some of the compounds exhibited
Chin. J. Chem. 2020, 37, XXX－XXX© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimwww.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Novel Anthranilic Diamides Derivatives Containing 4-Chlorine Substituted N-Pyridylpyrazole
Chin. J. Chem.
Biological Assay
All the title compounds were tested at organism reared in the
laboratory and the tested insects were cultured in accordance with
the literature.[41] The bioassay was replicated at 25 ±1 °C according
to statistical requirements. Assessments were made on a
dead/alive basis and mortality rates were corrected by applying
Abbott’s formula.[42] Evaluation standard was based on a
percentage scale of 0-100, in which 0 has no activity and 100 equals
total kill.
Figure 3. Effects of 8m on [Ca2+]i in the central neurons of M. separata,
the central neurons of M. separata were dyed by loading with fluo-3 AM
Larvicidal activity against oriental armyworm
The insecticidal activity of compounds 8a–8n and
Chlorantraniliprole against oriental armyworm was conducted
according to the leaf-dip method by referring to the reported
method.[43] The summarized larvicidal activity was shown in Table
1.
Conclusions
In summary, 14 novel pyrazole-4-chlorine anthranilic diamide
analogues were designed, synthesized and their insecticidal
activities were evaluated against M. separata and P. xylostellla.
Some title compounds showed good to remarkable activity against
M. separata and P. xylostellla. It was noteworthy that 8a and 8m
exhibited 40 % and 80 % larvicidal activity against P. xylostellla at
5×10-6 m·L-1 respectively and the LC50 of 8a and 8m for P. xylostellla
were correspondingly were 1.8×10-5 mg·L-1 and 3.7×10-6 mg·L-1,
which were much more active than Chlorantraniliprole （ LC50,
1.0×10-4 mg·L-1）. The calcium imaging technique experimental
results demonstrated that the title compound 8m could effectively
modulate the insect calcium channel indeed in M. separata,
implying that the modified compounds were the potent activators
of the RyRs. It is believed that the preliminary results will provide
useful information for further design of new RyRs activators in
insecticidal research.
Larvicidal activity against diamondback moth
The insecticidal activity of compounds 8a-8n and
Chlotantraniliprole was tested by the leaf-dip method according to
the reported method.[44] The larvicidal activity was summarized in
Table 2.
Calcium Imaging
The mechanism of title compounds was investigated referring to
the previous articles.[45] Fluorescence values were expressed as
F/F0, where F0 meant the resting (or baseline) fluorescence and
represented the change in fluorescence after the application of
drug.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Experimental
Instruments and Materials.
Acknowledgement
1H and 13C nuclear magnetic resonance (NMR) spectra were
recorded at 400 MHz using a Bruker AV 400 spectrometer (Bruker
Co., Switzerland) in CDCl3 (Heowns, Tianjin, China) or DMSO-d6 (J&K
Scientific, China) solution with tetramethylsilane as the internal
standard, and chemical shift values were given in parts per million
(ppm). The melting points were determined on an X-4 binocular
microscope melting point apparatus (Beijing TechInstrument Co.,
Beijing, China) and the temperature were uncorrected. Analytical
thin layer chromatography was performed on silica gel GF254. Flash
chromatography was performed with silica gel (200-300 mesh)
(Energy Chemical, Shanghai, China). High-resolution mass
spectrometry (HRMS) dates were obtained on a Varian QFT-ESI
instrument.
The project was supported by National Key Research Program-
The Innovation of Eco-Modulator of Insect Ryanodine Receptor
(2018YFD0200100, 2017YFD0200505), the National Natural
Science Foundation of China (No 31972287 21602118).
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Novel Anthranilic Diamides Derivatives Containing 4-Chlorine Substituted N-Pyridylpyrazole
Chin. J. Chem.
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Novel Anthranilic Diamides Derivatives Containing 4-Chlorine Substituted N-Pyridylpyrazole
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Page No.6
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For diamondback moth, 8m exhibited better activity than Chlorantraniliprole at a hundred fold
preference. The calcium imaging technique experiment results suggested that compound 8m could
increase the intracellular [Ca2+]i and further experiments confirmed that the target of this series of
compounds could be RyRs in the central larvae neurons of oriental armyworm.
Huangong Li , Yangyang Zhao , Pengwei Sun, Li
Gao, Yuxin Li, Lixia Xiong , Na Yang, Sha Zhou*
and Zhengming Li *
Chin. J. Chem. 2020, 37, XXX－XXX© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimwww.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.