Design, synthesis and insecticidal activities of novel anthranilic diamides containing fluorinated groups as potential ryanodine receptors activitors

Article abstract of DOI:10.1016/j.cclet.2017.01.019

In order to search for novel potent and environmentally benign insecticides, a series of anthranilic diamides containing various fluorinated groups were designed and synthesized. Their structures were confirmed by ¹H NMR, ¹³C NMR,

Full text of DOI:10.1016/j.cclet.2017.01.019

Accepted Manuscript
Title: Design, synthesis and insecticidal activities of novel
anthranilic diamides containing fluorinated groups as potential
ryanodine receptors activitors
Authors: Chang-Chun Wu, Bao-Lei Wang, Jing-Bo Liu, Wei
Wei, Yu-Xin Li, Yang Liu, Ming-Gui Chen, Li-Xia Xiong, Na
Yang, Zheng-Ming Li
PII:
S1001-8417(17)30042-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2017.01.019
CCLET 3968
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
8-10-2016
30-11-2016
17-1-2017
Please cite this article as: Chang-Chun Wu, Bao-Lei Wang, Jing-Bo Liu, Wei Wei,
Yu-Xin Li, Yang Liu, Ming-Gui Chen, Li-Xia Xiong, Na Yang, Zheng-Ming Li,
Design, synthesis and insecticidal activities of novel anthranilic diamides containing
fluorinated groups as potential ryanodine receptors activitors, Chinese Chemical Letters
http://dx.doi.org/10.1016/j.cclet.2017.01.019
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Original article
Design, synthesis and insecticidal activities of novel anthranilic diamides containing
fluorinated groups as potential ryanodine receptors activitors
Chang-Chun Wu, Bao-Lei Wang, Jing-Bo Liu, Wei Wei, Yu-Xin Li, Yang Liu, Ming-Gui Chen, Li-Xia
Xiong, Na Yang, Zheng-Ming Li*
State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University,
Tianjin 300071, China
*Corresponding author.
E-mail address: nkzml@vip.163.com (Z.-M. Li).
ARTICLE INFO
Article history:
Received 9 October 2016
Received in revised form 30 November 2016
Accepted 20 December 2016
Available online

Graphical Abstract
A series of anthranilic diamides containing various fluorinated groups were designed, synthesized and characterized. Their
insecticidal activities against oriental armyworm and diamondback moth were evaluated accordingly. The preliminary structure-
activity relationship (SAR) was also discussed.
ABSTRACT
In order to search for novel potent and environmentally benign insecticides, a series of anthranilic diamides containing various fluorinated groups were
designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, 19F NMR, elemental analysis, HRMS or mass spectra. Their
insecticidal activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) were evaluated. The preliminary
structure-activity relationship (SAR) was discussed in detail. The biological assay indicated that most of the compounds exhibited moderate to
excellent insecticidal activities. Especially, Ia showed high larvicidal activity against oriental armyworm. Meanwhile, Iu had better larvicidal effects
against diamondback moth than commercial chlorantraniliprole.
Keywords: Anthranilic diamides, Fluorinated moieties, Insecticidal activities , Structure-activity relationship
Synthesis
1. Introduction
It is known that compounds containing fluorine and fluorinated moieties play an important role in a variety of applied chemistry
areas, such as pharmaceutical chemistry, agrochemical chemistry, and material science [1-3]. Introducing fluorine atom or fluoroalkyl
group into molecules of drug candidates and synthesis of new drug candidates from highly reactive fluorinated building blocks are
frequently used strategies in drug discovery [4-5]. Many fluorine-containing compounds also exhibit a broad spectrum of bioactivities
in the field of pesticides, such as herbicidal [6], insecticidal [7], acaricidal, and fungicidal [8] activities. For example, the commercial
pesticides Etoxazole, Picoxystrobin, Flazasulfuron, Triflumuron, Vaniliprole [9] and Flubendiamide each contain the fluorinated
groups within their structures.
In the current agrochemical markets of China, some conventional insecticides such as methamidophos, dicofol, monocrotophos,
fipronil etc. have been prohibited due to their toxicity to mammals or damage to the proliferation of bees. To overcome the serious
ecological problems, the discovery of new potent insecticides with novel modes of action is an important task for effective pest
management. Anthranilic diamides insecticides (Fig. 1) were discovered by DuPont as highly potent activators of the insect ryanodine
receptors (RyRs) [10]. They can evoke massive calcium release from intracellular stores, disrupt calcium homeostasis, and cause the
final death of insects [11]. Since the discovery of anthranilic diamides, some structural modifications have been reported. Most of
modifications were related to the aliphatic amide moiety [12-13], the amide bridge moiety [14-15] and the N-pyridylpyrazole moiety
[16-17]. Nevertheless, the modification of the methyl, chlorine or cyano substituents on the phenyl ring part was seldom reported [18-
19]. Considering that fluorine atom was a good hydrogen bond acceptor, the introduction of fluorinated groups to certain insecticide
might increase the affinity of the parent compound to its receptors. On the basis of the above viewpoints, a series of novel anthranilic
diamide derivatives containing various fluorinated moieties in the phenyl part were designed and synthesized. Their insecticidal
activities against oriental armyworm and diamondback moth were tested accordingly. The preliminary structure-activity relationship
(SAR) was also summarized.
2. Results and discussion.
2.1. Synthesis and spectra characterization
As shown in Scheme 1, target compounds Ia-Ik and In-Iw were synthesized referring to the previous literature in moderate to good
1
yields [20]. Diamides Ij and Ik were oxidized with m-CPBA to give the target compounds Il and Im. In the H NMR spectra, the
active proton signals of the amide moieties Ph-NH-CO- and Ph-CO-NH- were observed at δ 10.53 - 13.24 and 8.45 - 9.37 in DMSO-d6,

respectively. In the 19F NMR spectra, the signals of fluorine atoms in CF3, CF3O, and CF3S groups appeared as singlet at -62.18 - -
58.27ppm, -56.78 - -56.75ppm and -42.34 - -41.49 ppm, respectively.
2.2. Structure-activity relationship (SAR)
Larvicidal activity against oriental armyworm: The larvicidal activities of target compounds Ia-Iw and chlorantraniliprole against
oriental armyworm were summarized in Table 1. The biological assay indicated that most of the title compounds had significant
larvicidal activities against oriental armyworm. For example, Ia, Ib, Id, Ih and Ii exhibited 90%, 60%, 60%, 60% and 50% lethal rates
at 1.0 mg/L, respectively. In particular, Ia showed 43% larvicidal activity against oriental armyworm at 0.2 mg/L, which was slightly
lower than that of the commercial chlorantraniliprole (0.2 mg/L, 60%).
To explore the effect of the substituent groups in the ortho-position of the amide moiety on the larvicidal activities, compounds Ia
(R = 2-CF3, 4-Cl), Ie (R = 2-H, 4-Cl), and Ii (R = 2-OCF3, 4-Cl) were tested for their insecticidal activities. The results indicated that
the sequence of the larvicidal activity was CF3 (Ia) > CF3O (Ii) > H (Ie). The R1 groups in the pyrazole ring had little influence on the
larvicidal activity. The sequence of the larvicidal activity was generally Br > Cl (Ia > Ib, Id > Ic, In > Io, Iu > Iv). On the other hand,
the larvicidal activities of compounds with CF3 group at the C-3' position were generally near to those of the brominated pyrazole
diamides (Ij, Ik, Il, Im, Ip, Iq, It, Is). However, the brominated pyrazole diamides Iu showed higher insecticidal activity than that of
the corresponding trifluoromethyl-substituted diamide Iw. In addition, when R1 was fixed as Br, the bioactivity of compounds Ie, Ik,
Im, Is revealed the trend of 4-Cl > 4-SCF3 > 4-SCH3, 4-SO2CH3. These observations clearly showed that the substituent Cl at the C-4
position of benzene ring was a key pharmacophore for the maintenance of insecticidal activity. Compounds In-Ir with the fluorinated
substituents at the C-3 position exhibited very low activities at 10 mg/L. These results indicated that getting rid of the substituent
groups at the C-2 position of phenyl ring had a negative effect on the larvicidal activity. The LC50 value of Ia was 0.2241 mg/L, higher
than that of chlorantraniliprole (0.0664 mg/L, Table 2), which was in accordance with the corresponding results in Table 1.
Larvicidal activity against diamondback moth: Some representative compounds with moderate to high larvicidal activities against
oriental armyworm were further investigated. From Table 3, it was found that the tested compounds generally showed moderate to
excellent insecticidal activities against diamondback moth. Especially, If exhibited 100% and 40% larvicidal activities at 1 and 0.1
mg/L, respectively. It was worthy of note that Iu showed a 70% lethal rate at 0.01 mg/L against diamondback moth, slightly higher
than that of chlorantraniliprole (65%, 0.01 mg/L). These results revealed that the substituents at the C-2 and C-4 positions of the phenyl
ring part had an important influence on the bioactivities. The LC50 value of Iu was 0.0053 mg/L, lower than that of chlorantraniliprole
(0.0334 mg/L, Table 4), which indicated that Iu was more effective than commercial chlorantraniliprole against diamondback moth.
3. Conclusion
In summary, 23 novel fluorinated anthranilic diamide analogues were designed, synthesized, and evaluated against oriental
armyworm and diamondback moth for their insecticidal activities. The preliminary bioassay indicated that some of them exhibited
favorable larvicidal activities. In particular, Ia showed 43% larvicidal activity against oriental armywarm at 0.2 mg/L, with the LC50
value of 0.2241 mg/L. Moreover, Iu displayed 70% larvicidal activity against diamondback moth at 0.01 mg/L, higher than that of
chlorantraniliprole. The present work demonstrated that compounds Ia and Iu could be used as novel lead structures for the
development of new insecticides.
4. Experimental
4.1. Synthetic procedures
Commercial chlorantraniliprole was synthesized according to procedures in the literature [20]. N-Pyridylpyrazole carboxylic acids
16a-16c were synthesized from the starting materials 3-chloro-2-hydrazinylpyridine [21] and 2-acetylfuran [14] referring to our
previous work. Detailed synthetic procedures and spectral data for title compounds Ia-Iw and intermediates 5a-5k were given in the
Supporting information.
4.2. Biological assay
All biological assays were performed on test organisms reared in a greenhouse. 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. Error of the experiments was 5%. LC50 values were calculated by probit analysis [16]. The larvicidal activity of title
compounds Ia-Iw against oriental armyworm (M. separata) was tested according to the leaf-dip method using the reported procedure
[21]. The larvicidal activity of some representative title compounds against diamondback moth (P. xylostella) was tested according to
the reported leaf-dip method [14]. For comparative purposes, commercial chlorantraniliprole was tested as positive control under the
same conditions.
Acknowledgment
This work was financially supported by the National Natural Science Foundation of China (No. 21372133), 973 Program (No.
2010CB126106), and “111” Project of Ministry of Education of China (No. B06005).

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Fig. 1. Design of the title compounds
Scheme 1. Synthetic route of title compounds Ia-Iw

Table 1 Insecticidal activities of compounds Ia-Iw and chlorantraniliprole against oriental armyworm
larvicidal activity (%) at a concentration of (mg/L)
Compd.
R
R1
200
100
100
100
10
5
2
1
0.5
75
0.2
43
Ia
Ib
Ic
Id
Ie
If
2-CF3, 4-Cl
2-CF3, 4-Cl
2-CF3, 4-Br
2-CF3, 4-Br
4-Cl
Br
Cl
Cl
Br
Br
100
100
100
90
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
100
100
100
100
100
100
100
100
10
100
100
100
80
80
50
80
40
20
60
80
60
60
30
60
30
40
20
40
20
2-OCF3, 4-Br Br
2-OCF3, 4-Br Cl
2-OCF3, 4-Cl Cl
2-OCF3, 4-Cl Br
60
Ig
Ih
Ii
80
40
60
50
20
40
40
100
80
20
Ij
4-SCH3
4-SCH3
4-SO2CH3
4-SO2CH3
3-F, 4-F
3-F, 4-F
3-CF3
CF3
Ik
Il
Br
100
80
40
CF3
Br
30
Im
In
Io
Ip
Iq
Ir
Is
70
20
Br
100
90
40
30
30
Cl
30
CF3
Br
100
90
50
3-CF3
20
3-CF3, 4-I
4-SCF3
Br
40
Br
100
100
100
60
30
40
80
20
20
40
It
4-SCF3
CF3
Br
60
Iu
2-Cl, 4-SCF3
100
20
Iv
2-Cl, 4-SCF3
2-Cl, 4-SCF3
Cl
100
100
100
100
100
100
60
20
Iw
CF3
60
20
Chlorantraniliprole
100
100
100
100
100
60
Table 2 LC50 values of compound Ia and chlorantraniliprole against oriental armyworm
Compd.
Ia
chlorantraniliprole
y = a + bx
y = 6.2847 + 1.9779x
y = 7.8167 + 2.3918x
R
LC50 (mg/L)
0.2241
0.0664
0.9923
0.9831

Table 3 Insecticidal activities of compounds Ia-Ig, Ii, Iu, Iw and chlorantraniliprole against diamondback moth
larvicidal activity (%) at a concentration of (mg/L)
Compd.
100
100
100
100
100
100
100
100
100
100
100
50
25
10
1
0.1
20
35
0.01
Ia
Ib
Ic
Id
Ie
If
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
85
90
60
50
85
100
80
70
100
70
100
20
40
10
30
90
30
90
Ig
Ii
Iu
Iw
70
65
chlorantraniliprole 100
Table 4 LC50 values of compound Iu and chlorantraniliprole against diamondback moth
Compd.
y = a + bx
R
LC50 (mg/L)
0.0053
0.0334
Iu
y = 8.5328 + 1.5517x
y = 8.9661 + 2.6871x
0.9381
0.9463
chlorantraniliprole