Novel Anthranilic Diamide Scaffolds Containing N-Substituted Phenylpyrazole as Potential Ryanodine Receptor Activators

Article abstract of DOI:10.1021/acs.jafc.6b00380

To discover potent insecticides targeting ryanodine receptors (RyRs), a series of novel anthranilic diamides analogues (12a-12u) containing N-substituted phenylpyrazole were designed and synthesized. These compounds were characterized by ¹H NMR, ¹³C NMR, and HRMS, and the structure of compound 12u was confirmed by X-ray diffraction. Their insecticidal activities indicated that these compounds displayed moderate to excellent activities. In particular, 12i showed 100 and 37% larvicidal activities against oriental armyworm (Mythimna separata) at 0.25 and 0.05 mg L^-1, equivalent to that of chlorantraniliprole (100%, 0.25 mg L^-1; and 33%, 0.05 mg L^-1). The activity of 12i against diamondback moth (Plutella xylostella) was 95% at 0.05 mg L^-1, whereas the control was 100% at 0.05 mg L^-1. The calcium-imaging technique experiment results showed that the effects of 12i on the intracellular calcium ion concentration ([Ca²⁺]_i) in neurons were concentration-dependent. After the central neurons of Helicoverpa armigera were dyed by loading with fluo-5N and treated with 12i, the free calcium released in endoplasmic reticulum indicated the target of compound 12i is RyRs or IP₃Rs. The activation of RyRs by natural ryanodine completely blocked the calcium release induced by 12i, which indicated that RyRs in the central neurons of H. armigera third-instar larvae is the possible target of compound 12i.

Full text of DOI:10.1021/acs.jafc.6b00380

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Article
Novel Anthranilic Diamides Scaffolds Containing N-Substituted
Phenylpyrazole as Potential Ryanodine Receptor Activators
Jingbo Liu, Yuxin Li, xiulan zhang, Xue-Wen Hua, Changchun Wu, Wei Wei, Yingying
Wan, Dandan Cheng, Lixia Xiong, Na Yang, Haibin Song, and Zheng-Ming Li
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.6b00380 • Publication Date (Web): 24 Apr 2016
Downloaded from http://pubs.acs.org on April 27, 2016
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Journal of Agricultural and Food Chemistry
Novel Anthranilic Diamides Scaffolds Containing N-Substituted
Phenylpyrazole as Potential Ryanodine Receptor Activators
Jing-Bo Liu, Yu-Xin Li*, Xiu-Lan Zhang, Xue-Wen Hua, Chang-Chun Wu, Wei Wei, Ying-Ying Wan,
Dan-Dan Cheng, Li-Xia Xiong, Na Yang, Hai-Bin Song, Zheng-Ming Li*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai
University, Tianjin 300071, China
*Corresponding Author: Zheng-Ming Li (nkzml@vip.163.com, Tel.: 0086-22-23503732, Fax: 0086-
22-23505948.); Yu-Xin Li (liyx128@nankai.edu.cn, Tel.: 0086-22-23503798)
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ABSTRACT: In order to discover potent insecticides targeting at ryanodine receptors (RyRs), a
series of novel anthranilic diamides analogs (12a-u) containing N-substituted phenylpyrazole were
designed and synthesized. These compounds were characterized by 1H NMR, 13C NMR and HRMS,
and the structure of compound 12u was confirmed by X-ray diffraction. Their insecticidal activities
indicated that these compounds displayed moderate to excellent activities. In particular, 12i showed
100% and 37% larvicidal activities against oriental armyworm (Mythimna separata) at 0.25 and 0.05
mg L−1, equivalent to that of chlorantraniliprole (100%, 0.25 mg L-1and 33 %, 0.05 mg L-1). The
activity of 12i against diamondback moth (Plutella xylostella) was 95% at 0.05 mg L−1, while the
control was 100% at 0.05 mg L−1. The calcium-imaging technique experiment results showed that
the effects of 12i on the intracellular calcium ion concentration ([Ca2+]i) in neurons were
concentration-dependent. After the central neurons of Helicoverpa Armigera were dyed by loading
with fluo-5N and treated with 12i, the free calcium released in endoplasmic reticulum indicated the
target of compound 12i is RyRs or IP3Rs. The activation of the RyRs by natural ryanodine
completely blocked the calcium release induced by 12i, which indicated that RyRs in the central
neurons of Helicoverpa Armigera third-instar larvae is the possible target of compound 12i.
Keywords: Insectical activity, N-substituted phenylpyrazole, Nitro, Chlorine, Calcium channel
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INTRODUCTION
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The increasing resistance to insecticides has been a major factor in insect control and pest
management due to the frequent and widespread use of conventional pesticides with the same mode
of action.1-3 Therefore, to cope with the issue of pest resistance discovering novel potent insecticides
with a new mode of action has become an urgent task for scientists. In recent years,
chlorantraniliprole (Figure 1A),4 the first commercial anthranilic diamide insecticide discovered by
Dupont, has been proved to bind selectively to insect ryanodine receptor and the binding mode of
action is different from that of other traditional insecticides. It causes unregulated release of internal
calcium stores leading to Ca2+ deletion, feeding cessation, lethargy, muscle paralysis, and ultimately
death of insect.5 Chlorantraniliprole has opened a new era of synthetic insecticides and the insect
ryanodine receptor has been considered as one of the key targets to discover novel insecticides.
Chlorantraniliprole has aroused interests worldwide due to its high efficiency, low toxicity and
broad insecticidal spectra. Most modifications for chlorantraniliprole were focused on the
anthraniloyl moiety,6-10 the aliphatic amide moiety11-14 and the pyrazole moiety.15-17 Nevertheless, the
modifications about the pyridine part were seldom reported in the previous work.18 Recently, our
research group has reported novel anthranilic diamides containing N-substituted nitrophenylpyrazole
with high insecticidal activities against Lepidoptera,19 indicating that the nitrobenzene moiety can be
considered as a bioisostere of pyridine moiety. Moreover, the nitrobenzene moiety will provide more
structural modification from the point of synthesis. Enlightened by the descriptions above, in order to
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systematically explore relationship of structural modification and insecticidal activity, a series of
novel anthranilic diamides analogues were designed and synthesized by introducing N-
phenylpyrazole substructure and exploring the favorable position of nitro and chloro groups on
benzene ring (Figure. 1B). To further investigate the mechanism of action, the effects of 12i on
intracellular calcium ion concentration ([Ca2+]i) in the central neurons isolated from the third instar
of M. Separata and H. armigera were studied by the calcium imaging techniques after the neurons
dyed with fluo-3 AM and fluo-5N AM. The current research also explored the possible effect of 12i
on the calcium signaling pathway in the neurons.
MATERIALS AND METHODS
Chemicals
Deuterotrichloromethane (CDCl3), Petroleum ether (60-90), Ethyl acetate,
Dichloromethane, Ethanol, n-Hexane, N,N-dimethylformamide (DMF), Glacial acetic acid, Sodium
nitrite, Sodium hydroxide, Tin (II) chloride, Sodium bicarbonate, Sodium sulfate, Potassium
carbonate, and Sodium dihydrogen phosphate (Heowns, Tianjin, China); Dimethylsulfoxid-d6
(DMSO-d6), Acetone and Potassium permanganate (J&K Scientific, China); Oxalyl chloride,
Trichloroisocyanuric acid (TCCA), 3-Nitroaniline (1a), 2-Fluoro-5-nitroaniline (1b), 2-Chloro-5-
nitroaniline (1c) and 4-Chloro-3-nitroaniline (1f) (Aladdin, Shanghai, China); Silica gel (200−300
mesh), Ammonium sulfide (20%), 1,3-Dinitrobenzene (2), 1-Fluoro-2-nitrobenzene (8a) and 1-
Fluoro-4-nitrobenzene (8b) (Energy Chemical, Shanghai, China).
Instruments and Materials. The melting points were determined on an X-4 binocular
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microscope melting point apparatus (Beijing Tech Instrument Co., Beijing, China) and were
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uncorrected. H NMR spectra were recorded at 400 MHz using a Bruker AV 400 spectrometer
(Bruker Co., Switzerland) in CDCl3 or DMSO-d6 solution with tetramethylsilane as the internal
standard, and chemical shift values (δ) were given in parts per million (ppm). High-resolution mass
spectrometry (HRMS) data were obtained on a Varian QFT-ESI instrument. Flash chromatography
was performed with silica gel (200−300 mesh). Reagents were all analytically pure. All solvents and
liquid reagents were dried by standard methods in advance and distilled before use.
2-Bromo-5-nitroaniline 1d and 2-chloro-3-nitroaniline 1g were synthesized according to the
references.20,21 3-chloro-5-nitroaniline 1e was prepared by referring to literature with some
modification as shown in Figure 2.22,23 Compounds 5 and 9 were synthesized according to the
method reported by our previous work.24 2-Amino-3,5-disubstituted benzamide derivatives 10a−f
were synthesized with 2-amino-3,5-disubstituted-benzoic acids as materials in moderate yield
referring to the literature.10 Commercial insecticide chlorantraniliprole was used only as contrast
compounds and synthesized referring to the literature.26
General Synthetic Procedure for Substituted Phenylhydrazine (4a−g).25 Phenylamine (1a−g,
25.0 mmol) was added to an ice-cold aqueous solution of concentrated hydrochloric acid (20 mL),
followed by the dropwise addition of sodium nitrite (1.52 g, 22.0 mmol) in distilled water (5 mL).
After stirring for 0.5 h at 0 °C, tin (II) chloride (11.28 g, 50 mmol) in concentrated hydrochloric acid
(30 mL) was added dropwise to the resulting mixture. The reaction mixture was stirred for 4 h at
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0 °C and filtered and successively washed with concentrated hydrochloric acid (10 mL). The
precipitate was dissolved in distilled water and filtered. When the filtrate was adjusted to pH 13 by
adding 6 mol/L sodium hydroxide under stirring, a large amount of solid formed and was filtered and
dried to obtain compounds 4a−g: yields 66.2%−75.5%.
General Synthetic Procedure for Compounds 6a−g.10 A mixture of phenylhydrazine (4a-g,
20.0 mmol), 1,1,1-trifluoro-4-(furan-2-yl)-4-hydroxybut-3-en-2-one (5, 4.12 g, 20.0 mmol) and
glacial acetic acid (15 mL) was refluxed for 5-6 h. The reaction mixture was condensed under
reduced pressure and ethyl acetate (35 mL) was added. The mixture was washed with saturated
sodium bicarbonate solution (15 mL) and brine (10 mL) and dried with anhydrous sodium sulfate.
The solvent was evaporated in a vacuum, and the residue was purified on silica gel with
petroleum/ethyl acetate (v/v, 50:1) to obtain compounds 6a−g: yields 59.1%−71.9%.
General Synthetic Procedure for Compounds 6h, 6i.19 Potassium carbonate (4.12 g, 30 mmol)
was added to a solution of 5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (9, 4.04 g, 20.0 mmol) in
N,N-dimethylformamide (15mL) and water (2 mL). The reaction mixture was stirred at 55–60 °C for
1 h. Then 1-fluoro-2-nitrobenzene (8a, 3.38 g, 24 mmol) or 1-fluoro-4-nitrobenzene (8b, 3.38 g, 24
mmol) in 5 mL of N,N-dimethylformamide was added dropwise to the mixture. The reaction mixture
was further stirred at 120−130 °C for 4 h and concentrated in vacuum. The residue was extracted
with ethyl acetate (30 mL × 3) and then washed with dilute hydrochloric acid (15 mL), saturated
sodium bicarbonate solution (15 mL) and brine (10 mL) successively, dried with anhydrous sodium
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sulfate. The solvent was evaporated in a vacuum, and the residue was purified on silica gel with
petroleum/ethyl acetate (v/v, 50:1) to obtain compounds 6h, 6i.
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General Synthetic Procedure for Compounds 7a−i.15 Potassium permanganate (22.12 g, 50.0
mol) was added in portion to a stirring mixture of 5-(furan-2-yl)-1-phenyl-3-(trifluoromethyl)-1H-
pyrazole (6a−i, 10.0 mmol) and sodium dihydrogen phosphate (1.20 g, 10.0 mmol) in 25 mL of
acetone and 25 mL of distilled wate. The reaction was slowly heated to reflux and kept for 0.5 h. The
resulting mixture was filtered and washed with ethyl acetate (35 mL). The filtrate was acidified with
dilute hydrochloric acid (5 mL) and dried with anhydrous sodium sulfate. The solvent was
evaporated to obtain compounds 7a−i, which were used directly in the next step without further
purification.
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General Synthetic Procedure for Title Compounds 12a−u. To a solution of 1-phenyl-3-
(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (7a−i, 0.5 mmol) in 5 mL of anhydrous
dichloromethane were added successively oxalyl chloride (0.127 g, 1.0 mmol) and one drop of N,N-
dimethylformamide (DMF) at room temperature. After stirring for 1.5 h, the solvent was evaporated.
The resulting carbonyl chloride was dissolved in 5 mL of anhydrous tetrahydrofuran and added to an
ice-cold solution of triethylamine (0.101 g, 1.0 mmol) and 2-amino-3-methylbenzamide derivatives
(10a−f, 0.5 mmol) in 5 mL of anhydrous tetrahydrofuran. After stirring at room temperature
overnight, the reaction mixture was added dichloromethane (20 mL), and washed with dilute
hydrochloric acid (10 mL × 2) and saturated sodium bicarbonate solution (10 mL× 2). The organic
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layer was dried and evaporated. The residue was purified on silica gel with petroleum/ethyl acetate
(v/v, 4:1) to obtain compounds 12a−u.
X-ray Diffraction. Compound 12u was recrystallized from a mixture of dichloromethane and n-
Hexane (v:v＝5:1) to colorless crystals with dimensions of 0.20 mm × 0.18 mm × 0.12 mm suitable
for X-ray single crystal diffraction. The diffraction data were collected on a Rigaku Saturn 724 CCD
diffractometer Mokα radiation (λ = 0.71073 Å). The crystal is a monoclinic system, space group
P2(1)/n, with crystallographic parameters: a =15.081 (3) Å, b = 33.486 (7) Å, c = 21.263 (4) Å, α =
90°, β = 93.41 (3)°, γ = 90°, V = 10719(4) Å3, Z = 16, Dc = 1.494 g cm−3, ꢀ= 1.692 mm−1, F(000) =
4864, R = 0.1126, T = 113 (2) K, wR= 0.1789, final R factor = 6.50%. The structure was solved by
direct methods with the SHELXL-97 program.27 All the non-H atoms were refined anisotropically by
full-matrix least-squares, and hydrogen atoms were located from a difference Fourier map and were
placed at calculated positions and were included in the refinements in the riding mode with isotropic
thermal parameters.
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 applying Abbott’s formula.28
Evaluation was based on a percentage scale of 0−100, in which 0 equals no activity and 100 equals
total kill. The standard deviations of the tested biological values were 5%. LC50 and LC95 values
were calculated by probit analysis.29
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Larvicidal Activity against Oriental Armyworm (M. separata). The larvicidal activity of title
compounds 12a−u and chlorantraniliprole against oriental armyworm was tested according to the
leaf-dip method using the reported procedure.30 The insecticidal activity is summarized in Table 1.
LC50 and LC95 values of compound 12i and chlorantraniliprole against oriental armyworm are listed
in Table 2.
Larvicidal Activity against Diamondback Moth (P. xylostella). The larvicidal activities of
compounds 12h−12j, 12o−12p and chlorantraniliprole were tested by the leaf-dip method using the
reported procedure.31 The insecticidal activity is summarized in Table 3.
Calcium Imaging Experiment. The insecticideal mechanism of these novel compounds was
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investigated according to calcium imaging experiment reported by our previous work.13,32
RESULT AND DISCUSSION
Chemistry. Compound 1e were prepared by referring to literature with some modification as
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shown in Figure 2.22,23 Compounds 4a−g were prepared from different substituted amines 1a−g
through diazotization and reduction in 66.2%−78.5% yields,25 in which the reaction temperature was
strictly controlled -5 °C − 0 °C to reduce the generation of byproducts.
In order to find the SAR, different substituted phenylpyrazole carboxylic acid (7a−i) were
synthesized. Firstly, compounds 4a−g were condensed with intermediate 5 to regioselectively give
compounds 6a−g, and compounds 6h, 6i were prepared according to the reported method.21 Then the
furan moiety of compounds 6a−i was oxidized with potassium permanganate at reflux to afford the
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corresponding carboxylic acid 7a−i. Compounds 7a−i were converted to the acyl chlorides and
coupled with compounds 10a−f to obtain the title compounds 12a−u as shown in Figure 5 in
56.6%−78.9% yields.
Crystal Structure Analysis. The molecular stucture of 12u is shown in Figure 6. Generally, the
average bond lengths and bond angles of benzene ring were normal.33-36 Due to the p-π conjugate
effect, the bond lengths of N (4)－C (5) and N (5)－C (13) were 1.353(7) Å and 1.347(7) Å,
respectively, much shorter than the normal C－N (1.47 Å), but close to C＝N (1.33 Å).37-39 The sum
of C (5)－N (4)－C (6), C (5)－N (4)－H (4) and C (6)－N (4)－H (4) angles was 360.00°,
indicating the sp2 hybridization state of the N (4) atom. Similarly, the N (5) atom also adopted a sp2
hybridization state. The benzene ring (C18 to C23) and pyrazole ring (N1/N2/C2/C3/C4) are non-
planar with a dihedral angle (θ) of 44.2°. The packing structure demonstrates the existence of
intermolecular hydrogenbond: N － H┄O, N － H┄F and N － H┄Br. Additionally, weak π-π
interactions occurred among the benzene and pyrazole rings of the adjacent molecules. These
interactions are estimated to stengthen the stability of the crystal strucuture.
Structure−Activity Relationship (SAR). Larvicidal Activity against Oriental Armyworm. The
larvicidal activity of target compounds 12a-12u against oriental armyworm is summarized in Table 1.
The bioassay results indicated that most compounds have moderate to excellent larvicidal activities
against oriental armyworm. For example, the larvicidal activity of 12h, 12i and 12j against oriental
armyworm was 100% at 1 mg L-1, same with that of chlorantraniliprole (1 mg L-1, 100%).
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Furthermore, 12i showed 37% larvicidal activity at 0.05 mg L-1, which was a little effective than the
standard chlorantraniliprole (0.05 mg L-1, 33%) against oriental armywarm.
To explore the relationship between activities of target molecules with the position of nitro on
benzene ring of phenylpyrazole moiety, compounds 12a (R'x = 4-NO2), 12b (R'x = 2-NO2) and 12c
(R'x = 3-NO2) were designed and synthesized. The larvicidal activity of 12a (R'x = 4-NO2), 12b (R'x
= 2-NO2) and 12c (R'x = 3-NO2) at concentration of 10 mg L−1 were 0%, 20% and 90%, respectively,
indicating that the position of nitro on benzene ring of phenylpyrazole moiety has an important effect
on the larvicidal activity. What is more, the sequence of the larvicidal activities was 12c (R'x =3-
NO2) > 12b (R'x =2-NO2) > 12a (R'x =4-NO2). Based on the above research, in order to further
investigate the effect of the position of subsitituent Cl on benzene ring of the phenylpyrazole moiety,
compounds 12h–k (R'x = 2-Cl, 5-NO2), 12l–n (R'x = 3-Cl, 5-NO2), 12o–q (R'x = 2-Cl, 3-NO2) and
12r–u (R'x = 4-Cl, 3-NO2) were designed and synthesized. Generally, the sequence of the larvicidal
activities of these compounds was 12h–k (R'x = 2-Cl, 5-NO2) > 12l–n (R'x = 2-Cl, 3-NO2) >> 12o–q
(R'x = 4-Cl, 3-NO2) ≥ 12r–u (R'x = 3-Cl, 5-NO2). Moreover, compounds 12h–k (R'x = 2-Cl, 5-NO2)
and 12o–q (R'x = 2-Cl, 3-NO2) showed much higher insecticidal activities against oriental armywarm
than that of 12c-g (R'x = 3-NO2). For example, 12h (R'x = 2-Cl, 5-NO2) and 12o (R'x = 2-Cl, 3-NO2)
showed 100% and 80% insecticidal activity at 0.25 mg L−1, respectively, whereas 12c (R'x = 3-NO2)
gave a death rate of 30% at only 5 mg L−1. These observations clearly showed that the substituent Cl
in the 2-position of benzene ring had a positive effect on the larvicidal activities, and is a key
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pharmacophore. However, the larvicidal activities of 12o–q (R'x = 4-Cl, 3-NO2) and 12r–u (R'x = 3-
Cl, 5-NO2) were lower than that of 12c-g (R'x = 3-NO2). For instance, the larvicidal activity of 12e
(R'x = 3-NO2) at 10 mg L−1 were 50%, whereas 12n (R'x = 3-Cl, 5-NO2) and 12t (R'x = 4-Cl, 3-NO2)
were almost inactive at the same dosage. The results indicated that the existence of 3-Cl or 4-Cl on
benzene ring of the phenylpyrazole moiety had a negative effect on the larvicidal activities. Hence,
the position of substituent Cl on benzene ring of phenylpyrazole moiety has a significant effect on
the larvicidal activity. In addition , as shown in Table 1, the bioactivity of target compounds 12a-u,
when R1 and R'x was fixed, indicated the sequence of larvicidal activity was i-propyl > t-Bu ≥ CH3 in
the aliphatic amide moiety (R2); and when R2 and R'x was fixed, indicated the sequence of larvicidal
activity was Cl > Br in the anthraniloyl moiety (R1).
From Table 2, it is noteworthy that the LC50 and LC95 values of 12i were 0.0772 and 0.4064 mg
L−1, respectively, slightly higher than that of chlorantraniliprole (0.0664 mg L−1 and 0.3237 mg L−1),
indicating that the larvicidal activity of 12i was comparable to that of chlorantraniliprole.
Larvicidal Activity against Diamondback Moth. The larvicidal activity of target compounds 12h-j,
12o and 12p against diamondback moth is showed in Table 3. Most of them had excellent
insecticidal activity against diamondback moth. At 1 mg L−1 all of the compounds showed 100%
larvicidal activity. It is worth noting that 12i showed a death rate of 95% at 0.05 mg L−1, equal to that
of chlorantraniliprole (0.05 mg L−1, 100%). The activities of target compounds, when R'x and R1
were fixed, indicated the sequence of larvicidal activity was i-propyl > CH3 in the R2; and when R'x
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and R2 were fixed, indicated the trend Cl > Br in the R1, which was consistent with the above
research.
Calcium Imaging. For studying the insecticidal mechanism of these novel compounds, we
examined the effects on the calcium concentration by using central neurons of M. Separata and H.
Armigera with calcium imaging technique after the neurons loading with fluo-3AM and fluo-5N AM
(the low-affinity Ca2+ indicator of ER). Figure 7A and 7B show the change of [Ca2+]i versus
recording time when the M. Separata and H. Armigera central neurons were treated with different
concentrations of compound 12i and chlorantraniliprole from 10 ppm, 5pm, 2ppm to 1 ppm in the
absence of extracellular calcium, respectively. The experiment results indicated that there is no
apparent difference effect on the calcium concentrations elevated by 12i between the central neurons
of M. Separata and H. Armigera. Based on the calcium cencentrations elevated by different
concentrations of 12i and chlorantraniliprole, it is concluded there is slight difference between the
insecticidal activities against M. Separata and H. Armigera.
Figure 8A shows that the enhancement of free calcium concentration in neurons in the presence of
extracellular calcium is the same as that in the absence of extracellular calcium because the peaks of
[Ca2+]i were all elevated to 105% of the initial value when the H. Armigera neurons were treated
with 10 ppm 12i. It indicates that elevation of Ca2+ concentrations is attributed to the release of
calcium ions from the endoplasmic reticulum and 12i could not activate the calcium channel on the
plasma membrane. To further determine the paths that induced the elevation of extracellular calcium
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in the neuron cells, the central neurons of H. Armigera were loaded with fluo-5N AM, and the results
show that 12i could release the calcium from the endoplasmic reticulum by RyRs or IP3Rs (Figure
8B).
Figure 9 shows that after application of caffeine (30 mM) and the co-application of 12i together
with ryanodine (3 ꢀM), caffeine (30 mM) and 12i could not induce the calcium responses. The
results demonstrate that 12i could activate ryanodine receptor, the same as caffeine.
Figure 10 shows the impact of 12i on the calcium response after the neurons pre-incubated by
thapsigargin. In our experiments, after the intracellular calcium store in the neurons of H. Armigera
was depleted by thapsigargin (30 ꢀM), 12i could not cause any calcium responses, meaning that
there are no other targets except ryanodine receptor.
In summary, a series of novel anthranilic diamides analogs (12a-u) containing N-substituted
phenylpyrazole were designed and synthesized. The premilinary structure-activity relationship (SAR)
of the target compounds indicated that the position of nitro and chlorine on benzene ring of
phenylpyrazole moiety exerted different effects on activity following the sequence 12h–k (R'x = 2-Cl,
5-NO2) > 12l–n (R'x = 2-Cl, 3-NO2) > 12c (R'x =3-NO2) > 12b (R'x =2-NO2) > 12a (R'x =4-NO2) >
12o–q (R'x = 4-Cl, 3-NO2) ≥ 12r–u (R'x = 3-Cl, 5-NO2), and indicating that R'x (2-Cl, 5-NO2) on
benzene ring of the phenylpyrazole moiety was a key pharmacophore for the maintenance of
insecticidal activity. Especially, compound 12i showed 100% and 37% larvicidal activities against
oriental armyworm at 0.25 mg L−1 and 0.05 mg L−1, respectively, equal to that of chlorantraniliprole
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(100%, 0.25 mg L−1 and 33%, 0.05 mg L-1). The activity of 12i against diamondback moth was 95%
at 0.05% mg L−1, while the control was 100% at 0.05% mg L−1. More importantly, the calcium
imaging technique experiments indicated that RyRs in the central neurons of H. Armigera is the
biochemical target, meaning that the title compounds were ryanodine receptor activators.
Associated Content
Supporting Information. The data and characterization of the intermediates 3, 1d, 1e, 1g, 4a–4g, 6a–
6i and the target compounds 12a–u is available free of charge via the Internet at http:// pubs. acs.org
Author Information
Corresponding Author
Tel.: 0086-22-23503732 (Z. Li.), 0086-22-23503798 (Y. Li.), Fax: 0086-22-23505948.
E-mail: nkzml@vip.163.com (Z. Li), liyx128@nankai.edu.cn (Y. Li).
Acknowledgment
This work was supported by the National Science Foundation of China (No. 21272129, No.
31370039) and the “111” Project of Ministry of Education of China (No. B06005).
Notes
The authors declare no competing financial interest.
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Figure Captions
Figure 1 Chemical structures of the design of target compounds
Figure 2 Synthetic Route of Compound 1e
Figure 3 Synthetic Route of Compounds 6a−g
Figure 4 Synthetic Route of Compounds 6h and 6i
Figure 5 Synthetic Route of Title Compounds 12a−u
Figure 6 Crystal structure of compound 12u
Figure 7 Effects of different concentration of 12i and chlorantaniliprole on [Ca2+]i in the central
neurons of M. Separata (A) and H. Armigera (B) when extracellular calcium was in absence ( EGTA
replaced calcium). The central neurons of M. Separata and H. Armigera third-instar larvae were dyed
by loading with fluo-3 AM.
Figure 8 Effect of treatments with 10 ppm of 12i in isolated H. Armigera in the presence or absence
of extracellular calcium. The central neurons of H. Armigera third-instar larvae were dyed by loading
with fluo-3 AM (A). Effect of treatments with 10 ppm of 12i on intracellular Ca2+ at different time in
the absence of extracellular Ca2+ (EGTA replaced Ca2+). The central neurons of H. Armigera third-
instar larvae were dyed by loading with fluo-5N (B).
Figure 9 Characterization of 12i stimulated calcium responses in the central neurons of H. Armigera
third-instar larvae. Repeated challenges with caffeine, 12i, co-application of ryanodine together with
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12i, caffeine and 12i in standard saline. The central neurons of H. Armigera third-instar larvae were
dyed by loading with fluo-3 AM.
Figure 10 Effects of 100 ppm of 12i on [Ca2+]i in the central neurons of H. Armigera when the
neurons preincubated thapsigargin. The central neurons of H. Armigera third larvae were dyed by
loading with fluo-3 AM.
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Figure 1
Figure 2
Figure 3
Figure 4
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Figure 5
Figure 6
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Figure 7
Figure 8
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Figure 9
Figure 10
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Table 1 Insecticidal Activities of Compounds 12a−u and Chlorantraniliprole against Oriental
Armyworm
larvicidal activity (%) at a concentration of (mg/L)
Compd.
12a
12b
12c
12d
12e
12f
R'x
4-NO2
2-NO2
3-NO2
3-NO2
R1
Cl
Cl
Cl
Cl
Br
Cl
R2
200 100 50
100 100 100 80
100 100 100 100 20
100 100 100 100 90
25
10
5
1
0.25 0.1 0.05
CH3
CH3
CH3
30
cyclopropyl 100 100 100 100 100 60
3-NO2
2-F, 5-NO2
CH3
CH3
CH3
100 100 100 100 50
100 100 100 100 20
100 100 100 100 100 40
100 100 100 100 100 100 100 100 40
100 100 100 100 100 100 100 100 53
100 100 100 100 100 100 100 100 45
100 100 100 100 100 100 60
100 100 40
100 100 70
100 100 20
100 100 100 100 100 100 100
100 100 100 100 100 100 100
100 100 100 100 100 100 70
100 100 100 10
12g
12h
12i
2-Br, 5-NO2 Cl
2-Cl, 5-NO2 Cl
2-Cl, 5-NO2 Cl
2-Cl, 5-NO2 Cl
2-Cl, 5-NO2 Br
3-Cl, 5-NO2 Cl
3-Cl, 5-NO2 Cl
3-Cl, 5-NO2 Br
2-Cl, 3-NO2 Cl
2-Cl, 3-NO2 Cl
2-Cl, 3-NO2 Br
CH3
i-propyl
t-butyl
CH3
CH3
i-propyl
CH3
CH3
i-propyl
CH3
CH3
i-propyl
CH3
37
12j
12k
12l
12m
12n
12o
12p
12q
12r
12s
80
90
4-Cl,3-NO2
4-Cl,3-NO2
4-Cl,3-NO2
4-Cl,3-NO2
Cl
Cl
Br
Br
100 100 100 30
100 100 50
100 100 70
12t
12u
t-butyl
100
chlorantraniliprole
100
100 100 100 100 100 100 60
33
Table 2 LC50 Values of Compound 12i and Chlorantraniliprole against Oriental Armyworm
Compd.
12i
y = a + bx
y=7.5368+2.2809x
y=7.8167+2.3918x
R
LC50 (mg/L)
0.0772
LC95 (mg/L)
0.4064
0.3237
0.9888
0.9831
chlorantraniliprole
0.0664
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Table 3 Insecticidal Activities of Compounds 12h-j, 12o and 12p and Chlorantraniliprole against
Diamondback Moth
larvicidal activity (%) at a concentration of (mg/L)
Compd.
200
100
100
100
100
100
100
100
100
100
100
100
100
100
50
25
10
1
0.1
70
100
30
10
60
0.05
95
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
12h
12i
12j
12o
12p
chlorantraniliprole
100
100
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