Synthesis, insecticidal evaluation and mode of action of novel anthranilic diamide derivatives containing sulfur moiety as potential ryanodine receptor activators

Article abstract of DOI:10.1016/j.bmc.2019.01.009

Anthranilic diamide insecticide could control lepidopteran pests by selectively binding and activating insect ryanodine receptors (RyRs), and the unique mode of action is different from other conventional insecticides. In order to discover new anthranilic

Full text of DOI:10.1016/j.bmc.2019.01.009

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
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Bioorganic & Medicinal Chemistry
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Synthesis, insecticidal evaluation and mode of action of novel anthranilic
diamide derivatives containing sulfur moiety as potential ryanodine
receptor activators
⁎
⁎
Feng-Yun Lic, Yuan-Hong Wangb, Jing-Bo Liua,b, , Yu-Xin Lia, , Zheng-Ming Lia
a State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
b College of Horticulture and Landscape Architecture, Tianjin Agricultural University, Tianjin 300384, China
c College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Anthranilic diamide insecticide could control lepidopteran pests by selectively binding and activating insect
ryanodine receptors (RyRs), and the unique mode of action is different from other conventional insecticides. In
order to discover new anthranilic diamide insecticide as ryanodine receptors activators, a series of 11 novel
anthranilic diamides derivatives (Ia-k) were synthesized and confirmed by melting point, 1H NMR, 13C NMR and
elemental analyses. The preliminary bioactivity revealed that most title compounds showed moderate to re-
markable activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella).
Especially, compounds Ia and If, which exhibited 100% larvicidal activity against oriental armyworm at
1.0 mg L−1, and comparable to that of chlorantraniliprole (100% at 1 mg L−1). If displayed 60% insecticidal
activity against diamondback moth at 0.01 mg L−1, better than chlorantraniliprole (45% at 0.01 mg L−1). The
preliminary structure activity relationships were discussed. In addition, the calcium imaging experiment in-
dicated that the insect ryanodine receptor is the potential target of If.
Anthranilic diamides
Sulfur-containing structure
Insecticidal activity
Ryanodine receptor
1. Introduction
remarkable insecticidal efficiency focused on modification of the pyr-
idine moiety, which was replaced by a benzene ring with halogen,
The control of pest is very important in agriculture, because pests
can lead to severe losses to horticulture crops and agriculture, even
emerged threat to global food security.1 Some practical measures have
been taken to prevent their damage, and the most effective way is
chemical insecticide control. However, due to the frequent use of che-
mical insecticides with the same mode of action, the increasing in-
secticide resistance has become serious issues for insect control.2,3
Thus, novel potent insecticides with novel mode of action are critically
needed. Chlorantraniliprole, binding selectively to insect ryanodine
receptors, is the first commercial anthranili diamide insecticide dis-
covered by DuPont.4 The unique insecticidal mechanism of Chloran-
traniliprole is different from that of conventional insecticides, which
has begun a new era of synthetic chemical insecticides.
nitro, trifluoromethyl, and amide (Fig. 1, F).10–13
The sulfur-containing structures are important active scaffolds
widely used in pesticide and drug. Moreover, a number of recently
developed sulfur-containing agrochemical molecules represent a class
of chemical compounds with novel modes of action. For example,
Flubendiamide (Fig. 1, B), in which sulfone group played an important
role in insecticidal activity, activated insect ryanodine receptor.14 Sul-
foxaflor (Fig. 1, C), in which N-cyanosulfoximine group had a sig-
nificant effect on insecticidal activity, acted on insect nicotinic acet-
ylcholine receptors (nAChR).15 Moreover, our research group found
that replacing the sulfone group of Flubendiamide with N-tri-
fluoroacetyl sulfilimine (Fig. 1, D) or N-cyano sulfilimine (Fig. 1, E) can
maintain or improve the insecticidal activity.16,17 Considering the
above mentioned facts, sulfur-containing structures were introduced
into anthranilic diamides scaffolds to investigate the effects on in-
secticidal activity. To further study the insecticidal mechanism, the
influence of compound If on intracellular calcium homeostasis in the
Since the discovery of Chlorantraniliprole, researchers have con-
ducted various structural modifications, and developed many novel
compounds with excellent insecticidal activity.5–9 Our research group
have also reported some novel anthranilic diamide derivatives with
⁎ Corresponding authors at: College of Horticulture and Landscape Architecture, Tianjin Agricultural University, Tianjin 300384, China (J.-B. Liu); State Key
Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China (Y.-X. Li and Z.-M. Li).
E-mail addresses: liujingbo0626@126.com (J.-B. Liu), liyx128@nankai.edu.cn (Y.-X. Li), nkzml@vip.163.com (Z.-M. Li).
https://doi.org/10.1016/j.bmc.2019.01.009
Received 25 November 2018; Received in revised form 3 January 2019; Accepted 14 January 2019
0968-0896/©2019ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:Li,F.-Y.,Bioorganic&MedicinalChemistry,https://doi.org/10.1016/j.bmc.2019.01.009

F.-Y. Li et al.
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Fig. 1. Design strategy of the title compounds.
central neurons isolated from the third instar of oriental armyworm
were conducted.
2.2. Structure–activity relationship
2.2.1. Larvicidal activity against oriental armyworm.
The larvicidal activity of title compounds Ia-k against oriental ar-
myworm is listed in Table 1. The results indicated that most title
compounds have moderate to remarkable insecticidal activities against
oriental armyworm. For example, the insecticidal activity of Ia, and Ie-j
was 100% at 2.5 mg L−1. Especially, Ia and If still exhibited 100% in-
secticidal activity at 1 mg L−1, comparable with the control chloran-
traniliprole (100% at 1 mg L−1). Moreover, If displayed excellent lar-
vicidal activity, even at 0.5 mg L−1 with 60% larvicidal activity. On the
whole, sulfur-containing compounds Ie-g exhibited better insecticidal
activity than that of rest compounds, except for Ia. When the R group
contained sulfur, sulfone-containing compound If still displayed 60%
insecticidal activity at 0.5 mg L−1, but the other compounds showed no
insecticidal activity, indicating that sulfone group had a positive effect
on the insecticidal activity. When the R group contained no sulfur,
ester-containing compound Ia exhibited 100% insecticidal activity at
1 mg L−1, better than that of others.
2. Result and discussion
2.1. Chemistry
The synthetic route of Ia was depicted in Scheme S1 (Supporting
information). In the initial step, we attempted to prepare intermediate 5
according to our previous reported method,10 however, intermediate 5
was not obtained successfully, and finding that the ester on the benzene
ring was hydrolyzed. Finally, based on our previous reported method
with some improvement, intermediate 5 was obtained successfully by
addition of KH2PO4 (1 equiv) as shown in Scheme S1 (Supporting in-
formation). The title compounds Ib-k were synthesized as illustrated in
Schemes 1–3. The ester group of Ia was reduced by LiAlH4 at 0 °C to
obtain intermediate 6, which was oxidized into aldehyde to afford Ib.
Subsequently, Ib was converted to the corresponding oxime Ic-d by
treatment with hydroxylamine in the presence of Et3N. Ie was synthe-
sized in good yield through two steps nucleophilic substitution reac-
tions from intermediate 6. Then Ie was inverted to If with sulfone group
in the presence of 2 equivalent m-CPBA at 0 °C, and also converted to Ig
with N-cyano sulfilimine group in the presence of PhI(OAc)2 and
NH2CN in anhydrous tetrahydrofuran at 0 °C for 5 min.17 Then Ig was
oxidized by PhI(OAc)2 in the presence of K2CO3 at 0 °C to afford Ii.
Subsequently, the N-cyano sulfilimine group of Ig and Ii was converted
to N-trifluoroacetyl sulfilimine in the presence of TFA to obtain Ih and
Ij, respectively. Then the N-trifluoroacetyl sulfilimine group of Ij was
hydrolyzed with K2CO3 to prepare Ik.16
2.2.2. Larvicidal activity against diamondback moth
On the base of the above research, Ia, Ib, and Ie-j were further
tested against diamondback moth, and the result is shown in Table 2
and Fig. 2. The tested compounds except for Ib exhibited 100% larvi-
cidal activity at 1 mg L−1, as same as that of the control chloran-
traniliprole (100% at 1 mg L−1). In particular, If against diamondback
moth showed 60% larvicidal activity at 0.01 mg L−1, better than that of
chlorantraniliprole (45% at 0.01 mg L−1). Moreover, as shown in
Table 3, it is noteworthy that the LC50 value of If was 0.0046 mg L−1
,
Scheme 1. Synthetic route of title compounds Ia-d. Reagent and conditions: (i) LiAlH4, THF, 0 ℃, 5 h; (ii) MnO2, CH2Cl2, rt, 7 h; (iii) NH2OR HCl, ethanol, Et3N,
reflux, 5–6 h.
2

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Scheme 2. Synthetic route of title compounds Ie-f. Reagent and conditions: (i) CH3SO2Cl, pyridine, 4 h; (ii) NaSCH3 (20% aq), acetone, rt, 3 h; (iii) m-CPBA, THF, 0
℃, 30 min.
slightly lower than that of the commercial chlorantraniliprole
(0.0051 mg L−1), indicating that the insecticidal activity of If was
comparable to that of chlorantraniliprole and sulfone group in this kind
of compounds played an important role in the insecticidal activity.
From Table 2, we can see that the structure activity relationship was
similar with that of insecticidal activity against oriental armywarm.
at 40 ppm in the absence of extracellular calcium. The result is similar
to our previous report.10–13 The calcium can be increased when If and
chlorantraniliprole applied to the isolated neurons. The peaks of [Ca2+
]
i were increased to 106.7
3.2 (n = 7) and 108.4
3.2 (n = 8)
compared with the initial value when the isolated neurons treated with
40 ppm If and chlorantraniliprole, respectively. Due to the absence of
extracellular calcium, the result reveals that If can release stored cal-
cium ions from neurons of oriental armyworm.
2.3. Heart (dorsal vessel) rate against Periplaneta americana
As shown in Fig. 5, when the isolated neurons of oriental armyworm
were treated with 40 ppm If, the peaks of free calcium concentration in
neurons in the absence and presence of extracellular calcium were all
enhanced to 107.1% of the initial value. This result revealed that If
could not activate the calcium channel on the plasma membrane and
the increasement of Ca2+ was caused by the release of Ca2+ from the
endoplasmic reticulum.
It is well known that Periplaneta americana has well-developed cir-
culatory system with 12 ventricles. In order to avoid the errors in dif-
ferent heart, the obtained data in this research was from at least three
different Periplaneta americanas in one time. As shown in Fig. 3, after
10 min the heart was treated, compound If and chlorantraniliprole
could raise the beat rate of heart, compared with the control. And then,
To further search the paths that caused the enhancement of extra-
cellular calcium in the isolated neurons of oriental armyworm, the
central neurons were loaded with fluo-5N. As shown in Fig. 6, when the
central neurons were treated with 40 ppm If, the concentrate of free
calcium was reduced to 75.2%. Meanwhile, Fig. 7 showed that the
fluorescence intensity was obviously decreased after compound If was
added, due to the fall of free calcium in neurons. These results indicated
that If was an effective calcium activator for ryanodine receptors or
IP3Rs in insect cells.
a
weak cardio-inhibitory response to compound If and chloran-
traniliprole was observed. After 60 min, the beat rates of heart were all
reduced, similar to that of the previous report.18 Meanwhile, these
cardio-inhibitory effects also displayed dose dependence. The com-
pound If and chlorantraniliprole could also strengthen the cardiac
contraction. Based on the previous report,18 we speculated that rya-
nodine receptors in the heart of the Periplaneta americana may be the
target of compound If.
To further investigate the biochemical target (ryanodine receptors
or IP3Rs) of If, the isolated neurons of oriental armyworm were pre-
incubated thapsigargin which is widely used inhibitor of Ca2+-ATPases
in mammalian cells. As shown in Fig. 8, title compound If could not
bright about any calcium concentrate responses after the intracellular
calcium store in the neurons of oriental armyworm was depleted by
thapsigargin, revealing that ryanodine receptors in the oriental army-
worm neurons are the potential biochemical target of If, in other words,
2.4. Calcium imaging
In order to investigate the insecticidal mechanism of the title com-
pounds, we studied the effects of If on calcium homeostasis in the
central neurons isolated from third instar of oriental armyworm with
calcium imaging technique after neuron were dyed by loading with
fluo-3 AM. The change of [Ca2+]i versus recording time was shown in
Fig. 4 when the isolated neurons treated with If and chlorantraniliprole
Scheme 3. Synthetic route of title compounds Ig-k. Reagent and conditions: (i) PhI(OAc)2, CH2CN, THF, 0 ℃, 5 min; (ii) TFA, THF, rt, 1 h; (iii) m-CPBA, K2CO3,
ethanol, 0 ℃, 30 min; (iv) TFA, THF, rt, 1 h; (v) K2CO3, THF, 0 ℃, 30 min.
3

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Table 1
Insecticidal activities of title compounds Ia-k and chlorantraniliprole against oriental armyworm.
Compd
R
Larvicidal activity (%) (mg L−1
)
200
100
100
100
50
25
10
5
2.5
1
0.5
20
Ia
Ib
100
100
100
100
100
100
100
100
100
100
100
100
20
0
Ic
100
100
100
100
100
100
100
100
100
100
100
40
Id
Ie
If
100
100
100
100
100
100
100
100
100
100
100
100
100
100
20
100
60
Ig
Ih
100
100
100
100
100
100
100
100
100
100
100
100
100
100
40
40
Ii
Ij
100
100
100
100
100
100
100
100
100
100
100
100
100
100
40
60
Ik
100
100
100
100
100
100
100
100
100
100
100
100
50
Chlorantraniliprole
–
100
100
100
Table 2
Insecticidal activities of some title compounds and chlorantraniliprole against
diamondback moth.
Compd
Larvicidal activity (%) (mg L−1
)
200
10
5
1
0.1
0.01
40
Ia
Ib
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
90
100
50
100
100
100
100
100
100
100
50
95
60
Ig
Ih
Ii
55
80
40
20
25
45
70
Ij
80
Chlorantraniliprole
100
Fig. 2. Overall insecticidal activity of some title compounds and
Chlorantraniliprole (CK) against Diamondback moth.
If was the activator of ryanodine receptors in oriental armyworm.
and diamondback moth. Compounds Ia and If against oriental army-
worm displayed 100% larvicidal activity at 1 mg L−1, equivlent to that
of chlorantraniliprole (100% at 1 mg L−1). Moreover, If against dia-
3. Conclusion
A series of novel anthranilic diamides derivatives (Ia-k) containing
ester, aldehyde, oxime, and sulfone group were designed and synthe-
sized. The insecticidal activity result showed that most title compounds
showed moderate to remarkable activities against oriental armyworm
mondback moth exhibited 60% insecticidal activity at 0.01 mg L−1
,
superior to the control chlorantraniliprole (45% at 0.01 mg L−1). The
structure activity relationship revealed that sulfone in this kind of
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Table 3
LC50 values of compound If and chlorantraniliprole against diamondback moth.
Compd.
y = a + bx
R
LC50 (mg L−1
)
If
y = 13.45 + 2.39x
y = 15.83 + 2.54x
0.99
0.98
0.0046
0.0051
chlorantraniliprole
Fig. 5. Influence of treatments with If (40 ppm) in isolated neurons of oriental
armyworm in the presence or absence of extracellular calcium. The central
neurons were dyed by loading with fluo-3 AM.
Fig. 3. Influences of If and chlorantraniliprole on the heart of Periplaneta
americana.
Fig. 6. Influence of treatments with If (40 ppm) on intracellular calcium in
isolated neurons of oriental armyworm at different times in the absence of
extracellular calcium (EGTA replaced calcium). The central neurons of third-
instar larvae were dyed by loading with fluo-5N.
apparatus (Beijing Tech Instrument Co., Beijing, China) and were un-
corrected. Elemental analyses were performed on a Vario EL elemental
analyzer (Elementar Co., Germany). Flash chromatography was per-
formed with silica gel (300–400 mesh). Reagents were all analytically
pure. All solvents and liquid reagents were dried by standard methods
in advance and distilled before use.
Fig. 4. Influence of 40 ppm If and chlorantraniliprole on [Ca2+]i in the central
neurons of oriental armyworm when extracellular calcium was absent (EGTA
replaced calcium). The central neurons of third-instar larvae were dyed by
loading with Fluo-3 AM.
4.1.1. Synthetic procedure for Ia
1-(2-Chloro-5-(methoxycarbonyl)phenyl)-3-(trifluoromethyl)-1H-
pyrazole-5-carboxylic acid 5 (3.48 g, 10 mmol) was dissolved in 25 mL
anhydrous tetrahydrofuran, and oxalyl chloride (2.54 g, 20 mmol) and
one drop of DMF were added successively at room temperature. After
stirring for 1 h, the tetrahydrofuran was evaporated and obtained the
crude carbonyl chloride. Then the carbonyl chloride was dissolved in
10 mL anhydrous tetrahydrofuran and added to an ice-cold solution of
DIPEA (1.94 g, 15 mmol) and 2-amino-5-chloro-N,3-dimethylbenza-
mide (1.98 g, 10 mmol) in 15 mL anhydrous tetrahydrofuran. After
stirring for 7 h at room temperature, the solvent was evaporated, and
dichloromethane (25 mL) was added, then washed with dilute hydro-
chloric acid (15 mL) and saturated sodium bicarbonate solution
(15 mL). The organic layer was dried and evaporated to obtain title
compound Ia. White solid, yield: 68.9%, m.p. 181–182 °C. 1H NMR
(400 MHz, DMSO‑d6) δ 10.36 (s, 1H, Ph-NH-CO), 8.30 (d, J = 4.5 Hz,
1H, Ph-CO-NH), 8.10–8.05 (m, 2H, 2Ph-H), 7.81 (d, J = 9.0 Hz, 1H, Ph-
compounds played an important role in the insecticidal activities
against oriental armyworm and diamondback moth. In addition, the
calcium imaging technique experiments results revealed that ryanodine
receptor (RyR) is the potential biochemical target of these novel title
compounds.
4. Experimental section
4.1. Materials and methods
1H NMR and 13C NMR were recorded at 400 MHz using a Bruker AV
400 spectrometer (Bruker Co., Switzerland) in CDCl3 or DMSO‑d6 so-
lution with tetramethylsilane as the internal standard. Chemical shift
values (δ) were given in parts per million (ppm). The melting points
were determined on an X-4 binocular microscope melting point
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Fig. 7. Fluorescence intensity of 40 mg/L
compounds If effects on [Ca2+]i in the
central neurons of oriental armyworm. The
fluorescence intensity before compound If
was added (left); The fluorescence intensity
after compound If acted on the central
neurons for 8 min (right). The central neu-
rons of third-instar larvae were dyed by
Fluo-5 N AM.
4.1.3. Synthetic procedure for Ic and Id
Compound Ib (0.2 g, 0.4 mmol) was dissolved in 10 mL anhydrous
ethanol, and hydroxylamine hydrochloride (0.8 mmol) and Et3N
(0.81 g, 0.8 mmol) were added successively. The reaction was refluxed
for 6 h and filtered. The filtrate was concentrated to afford Ic and Id.
Ic: White solid, yield: 76.7%, m.p. 143–144 °C. 1H NMR (400 MHz,
DMSO‑d6) δ 11.56 (s, 1H, N-OH), 10.35 (s, 1H, Ph-NH-CO), 8.33 (d,
J = 4.4 Hz, 1H, Ph-CO-NH), 8.21 (s, 1H, Ph-H), 7.82–7.71 (m, 3H, 2Ph-
H and Pyrazole-H), 7.65 (d, J = 8.2 Hz, 1H, N = CH), 7.48 (s, 1H, Ph-
H), 7.35 (s, 1H, Ph-H), 2.64 (d, J = 4.2 Hz, 3H, NHCH3), 2.18 (s, 3H,
Ph-CH3). 13C NMR (101 MHz, DMSO‑d6) δ 166.66, 156.15, 146.78,
141.96, 139.84, 139.20, 138.22, 136.44, 133.57, 131.97, 131.66,
131.40, 131.07, 130.51, 128.64, 127.13, 125.84, 121.33, 107.08,
26.56, 18.13. Anal. calcd for C21H16Cl2F3N5O3: C, 49.04; H, 3.14; N,
13.62; found: C, 49.09; H, 3.17; N, 13.65.
Id: White solid, yield: 72.6%, m.p. 151–152 °C. 1H NMR (400 MHz,
DMSO‑d6) δ 10.36 (s, 1H, Ph-NH-CO), 8.30 (d, J = 4.5 Hz, 1H, Ph-CO-
NH), 8.10–8.05 (m, 2H, 2Ph-H), 7.87 (s, 1H, N = CH), 7.81 (d,
J = 9.0 Hz, 1H, Ph-H), 7.76 (s, 1H, Pyrazole-H), 7.48 (d, J = 2.0 Hz,
1H, Ph-H), 7.34 (d, J = 2.1 Hz, 1H, Ph-H), 3.87 (s, 3H, CH3O), 2.62 (d,
J = 4.5 Hz, 3H, NHCH3), 2.17 (s, 3H, Ph-CH3). 13C NMR (101 MHz,
DMSO‑d6) δ 166.61, 165.03, 156.12, 142.16, 139.81, 139.18, 138.32,
136.49, 135.97, 131.96, 131.89, 131.65, 131.42, 130.83, 129.80,
129.77, 125.85, 121.29, 107.14, 53.13, 26.48, 18.10. Anal. calcd for
Fig. 8. Influence of If (100 ppm) on intracellular calcium in the isolated neu-
rons of oriental armyworma when the neurons were pre-incubated thapsi-
gargin. The central neurons were dyed by loading with fluo-3 AM.
H), 7.76 (s, 1H, Pyrazole-H), 7.48 (d, J = 2.0 Hz, 1H, Ph-H), 7.34 (d,
J = 2.1 Hz, 1H, Ph-H), 3.87 (s, 3H, CH3O), 2.62 (d, J = 4.5 Hz, 3H,
NHCH3), 2.17 (s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO‑d6) δ
166.61, 165.03, 156.12, 142.16, 139.81, 139.18, 138.32, 136.49,
135.97, 131.96, 131.89, 131.65, 131.42, 130.83, 129.80, 129.77,
125.85, 121.29, 107.14, 53.13, 26.48, 18.10. Anal. calcd for
C22H18Cl2F3N5O3: C, 50.02; H, 3.43; N, 13.26; found: C, 50.11; H, 3.47;
N, 13.29.
C
22H17Cl2F3N4O4: C, 49.92; H, 3.24; N, 10.59; found: C, 49.97; H, 3.28;
4.1.4. Synthetic procedure for Ie
N, 10.64.
Compound 6 (2.5 g, 5 mmol) was dissolved in 30 mL anhydrous
tetrahydrofuran, and then methylsulfonyl chloride (0.69 g, 6 mmol) and
pyridine (0.48 g, 6 mmol) was added slowly to the mixture successively
at 0 °C. The mixture reaction was stirred for 5 h at room temperature.
The solvent was evaporated, and dichloromethane (20 mL) was added,
then washed with dilute hydrochloric acid (15 mL × 2) and saturated
sodium bicarbonate solution (15 mL × 2). The organic layer was eva-
porated to obtain 7. Compound 7 (2.312 g, 4 mmol) was dissolved in
20 mL acetone, and then 20% sodium methyl mercaptide (4.2 g,
12 mmol) was added in batches at room temperature. The reaction was
stirred for 3 h and evaporated. The filtrate was extracted with ethyl
acetate and washed with saturated sodium chloride (15 mL). Then the
organic layer was dried and evaporated to obtain title compound Ie.
White solid, yield: 75.2%, m.p. 150–151 °C. 1H NMR (400 MHz,
DMSO‑d6) δ 1H NMR (400 MHz, DMSO‑d6) δ 10.32 (s, 1H, Ph-NH-CO),
8.34 (d, J = 4.2 Hz, 1H, Ph-CO-NH), 7.71 (s, 1H, Ph-H), 7.59–7.53 (m,
2H, 2Ph-H), 7.48 (s, 2H, Ph-H and Pyrazole-H), 7.36 (s, 1H, Ph-H), 3.75
(s, 2H, CH2S), 2.66 (d, J = 4.2 Hz, 3H, NHCH3), 2.17 (s, 3H, Ph-CH3),
1.93 (s, 3H, CH3S). 13C NMR (101 MHz, DMSO‑d6) δ 166.19, 155.68,
141.26, 139.40, 139.05, 138.75, 137.05, 135.78, 131.56, 131.33,
131.22, 130.89, 129.43, 129.03, 128.23, 125.29, 120.85, 106.47,
35.56, 26.12, 17.60, 14.09. Anal. calcd for C22H19Cl2F3N4O2S: C, 49.73;
4.1.2. Synthetic procedure for Ib
Compound Ia (4.0 g, 8 mmol) was dissolved in 30 mL anhydrous
tetrahydrofuran, and LiAlH4 (0.608 g, 16 mmol) was added at 0 °C. The
reaction was stirred at 0 °C for 4 h. Then 5 mL of water was added
slowly to the mixture and filtered. The filtrate was extracted with ethyl
acetate, and the organic extract was separated, dried, filtered and
concentrated to obtain crude 6. Compound 6 (0.5 g, 1 mmol) was dis-
solved in 10 mL dichloromethane, and MnO2 (0.44 g, 5 mmol) was
added slowly to the mixture and stirred for 6 h. Then the mixture was
filtered and the filtrate was concentrated to obtain Ib. White solid,
yield: 85.8%, m.p. 164–165 °C. 1H NMR (400 MHz, DMSO‑d6) δ 10.41
(s, 1H, Ph-NH-CO), 10.05 (s, 1H, CHO), 8.32 (s, 1H, Ph-CO-NH), 8.16
(s, 1H, Ph-H), 8.08 (s, 1H, Ph-H), 7.90 (s, 1H, Ph-H), 7.81 (s, 1H,
Pyrazole-H), 7.48 (s, 1H, Ph-H), 7.35 (s, 1H, Ph-H), 2.65 (s, 3H,
NHCH3), 2.18 (s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO‑d6) δ
191.35, 166.12, 155.62, 141.00, 139.41, 138.70, 138.25, 136.41,
135.99, 135.52, 131.41, 131.21, 131.14, 130.96, 130.70, 129.65,
125.37, 121.30, 106.70, 26.03, 17.61. Anal. calcd for C21H15Cl2F3N4O3:
C, 50.52; H, 3.03; C, 46.90; found: C, 50.58; H, 3.07; C, 46.95.
6

F.-Y. Li et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
H, 3.60; N, 10.54; found: C, 49.76; H, 3.65; N, 10.59.
3H, CH3S), 2.64 (s, 3H, NHCH3), 2.17 (s, 3H, Ph-CH3). 13C NMR
(101 MHz, DMSO‑d6)
δ 167.36, 163.62, 163.39, 156.82, 142.80,
4.1.5. General synthetic procedure for If
140.58, 139.90, 138.68, 137.07, 135.28, 133.00, 132.81, 132.66,
132.43, 132.33, 132.12, 131.31, 126.50, 121.91, 107.91, 58.14, 38.85,
27.29, 18.83. Anal. calcd for C24H19Cl2F6N5O4S: C, 43.78; H, 2.91; N,
10.64; found: C, 43.83; H, 2.96; N, 10.68.
Compound Ie (0.28 g, 0.5 mmol) was dissolved in 10 mL anhydrous
tetrahydrofuran, and then m-CPBA (0.173 g, 1 mmol) was added to the
reaction at 0 °C. After 5 min, the solvent was evaporated and ethyl
acetate (15 mL) was added. The mixture was washed with saturated
sodium bicarbonate (15 mL) and saturated sodium chloride (15 mL)
successively, and dried with anhydrous sodium sulfate, and evaporated
to obtain If. White solid, yield: 92.7%, m.p. 211–212 °C. 1H NMR
(400 MHz, DMSO‑d6) δ 10.41 (s, 1H, Ph-NH-CO), 8.36 (d, J = 4.1 Hz,
1H, Ph-CO-NH), 7.90 (s, 1H, Ph-H), 7.69 (d, J = 8.1 Hz, 2H, 2Ph-H),
7.58 (d, J = 8.3 Hz, 1H, Pyrazole-H), 7.48 (s, 1H, Ph-H), 7.35 (s, 1H,
Ph-H), 4.61 (s, 2H, CH2SO2), 2.89 (s, 3H, CH3SO2), 2.65 (d, J = 3.9 Hz,
3H, NHCH3), 2.17 (s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO‑d6) δ
166.17, 155.65, 141.64, 139.42, 138.74, 137.26, 135.92, 133.47,
131.48, 130.92, 130.35, 129.92, 129.47, 128.80, 127.85, 125.37,
121.67, 106.64, 58.00, 29.60, 26.07, 17.64. Anal. calcd for
4.1.8. General synthetic procedure for Ii
Compound Ig (1.14 g, 2 mmol) and m-CPBA (0.519 g, 3 mmol) were
dissolved in 10 mL ethanol, and then a solution of potassium carbonate
(0.828 g, 6 mmol) in 5 mL water was added at 0 °C. The reaction was
stirred for 1 h at 0 °C. Ethyl acetate (25 mL) was added, then washed
with dilute hydrochloric acid (15 mL) and saturated sodium bicarbo-
nate solution (15 mL). The organic layer was dried and evaporated to
obtain Ii. White solid, yield: 83.1%, m.p. 163–164 °C. 1H NMR
(400 MHz, DMSO‑d6) δ 10.38 (s, 1H, Ph-NH-CO), 8.32 (d, J = 3.8 Hz,
1H, Ph-CO-NH), 7.81–7.72 (m, 3H, 2Ph-H and Pyrazole-H), 7.64 (d,
J = 8.1 Hz, 1H, Ph-H), 7.48 (s, 1H, Ph-H), 7.35 (s, 1H, Ph-H), 5.13 (s,
2H, CH2S), 3.33 (s, 3H, CH3S), 2.64 (d, J = 3.7 Hz, 3H, NHCH3), 2.17
(s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO‑d6) δ 166.37, 155.84,
142.32, 140.59, 138.92, 137.64, 136.08, 134.27, 131.89, 131.76,
131.63, 131.38, 131.14, 130.38, 127.17, 125.55, 121.00, 112.30,
106.90, 58.19, 38.78, 26.26, 17.81. Anal. calcd for C24H19Cl2F6N5O3S:
C, 44.87; H, 2.98; N, 10.90; found: C, 44.89; H, 2.99; N, 10.94.
C
22H19Cl2F3N4O4S: C, 46.90; H, 3.40; N, 9.94; found: C, 46.94; H, 3.44;
N, 9.95.
4.1.6. General synthetic procedure for Ig17
Compound Ie (1.68 g, 3 mmol) was dissolved in 20 mL anhydrous
tetrahydrofuran, and then PhI(AcO)2 (0.966 g, 3 mmol) and NH2CN
(0.139 g, 3.3 mmol) was added successively at 0 °C. After 5 min, the
solvent was evaporated and ethyl acetate (35 mL) was added. The
mixture was washed with sodium hydrogen sulfite (20 mL), and satu-
rated sodium chloride (20 mL) successively, and dried with anhydrous
sodium sulfate, and evaporated to obtain Ig. White solid, yield: 72.9%,
m.p. 164–165 °C. 1H NMR (400 MHz, DMSO‑d6) δ 10.35 (s, 1H, Ph-NH-
CO), 8.33 (d, J = 4.5 Hz, 1H, Ph-CO-NH), 7.73 (s, 1H, Ph-H), 7.71 (s,
2H, 2Ph-H), 7.54 (s, 1H, Ph-H), 7.51 (s, 1H, Pyrazole-H), 7.40 (d,
J = 1.9 Hz, 1H, Ph-H), 4.54 (d, J = 12.5 Hz, 1H, 1/2CH2S), 4.50 (d,
J = 12.4 Hz, 1H, 1/2CH2S), 2.80 (s, 3H, CH3S), 2.65 (d, J = 4.4 Hz, 3H,
NHCH3), 2.17 (s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO‑d6) δ
166.15, 162.01, 155.63, 141.44, 139.42, 138.75, 137.51, 135.90,
133.57, 131.48, 131.18, 130.91, 130.72, 130.02, 129.52, 128.90,
125.35, 121.37, 106.66, 52.07, 31.71, 26.09, 17.65. Anal. calcd for
4.1.9. General synthetic procedure for Ik16
Compound Ij (0.328 g, 0.5 mmol) was dissolved in 5 mL tetra-
hydrofuran, and then a solution of potassium carbonate (0.083 g,
0.6 mmol) in 5 mL water was added. The reaction was stirred for 2 h at
room temperature. Ethyl acetate (15 mL) was added, and washed with
saturated sodium chloride (15 mL). The organic layer was dried and
evaporated to obtain Ik. White solid, yield: 89.0%, m.p. 165–166 °C. 1H
NMR (400 MHz, DMSO‑d6) δ 10.36 (s, 1H, Ph-NH-CO), 8.35 (s, 1H, Ph-
CO-NH), 7.73 (s, 2H, Ph-H and Pyrazole-H), 7.66 (d, J = 8.0 Hz, 1H,
Ph-H), 7.59 (d, J = 7.6 Hz, 1H, Ph-H), 7.48 (s, 1H, Ph-H), 7.35 (s, 1H,
Ph-H), 4.45 (s, 2H, CH2S), 3.77 (s, 1H, S]NH), 2.73 (s, 3H, CH3S), 2.65
(s, 3H, NHCH3), 2.17 (s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO‑d6) δ
166.67, 156.15, 142.22, 139.91, 139.24, 137.53, 136.41, 133.95,
132.00, 131.66, 131.46, 131.41, 131.06, 130.44, 129.98, 125.84,
121.80, 107.10, 61.21, 40.87, 26.57, 18.13. Anal. calcd for
C
22H19Cl2F3N4O4S: C, 46.90; H, 3.40; N, 9.94; found: C, 46.94; H, 3.44;
N, 9.95.
C
22H20Cl2F3N5O3S: C, 46.98; H, 3.58; N, 12.45; found: C, 46.99; H,
4.1.7. General synthetic procedure for Ih
3.65; N, 12.49.
Compound Ig (0.285 g, 0.5 mmol) was dissolved in 10 mL anhy-
drous tetrahydrofuran, and then a solution of trifluoroacetic acid
(0.114 g, 1 mmol) in 5 mL tetrahydrofuran was added at 0 °C. The re-
action was stirred for 3 h at room temperature. The solvent was eva-
porated and ethyl acetate (20 mL) was added. The mixture was washed
with saturated sodium bicarbonate (15 mL), and saturated sodium
chloride (15 mL) successively, and dried with anhydrous sodium sul-
fate, and evaporated to obtain Ih. The synthetic procedure for Ij is si-
milar.
4.2. Biological assay
All biological assays were performed in a greenhouse. The bioassays
were replicated at each rate three times at 25
1 °C according to
statistical requirements. Assessments were made on a dead/alive basis
and corrected by applying Abbott’s formula.19 Evaluation was based on
a percentage scale of 0–100 (0 means no activity, and 100 means total
kill) with the standard deviations
by probit analysis.20
5%. LC50 values were calculated
Ih: White solid, yield: 75.8%, m.p. 157–158 °C. 1H NMR (400 MHz,
DMSO‑d6) δ 10.38 (s, 1H, Ph-NH-CO), 8.51 (d, J = 4.4 Hz, 1H, Ph-CO-
NH), 7.67 (s, 1H, Ph-H), 7.60 (s, 2H, 2Ph-H), 7.50 (s, 1H, Ph-H), 7.45 (s,
1H, Pyrazole-H), 7.41 (d, J = 1.7 Hz, 1H, Ph-H), 4.64 (d, J = 12.7 Hz,
1H, 1/2CH2S), 4.40 (d, J = 12.8 Hz, 1H, 1/2CH2S), 2.65 (s, 6H, NHCH3
and CH3S), 2.17 (s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO‑d6) δ
166.18, 165.03, 156.03, 141.02, 139.30, 139.15, 138.21, 135.80,
133.67, 132.47, 131.37, 131.20, 130.84, 130.37, 130.00, 129.47,
128.86, 125.24, 121.24, 106.51, 42.13, 30.01, 26.11, 17.43. Anal. calcd
for C23H19Cl2F3N6O3S: C, 47.03; H, 3.26; N, 14.31; found: C, 47.07; H,
3.28; N, 14.36.
4.2.1. Heart (dorsal vessel) rate against Periplaneta americana
The experiment was performed on adult males of the Periplaneta
americana according to the reported method.11
4.2.2. Larvicidal activity against oriental armyworm
The larvicidal activity of Ia-k and chlorantraniliprole against or-
iental armyworm was tested according to the leaf-dip method,21 and
the larvicidal activity is listed in Table 1.
Ij: White solid, yield: 86.4%, m.p. 147–148 °C. 1H NMR (400 MHz,
DMSO‑d6) δ 10.37 (s, 1H, Ph-NH-CO), 8.33 (s, 1H, Ph-CO-NH),
7.78–7.75 (d, J = 9.0 Hz, 3H, 2Ph-H and Pyrazole-H), 7.61 (s, 1H, Ph-
H), 7.49 (s, 1H, Ph-H), 7.35 (s, 1H, Ph-H), 5.18 (s, 2H, CH2S), 3.42 (s,
4.2.3. Larvicidal activity against diamondback moth
The larvicidal activity of Ia, Ib, Ie-j and chlorantraniliprole were
tested by the leaf-dip method,22 and the larvicidal activity is listed in
Table 2. LC50 values of If and chlorantraniliprole are listed in Table 3.
7

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Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
4.3. Calcium imaging experiment
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Acknowledgments
This study was financially supported by the National Key Research
and Development Program of China (No. 2018YFD0200100), Natural
Science Foundation of Tianjin (No. 16JCYBJC29400), the Scientific
Project of Tianjin Municipal Education Commission (No. 2018KJ008)
and National Student's Platform for Innovation and Entrepreneurship
Training Program (No. 201810061003).
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Appendix A. Supplementary data
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Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmc.2019.01.009.
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