Synthesis and insecticidal evaluation of novel N -pyridylpyrazolecarboxamides containing an amino acid methyl ester and their analogues

Article abstract of DOI:10.1021/jf500003d

On the basis of the commercial insecticide chlorantraniliprole, a series of novel N-pyridylpyrazolecarboxamides containing an amino acid methyl ester and their analogues were designed and synthesized. Their chemical structures were established on the basi

Full text of DOI:10.1021/jf500003d

Article
pubs.acs.org/JAFC
Synthesis and Insecticidal Evaluation of Novel
N‑Pyridylpyrazolecarboxamides Containing an Amino Acid Methyl
Ester and Their Analogues
Ming-Zhen Mao,‡ Yu-Xin Li,† Yun-Yun Zhou,† Xiu-Lan Zhang,† Qiao-Xia Liu,† Feng-Juan Di,†
Hai-Bin Song,† Li-Xia Xiong,† Yong-Qiang Li,† and Zheng-Ming Li*,†
†State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
‡Xi’an Modern Chemistry Research Institute, Xi’an 710065, People’s Republic of China
S
* Supporting Information
ABSTRACT: On the basis of the commercial insecticide chlorantraniliprole, a series of novel N-pyridylpyrazolecarboxamides
containing an amino acid methyl ester and their analogues were designed and synthesized. Their chemical structures were
established on the basis of corresponding 1 H NMR spectroscopy, 13C NMR spectroscopy, elemental analysis, and single-crystal
X-ray diffraction analysis. The insecticidal activities of the new compounds against oriental armyworm (Mythimna separata) and
diamondback moth (Plutella xylostella) were evaluated. The results of bioassays indicated that most of the compounds showed
moderate to high activities at the tested concentration, of which the compounds 6 containing a methyl acrylate substructure had
excellent larvicidal activity; for example, 6a displayed 100% larvicidal activity against P. xylostella at the concentration of 0.005
mg/L, whereas the activities of both compounds 6g and 6h against M. separata were 100% at 2.5 mg/L. The calcium imaging
technique experiment results showed that novel compound 6 could elevate the calcium concentration in the cytoplasm.
Furthermore, this study also provided evidence that compound 6h activates inositol 1,4,5-trisphosphate (IP3) sensitive
intracellular calcium release channels in the endoplasmic reticulum of Spodoptera exigua third-instar larva neurons.
KEYWORDS: insecticidal activity, N-pyridylpyrazolecarboxamides, amino acid methyl ester, methyl acrylate substructure,
calcium channel
amides at the ortho-position (Figure1D) could improve
biological properties. To our disappointment, these compounds
showed low larvicidal activity against oriental armyworm
(Mythimna separata). Interestingly, an elimination product of
the amino acid methyl ester containing methyl acrylate
substructure (Figure1E) showed excellent insecticidal activities
against oriental armyworm and diamondback moth. Building
on these developments, we designed and synthesized a series of
novel N-pyridylpyrazolecarboxamides containing an amino acid
methyl ester and analogue substructures in the ortho-position
(Figure1E). The larvicidal activities against oriental armyworm
and diamondback moth were evaluated, and the structure−
activity relationships were also discussed. To further explore the
mode of action for the target compounds, the effect of some
target compounds on intracellular calcium ion concentration
([Ca2+]i) in the central neurons isolated from the third instar of
S. exigua was studied by calcium imaging techniques. The
present study also explored the possible effect of novel
compounds on the calcium signaling pathway in the central
neurons.
INTRODUCTION
■
The discovery of novel insecticides with a new mode of action
is crucial to overcoming resistance and ecobiological problems
associated with some conventional insecticides. In recent years,
DuPont has discovered chlorantraniliprole1 (Figure1A), which
has an anthranilic diamide structure, exhibits exceptional broad-
spectrum activity, high potency, and low mammalian toxicity,
and has proved itself to be a selective activator of the insect
ryanodine receptor.2 Owing to their prominent insecticidal
activity, unique mode of action, and good environmental
profiles, anthranilic diamides and their chemical synthesis have
recently attracted considerable attention in the field of novel
agricultural insecticides.
Most of the modifications in chlorantraniliprole structure
preserve the anthranilic amide moiety,3−8 indicating that the
anthranilic amide is a key pharmacophore in this kind of
compound. However, structural modifications of the amides in
the ortho-position, such as cyano,9 hydrazone,10 and hetero-
cyclic groups, were also reported.11,12 Recently, a novel
pyrazolecarboxamide with a thiadiazol group in the ortho-
position (Figure1B, JS9117) was reported with high insecticidal
activity.13 Compound C (Figure1) containing an oxazoline
group reported by Kang et al. showed good larvicidal activity
against beet armyworm (Spodoptera exigua),14 indicating the
ortho-position is still attractive in further modification. Inspired
by these studies, we speculated that the introduction of
oxazoline-4-carboxylate moiety into N-pyridylpyrazolecarbox-
Received: September 26, 2013
Accepted: January 16, 2014
Published: January 16, 2014
© 2014 American Chemical Society
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Figure 1. Chemical structures of compounds A−E.
a
Scheme 1
a
Reagents and conditions: (i) CH3CN, pyridine, CH3SO2Cl, room temperature; (ii) CH3CN, L-cysteine methyl ester hydrochloride, Et3N, room
temperature, 10 min, then reflux; (iii) CH3CN, L-serine methyl ester hydrochloride, Et3N, room temperature, 10 min, then reflux; (iv) THF, SOCl2,
0 °C; (v) CH2Cl2, CH3SO2Cl, Et3N, 0 °C, then room temperature.
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Scheme 2. Proposed Formation of 6a, 7a, and 8a
added to quench the excess amount of thionyl chloride. The resulting
mixture was extracted with ethyl acetate (3 × 20 mL), and then the
combined organic extracts were washed with brine and dried with
magnesium sulfate. The solvent was evaporated in a vacuum, and the
residue was purified on silica gel with petroleum/ethyl acetate (v/v,
4:1) to give 6a.21
X-ray Diffraction. The crystal structure of compound 6g was
determined, and X-ray intensity data were recorded on a Bruker
SMART 1000 CCD diffraction meter using graphite monochromated
Mo Kα radiation (λ = 0.71073 Å). All calculations were refined
anisotropically. All 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.
MATERIALS AND METHODS
■
Instruments. The measurement of melting points was conducted
on a Yanaco MP-500 micromelting point apparatus without
calibration. 1H NMR spectra were recorded on a Bruker AC-400
instrument in CDCl3 as solvent and Me4Si as internal standard.
Chemical shifts were reported as δ values in parts per million (ppm).
Elemental analysis was performed on a Yanaco CHN Corder MF-3
automatic elemental analyzer. All chemical reagents and solvents were
of analytical grade.
Compounds 1a−c were synthesized according to the method
reported by our previous work.15−17 2-Amino-5-substuituted-3-
methylbenzoic acids (2a−c) were prepared by referring to the
known procedure.15,16 The intermediates 3a−h were synthesized
according to the literature.18 The title compounds were prepared as
shown in Scheme 1.
General Procedure for the Synthesis of Compounds 4 and
5.19 L-Cysteine methyl ester hydrochloride (1.0 mmol) was added to
20 mL of acetonitrile under stirring, followed by the addition of
triethylamine (1.2 mmol). After stirring for 0.5 h at room temperature,
3a (1.0 mmol) was added and the resulting mixture was refluxed for a
further 12 h (monitored by TLC). After completion of the reaction,
the solvent was evaporated in vacuum and the residue was purified on
silica gel, eluting with petroleum/ethyl acetate (v/v, 1:1), and 4a was
obtained.
Compounds 5a−f were prepared following the same procedures
described in the preparation of compound 4a using L-serine methyl
ester hydrochloride instead of L-cysteine methyl ester hydrochloride.
General Procedure for the Synthesis of Compounds 6−8.20
To an ice-cold solution of 5 (1 mmol) in 20 mL of dichloromethane
were added successively triethylamine (3 mmol) and methanesulfonyl
chloride (1.5 mmol) with stirring. Then the reaction mixture was
allowed to warm to room temperature and stirred until the reaction
completed, monitored by TLC. After completion, the mixture was
then washed with dilute hydrochloric acid solution and brine and dried
with magnesium sulfate. The solvent was evaporated in a vacuum, the
residue was purified on silica gel with petroleum/ethyl acetate (v/v,
4:1), and 6a, 7a, and 8a were obtained.
Biological Assay. Insecticidal activities against oriental armyworm
(Mythimna separata) and diamondback moth (Plutella xylostella) 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.22 Evaluation was based on a
percentage scale of 0−100, where 0 equals no activity and 100 equals
total kill. Error of the experiments was 5%. For comparative purposes,
chlorantraniliprole was tested as control under the same conditions.
Larvicidal Activity against Oriental Armyworm (M. separa-
ta). The insecticidal activities of compounds 4a−8a and chloran-
traniliprole were evaluated using the reported procedure.23 For the
foliar armyworm tests, individual corn leaves were placed on
moistened pieces of filter paper in Petri dishes. The leaves were
then sprayed with the test solution and allowed to dry. The dishes
were infested with 10 fourth-instar oriental armyworm larvae.
Percentage mortalities were evaluated 2 days after treatment. Each
treatment was performed three times.
Larvicidal Activity against Diamondback Moth (P. xylostel-
la). The larvicidal activities of compounds 4a−8a and chlorantrani-
liprole were tested by the leafdip method. First, a solution of each test
sample in DMSO (AR, purchased from Alfa Aesar) at a concentration
of 200 mg/L was prepared and then diluted to the required
concentration with water (distilled). Leaf disks (6 cm × 2 cm) were
cut from fresh cabbage leaves and then were sprayed with the test
solution for 3 s and allowed to dry. The resulting leaf disks were placed
individually into glass tubes. Each disk was infested with 30 second-
Compound 5 (1 mmol) was dissolved in 20 mL of tetrahydrofuran
and cooled in an ice bath. With constant agitation, thionyl chloride (2
mmol) was added dropwise, and the reaction mixture was stirred at 0
°C until the reaction completed, monitored by TLC. After the
reaction, saturated sodium bicarbonate solution (30 mL) was then
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instar diamondback moth larvae. Percentage mortalities were evaluated
2 days after treatment. Each treatment was performed in triplicate.
Calcium Imaging. Calibration of the fluorescence signal was
obtained using the procedure of Iakahashi et al. with minor
modifications.24,25 The attached neurons were rinsed in standard
physiological saline [(mM) 150 NaCl, 4 KCl, 2 MgCl2, 2 CaCl2, 10
HEPES, buffered to pH 7.0] and then incubated in the dark at 28 °C
in standard external saline containing the dye Fluo-3 AM (Sigma, 10
μM). After dye loading, cells were again rinsed in physiological saline
twice.
To block IP3Rs, cells were incubated with heparin for 10 min.
Calcium ratio imaging studies were conducted using the imaging
system coupled to an inverted fluorescence microscope with a Fluor
40× oil immersion objective (Olympus IX71). Cells excited at 488 and
530 nm under fluorescence emission were acquired by using a CCD
(Image Pri-6.0).
Figure 2. Crystal structure of compound 6g.
Each experiment was replicated at least six times. The data were
analyzed by using SPSS Inc., version 17.0, and Microcal Origin, version
8.0 (Origin Lab Corp., Northampton, MA, USA). Results were
some compounds have excellent larvicidal activities against
oriental armyworm. Compounds 4a and 5a−h containing an
amino acid methyl ester displayed moderate activities against
oriental armyworm; the insecticidal activities were below 100%
at 100 mg/L except for compound 4a, which showed 60% at 50
mg/L. Compound 7a containing oxazoline-4-carboxylate also
showed low larvicidal activity against oriental armyworm; the
mortality was only 60% at 200 mg/L. The larvicidal activity of
mesylation product 8a at a concentration of 10 mg L−1 was
50%, much higher than that of 5a, indicating that the
introduction of a mesyl in the hydroxyl group has a positive
effect on larvicidal activities. The elimination products
containing methyl acrylate substructure 6a−h showed excellent
insecticidal activities against oriental armyworm, especially
compounds 6g and 6h, which showed 100% larvicidal activities
at the concentration of 2.5 mg/L. Activities varied significantly
depending upon the types of substituents on the 3-position of
pyrazole. Compared with 3-Br and 3-CF3 in pyrazole,
compounds with 3-OCH2CF3 substituents showed higher
insecticidal activities against oriental armyworm, which suggests
that the introduction of the 2,2,2-trifluoroethoxy groups in the
3-position of pyrazole has a positive effect on the larvicidal
activities. The substituents on the aromatic ring showed no
significant effect on the activity.
The larvicidal activity of compounds 6a−h against diamond-
back moth was evaluated as shown in Table 2. Most of them
had excellent larvicidal activity against diamondback moth; all
of the compounds showed 100% activity at 1 mg/L.
Compounds with 3-Br substituents on the 3-position of
pyrazole showed higher insecticidal activities against diamond-
back moth, which was different from the activities against
oriental armyworm. For instance, the larvicidal activities of 6a−
c at 0.01 mg/L were 100, 57, and 43%, respectively, whereas
6d−h had no more than 43% at the same dosage. In particular,
compound 6a had 100% mortality at the concentration of 0.005
mg/L, equal to that of chlorantraniliprole, but its LC50 was
0.0008 mg/mL, still higher than that of chlorantraniliprole
(0.00009 mg/mL, Table 3).
expressed as the mean
SD (n = number of cells). Statistical
significance was determined by Student’s paired or unpaired t test.
Fluorescence values were expressed as F/F0, with F0 being the resting
(or baseline) fluorescence and F the change in fluorescence from
baseline after drug application.26
RESULTS AND DISCUSSION
■
Chemistry. Compounds 5a−h were prepared by treating
compounds 3a−h with L-serine methyl ester hydrochloride
using triethylamine as alkali in acetonitrile, affording the desired
product in good yields. Compound 4a was prepared following
the same procedures described in the preparation of
compounds 5a−h using L-cysteine methyl ester hydrochloride
instead of L-serine methyl ester hydrochloride.
In the initial step,20 we attempted to treat 5a with
methanesulfonyl chloride in the presence of triethylamine to
prepare 7a. Surprisingly, the elimination product 6a was
obtained as the main product, together with compounds 7a and
8a in low yields as shown in Scheme 1. On the basis of the
literature previously reported, a mechanism that can possibly
explain the formation of 6a, 7a, and 8a was proposed and is
illustrated in Scheme 2. In the presence of methanesulfonyl
chloride in dichoromethane, compound 5a first undergoes
initial mesylation to give the intermediate 8a and then
generates nitrogen anion 9 and carbanion 11. The nitrogen
anion 9 subsequent isomerizes to 10, which undergoes
intramolecular nucleophilic attack to form the oxazoline ring
closure compound 7a, whereas compound 6a is obtained by
elimination of 11.
Due to the low insecticidal activities of 7a, the synthesis of
this derivative was not further processed. Another alternative
synthetic route was explored to prepare the target compound
6a21 by using thionyl chloride in tetrahydrofuran at 0 °C, which
resulted in high yields and purity of 6a.
Crystal Structure Analysis. Compound 6g was recrystal-
lized from a mixture of dichloromethane and petroleum ether
(60−90 °C) to give colorless crystals (0.22 mm × 0.14 mm ×
0.12 mm) suitable for X-ray single crystal diffraction as shown
in Figure 2 with the following crystallographic parameters: a =
15.005(2) Å, b = 15.005(2) Å, c = 21.630 (4) Å, α = 90°, β =
90°, γ = 120°, V = 4217.8 (12) Å3, Z = 6, Dc = 1.553 g cm−3, μ
= 0.486 mm−1, F(000) = 2004, R = 0.0498, T = 113 (2) K, wR
= 0.0988, final R factor = 4.63%.
Previously, the neurons of S. exigua were used for studying
the mechanism of diamide insecticides, and we also found the
increase of [Ca2+]i was positive for the insecticidal activity
against oriental armyworm. To determine whether compounds
6a−h might be involved in calcium signaling transduction, we
examined the effects of several novel compounds on the central
neurons of S. exigua on the calcium homeostasis with calcium
imaging technique after neuron loading with Fluo-3 AM. Figure
3 shows the change of [Ca2+]i versus recording time when the
neurons were treated with compounds 6a, 6d, 6g, and 6h in the
Structure−Activity Relationship (SAR). The larvicidal
activity of compounds 4a−8a against oriental armyworms is
summarized in Table 1. The bioassay results indicated that
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Table 1. Insecticidal Activities of Compounds 4a, 5a−h, 6a−h, 7a, and 8a and Chlorantraniliprole against Oriental Armyworm
larvicidal activity (%) at a concentration of
compd
200 mg/L
100 mg/L
50 mg/L
60
10 mg/L
5 mg/L
2.5 mg/L
1 mg/L
4a
5a
5b
5c
5d
5e
5f
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
100
80
50
40
60
30
80
5g
5h
6a
6b
6c
6d
6e
6f
70
100
100
100
100
100
100
100
100
100
40
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
60
40
73.3
60
50
6g
6h
7a
8a
100
100
100
100
40
40
100
100
100
100
100
100
50
chlorantraniliprole
100
100
100
100
Table 2. Insecticidal Activities of Compounds 6a−h and Chlorantraniliprole against Diamondback Moth
larvicidal activity (%) at a concentration of
compd
10 mg/L
1 mg/L
0.1 mg/L
0.01 mg/L
0.005 mg/L
100
0.001 mg/L
57
0.0005 mg/L
29
6a
6b
6c
6d
6e
6f
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
86
100
57
43
43
29
0
71
100
100
43
6g
6h
43
0
86
29
100
chlorantraniliprole
100
100
90
80
Table 3. LC Values of Compound 6a and
50
Chlorantraniliprole against Diamondback Moth
compd
y = a + bx
LC50 (mg/L)
R
6a
chlorantraniliprole
y = 13.28 + 2.65x
y = 9.66 + 1.07x
0.0008
0.99
0.93
0.00009
absence of extracellular calcium. Application of 1000 mg/L
compound 6 and chlorantraniliprole to isolated S. exigua
neurons caused an increase in the cytosolic calcium
concentration. The peak of [Ca2+]i was increased to 104.13
2.88% (n = 9), 103.6 3.10% (n = 16), 106.00 2.17% (n =
12), 106.59 2.41% (n = 15), and 115.42 2.37% (n = 12) of
the initial value after the neurons were treated with compounds
6a, 6d, 6g, and 6h for <10 s, respectively. Thus, calcium
released from the calcium store elevated the cytosolic calcium
levels. The calcium concentration in the neurons elevated by
compounds 6a and 6h (Figure 4) is in a concentration-
dependent manner, the same as previously reported for diamide
insecticides by our research group.
Figure 3. Effects of different concentrations of compounds 6a, 6d, 6g,
and 6h on [Ca2+]i in the central neurons of S. exigua when extracellular
Ca2+ was absent (EGTA replaced Ca2+). The central neurons of S.
exigua third-instar larvae were dyed by loading with Fluo-3 AM.
When external Ca2+ was free, IP3 receptors were blocked by
using heparin, and the increase of [Ca2+]i was only attributed to
the release by RyRs. Preincubated by heparin, the effect of
compound 6h on F/F0 was reduced to 103.63 2.04% (n =
13) (Figure 5). Inhibiting IP3Rs with heparin can activate the
RyRs, meaning that using heparin can actually cause an increase
in calcium. Figure 5 demonstrates compound 6h could activate
IP3Rs and RyRs, so it is elucidated that these compounds have
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AUTHOR INFORMATION
Corresponding Author
*(Z.-M.L.) E-mail: nkzml@vip.163.com.
■
Funding
This work has been supported by the National Basic Research
Program of China (973 Project 2010CB126106), the National
Natural Science Foundation of China (NNSFC 31370039), and
the National Key Technologies Research and Development
Program (2011BAE06B05).
Notes
The authors declare no competing financial interest.
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and diamondback moth (P. xylostella). Especially, compound 6a
showed 100% larvicidal activity against P. xylostella at the
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, melting points, yields, and elemental analysis data for
4a, 5a−h, 6a−h, 7am and 8a; 13CNMR data for 6a−h, 7am
and 8a. This material is available free of charge via the Internet
at http://pubs.acs.org.
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Q. Zhao, Y.; Wang, G. (Pyrazolecarbonyl)thiourea derivatives as
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