Synthesis and biological evaluation of nitromethylene neonicotinoids based on the enhanced conjugation

Article abstract of DOI:10.1021/jf403272h

The neonicotinoids with a nitroconjugated system had excellent bioactivity, which could rival imidacloprid, and has been previously reported. However, the photodegradation and hydrolysis of this series of neonicotinoids was very quick according to our further investigation, which cannot be developed as a pesticide further. The approach to further enhance the conjugation was tried not only to increase the bioactivities but also to improve the stability in water and in the sun. A substituted phenyl group was introduced into the furan ring of compound 3. A total of 13 novel neonicotinoid analogues with a higher conjugation system were designed and synthesized. The target molecular structures have been confirmed on the basis of satisfactory analytical and spectral data. All compounds presented significant insecticidal activities on cowpea aphid (Aphis craccivora), cotton aphid (Aphis gossypii), and brown planthopper (Nilaparvata lugens). The stability test exhibited that the stability of novel analogues in water and under the mercury lamp has been improved significantly in comparison to compound 3.

Full text of DOI:10.1021/jf403272h

Article
pubs.acs.org/JAFC
Synthesis and Biological Evaluation of Nitromethylene
Neonicotinoids Based on the Enhanced Conjugation
Siyuan Lu,† Yingying Zhuang,† Ningbo Wu,† Yue Feng,† Jiagao Cheng,† Zhong Li,† Jie Chen,‡ Jing Yuan,‡
and Xiaoyong Xu*,†
†Shanghai Key Laboratory of Chemistry Biology, Institute of Pesticides and Pharmaceuticals, East China University of Science and
Technology, Shanghai 200237, People’s Republic of China
‡Zhejiang Research Institute of Chemical Industry, Limited, Hangzhou 310023, People’s Republic of China
S
* Supporting Information
ABSTRACT: The neonicotinoids with a nitroconjugated system had excellent bioactivity, which could rival imidacloprid, and
has been previously reported. However, the photodegradation and hydrolysis of this series of neonicotinoids was very quick
according to our further investigation, which cannot be developed as a pesticide further. The approach to further enhance the
conjugation was tried not only to increase the bioactivities but also to improve the stability in water and in the sun. A substituted
phenyl group was introduced into the furan ring of compound 3. A total of 13 novel neonicotinoid analogues with a higher
conjugation system were designed and synthesized. The target molecular structures have been confirmed on the basis of
satisfactory analytical and spectral data. All compounds presented significant insecticidal activities on cowpea aphid (Aphis
craccivora), cotton aphid (Aphis gossypii), and brown planthopper (Nilaparvata lugens). The stability test exhibited that the
stability of novel analogues in water and under the mercury lamp has been improved significantly in comparison to compound 3.
KEYWORDS: Neonicotinoids, conjugation, insecticidal activity
exhibited a very high insecticidal activity against cowpea aphid
(A. craccivora) with a LC50 value of 3.72 μmol L−1.16
Unfortunately, the half-life of compound 3 was 0.77 min
under the irradiation of a 300 W high-pressure mercury lamp,
and its hydrolysis half-life in water was only 2.40 h. It is well-
known that the degradation of compounds as pesticides
occurring in the environment is a key factor in insecticide
research and development. Inspired by the model, we tried to
enhance the conjugation system and improve the conjugation
effect of the nitromethylene pharmacophore for the sake of
improved stability, which was contributed to the formation of
the π−π interaction.
Therefore, a substituted phenyl group was introduced into
the furan ring. In addition, the binding affinity and insecticidal
activity were also expected to be enhanced by a possible π−π
interaction. Synthesis of 13 nitromethyleneneonicotinoids, their
significant insecticidal activities, and increased stabilities were
reported in this paper.
INTRODUCTION
■
Neonicotinoids, as a milestone of integrated pest management
(IPM) during the past 30 years, are a kind of insecticide that
acts selectively on the central nervous system of the insect and
can be efficient ligands for the nicotinic acetylcholine receptors
(nAChRs) of insects.1−3 However, with the increase of
neonicotinoids used on the crop protection for a long time,
the problems of resistance, cross-resistance,4−7 and bee toxicity8
have received more attention, which calls for a new strategy of
molecular design to find new leading compounds.
The mode of action of neonicotinoids targeting nAChRs
attracted widely interests,9−11 several papers about acetylcho-
line receptor binding protein imidacloprid (AChBPs-IMI) were
reported.2,12 Qian et al. also proposed a new mode of action by
computational modeling, which demonstrated the importance
of hydrogen bonding and the cooperative π−π interaction
between the molecule and amino acid residues.13 On the basis
of this model, series 1 of phenylazoneonicotinoids (compound
1 in Figure 1) were designed and synthesized. The diazene
moiety was introduced to enhance the π−π stacking interaction
to increase the electron scope and density of the conjugated
system.14,15 Some of synthesized compounds with electron-
donating groups (EDGs) on ortho positions of the phenyl ring
presented higher insecticidal activity than imidacloprid against
cowpea aphid (Aphis craccivora). Encouraged by this molecular
design of phenylazoneonicotinoids with well-conjugated
systems, we pay more attention to the neonicotinoids with a
nitroconjugation system (compound 2 in Figure 1). Series 2
exhibited excellent insecticidal activity comparable to that of
imidacloprid against cowpea aphid. Especially compound 3
MATERIALS AND METHODS
Instrumentation and Chemicals. High-resolution mass spectra
were recorded under electron impact (70 eV) conditions using a
MicroMass GCT CA 055 instrument. Melting points (mp) were
■
recorded on Buchi B540 apparatus and are uncorrected. Proton
̈
nuclear magnetic resonance (1H NMR) spectra were recorded on a
Bruker AM-400 (400 MHz) spectrometer with CDCl3 or DMSO-d6 as
the solvent and tetramethylsilane (TMS) as the internal standard.
Received: July 25, 2013
Revised: October 30, 2013
Accepted: November 1, 2013
Published: November 1, 2013
© 2013 American Chemical Society
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Figure 1. Design of compounds.
Scheme 1. Preparation of Intermediates 7a−7j
Scheme 2. Preparation of Intermediates 7k−7m
Chemical shifts are reported in δ (parts per million) values. Gas
chromatography (GC)−mass spectra were recorded using a HP 6890
gas chromatograph and a HP 5973 mass selective detector. Analytical
thin-layer chromatography (TLC) was carried out on precoated plates
(silica gel 60 F254), and spots were visualized with ultraviolet (UV)
light. An XPA series type merry-go-round photochemical reactor
(Xujiang Machine Factory, Nanjing, China) was equipped with a 300
W high-pressure mercury lamp. The working current of a 300 W high-
pressure mercury lamp was 2.2 A, and the operating voltage was 138.1
V.
Unless otherwise noted, reagents and solvents were used as received
from commercial suppliers.
Synthetic Procedures. Synthesis of Intermediates 7a−7j.
Intermediates 7a−7j were prepared as described in the literature
(Scheme 1).17,18
Substituted aniline (15 mmol) and concentrated hydrochloric acid
(10 mL) were stirred in H2O (50 mL) at 25 °C for 30 min and then
cooled to 0 °C. NaNO2 (18 mmol) in 5 mL of H2O was added
dropwise to the solution. After 1 h of stirring at 0 °C, furfural (15
mmol) in acetone (8 mL) and CuCl2·2H2O (3 mmol) in H2O (5 mL)
were slowly added successively. The resulting mixture was stirred for
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Scheme 3. Preparation of Compounds 4a−4m
12 h at room temperature and monitored by TLC (1:10 EtOAc/PE).
The solution was filtrated, and the filter cake was washed with EtOH,
giving the title compound.
Insecticidal Test for Armyworm (Pseudaletia separata
Walker). The activities of insecticidal compounds against armyworm
were tested by Zhejiang Research Institute of Chemical Industry, Ltd.
The insecticidal activity against armyworm was tested by foliar
application. Individual corn (Zea mays) leaves were placed on
moistened pieces of filter paper in Petri dishes. The leaves were
then sprayed with the compound solution and exposed to dry. The
dishes were infested with 10 s instar larvae and placed in the
conditioned room. The mortality rates were evaluated 48 h after
treatment. Each treatment had three repetitions, and the data were
adjusted and subject to probit analysis as before.
Hydrolysis and Photolysis Experiments. Ultraperformance
Liquid Chromatography (UPLC) Analysis Method. The concen-
trations of irradiated solutions 4a, 4b, 4c, 4f, 4g, 4i, 4k, 4l, 3, and IMI
were determined by UPLC. A Waters UPLC (Acquity UPLC H-Class)
equipped with a BEH C18 column (2.1 × 100 mm, 1.7 μm), column
oven (Acquity UPLC CH-B), quarter pump (Acquity UPLC QSM),
and Rheodyne injector (10 μL loop) was used. The following
instrumental parameters were adopted: eluent flow rate of 0.5 mL
min−1, gradient elution (0−1 min, 90:10% buffer/acetonitrile; 1−8
min, linear gradient to 100% acetonitrile; and 8−10 min, 100%
acetonitrile), 2 μL of injector volume, and 40 °C of column
temperature. A 5 min post-run time, back to the initial mobile-phase
composition, was used after each analysis. The buffer solution was
prepared by adding 0.01 M trifluoroacetic acid to Milli-Q water. λmax of
424, 424, 427, 437, 438, 437, 420, 450, 373, and 270 nm for
compounds 4a, 4b, 4c, 4f, 4g, 4i, 4k, 4l, 3, and IMI, respectively, were
adopted for analyst quantification. Quantification was performed by an
external standard calibration. Calibration curves were prepared in the
range from 0.02 to 0.1 mg/mL. Acetonitrile (Merck) was of high-
performance liquid chromatography (HPLC) grade, and water was
purified by a Millipore Milli-Q equipment.
Hydrolysis and Photolysis Experiments. To investigate the
hydrolysis, representative compounds 4a, 4b, 4f, 4i, 4k, 4l, and 3
were dissolved in Milli-Q water, respectively, and 1 mL of compounds
4a, 4b, 4f, 4i, 4k, 4l, and 3 aqueous solution (5 × 10−5 mol L−1)
contained in 1.5 mL brown sampler vials [9 mm, amber, screw top vial,
12 × 32 mm with cap and preslit polytetrafluoroethylene (PTFE)/
silicone septa] were prepared. The aqueous solutions were filtered by
an organic phase filter (13 × 0.22 μm) and then analyzed by UPLC to
monitor the peak area changes of compounds 4a, 4b, 4f, 4i, 4k, 4l, and
3 in water. The hydrolysis experiments would not stop until the
residues of compounds 4a, 4b, 4f, 4i, 4k, 4l, and 3 were <1%. All tests
were conducted at room temperature (25 3 °C). These data were
used to calculate half-lives.
Compounds 4c, 4g, 4k, and 4l have better stability in water than
others based on the hydrolysis test above. Then, these four compound
as representatives were selected to investigate the photolysis stability,
and 3, IMI, and NTN32692 were selected as controls. Compounds
were dissolved in Milli-Q water, and 40 mL of compounds 4c, 4g, 4k,
4l, 3, IMI, and NTN32692 aqueous solution (5 × 10−5 mol L−1)
contained in quartz cylindrical tubes (50 mL and 20 cm in height)
were prepared and irradiated with the 300 W high-pressure mercury
lamp. Dark control experiments were carried out at the conditions
similar to those described above, except that the tube was covered by
aluminum foil. Aliquots of 1 mL irradiated solutions and control
solutions were taken out at appropriate intervals, stored at 4 °C in the
dark, and then analyzed by UPLC to monitor the peak area changes of
compounds 4c, 4g, 4k, 4l, 3, IMI, and NTN32692. The experiments
would not stop until the residues of compounds were <1%.
Intermediates 7k−7m were prepared as described in the literature
(Scheme 2).19−21
Substituted phenylboronic acid (3.2 mmol), 5-bromo-2-furaldehyde
(3 mmol), and NaCO3 (8 mmol) were mixed in n-propanol (10 mL).
To the mixture with stirring, tetrakis(triphenylphosphine)palladium
(0.3 mmol) was added. The mixture was heated to reflux under an
argon atmosphere and monitored by TLC. The solution was filtrated
thought celite and extracted with EtOAc (10 mL × 3). The organic
layers were combined, washed with brine (50 mL), dried over MgSO4,
filtered, and concentrated. Crude product was purified by column
chromatography (1:10 EtOAc/PE) to give a yellow solid product.
General Synthetic Procedure for Compounds 4a−4m. A
catalytic amount of hydrochloric acid (12 M, 0.4 mL) was added to the
mixture of NTN32692 (4.0 mmol) and compound 7 (4.0 mmol) in
MeCN (20 mL). The resulting solution was stirred at 25 °C and
monitored by TLC. After filtration, the filter cake was rinsed with
MeCN (3 × 5 mL) and CH2Cl2 (3 × 5 mL), and then the resulting
filtrate was concentrated under reduced pressure to obtain pure
crystals (Scheme 3).
Biological Assay. According to statistical requirements, the
bioassay was repeated 3 times at 25
1 °C. All compounds were
dissolved in dimethylsulfoxide (AP, Shanghai Chemical Reagent Co.,
Ltd., Shanghai, China) and diluted with water containing Triton X-100
(0.1 mg L−1) to obtain series concentrations of 1, 0.5, and 0.25 mg L−1
and others for bioassays. For comparative purposes, imidacloprid
(IMI) and compound 3 were tested under the same conditions.
Insecticidal Test for Cowpea Aphid (A. craccivora). The
insecticidal activities of title compounds against cowpea aphid (A.
craccivora) were tested according to the previously reported
procedure.22 Horsebean seedling with 40−60 healthy apterous adults
were dipped in diluted solutions of the chemicals containing Triton X-
100 (0.1 mg L−1) for 5 s, and then the shoots were placed in the
conditioned room [25
1 °C and 50% relative humidity (RH)].
Water containing Triton X-100 (0.1 mg L−1) was used as a control.
The mortality rates were assessed after 24 h. Each treatment had three
repetitions, and the data were corrected and subject to probit analysis.
Insecticidal Test for Cotton Aphids (Aphis gossypii). The
activities against cotton aphid were tested by Zhejiang Research
Institute of Chemical Industry, Ltd. Cotton cotyledons with 30−40
healthy nymphs in Petri dishes were sprayed solutions (2.5 mL) with a
Potter spray tower (pressure, 5 lb/in2; settlement, 4.35 mg/cm2), and
then the cotyledons were placed in the conditioned room (25 1 °C
and 50% RH). Water containing Tween 80 (0.1%) was used as a
control. The mortality rates were assessed after 48 h. Each treatment
had three repetitions, and the data were corrected and subject to
probit analysis.
Insecticidal Test for Brown Planthopper (Nilaparvata
lugens). The activities against brown planthopper were tested by
Zhejiang Research Institute of Chemical Industry, Ltd. The insecticidal
activity against brown planthopper was tested by foliar application.
Rice seedlings were placed on moistened pieces of filter paper in Petri
dishes. The dishes were infested with third instar larvae and then
sprayed with the compound solutions (2.5 mL) using a Potter spray
tower (pressure, 5 lb/in2; settlement, 4.35 mg/cm2). Samples were
placed in the conditioned room. The mortality rates were evaluated 48
h after treatment. Each treatment had three repetitions, and the data
were adjusted and subject to probit analysis as before.
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Table 1. Insecticidal Activities of Compounds 4a−4m
A. craccivora
A. gossypii
N. lugens
P. separata Walker
compound
R
mortality (%, 1 mg L−1
)
LC50 (μmol L−1
)
LC50 (μmol L−1
)
LC50 (μmol L−1
)
mortality (%, 100 mg L−1
)
4a
2-NO2
67.0
88.0
100
100
100
97.0
88.4
100
97.6
90.0
100
69.4
92.6
nt
1.67
1.34
0.33
0.38
1.00
0.51
0.80
0.82
0.63
0.59
0.78
1.30
0.91
0.63
2.04
0.64
1.20
0.88
0.69
0.85
1.14
1.28
0.42
1.03
0.72
0.98
1.63
1.31
1.13
nt
0.38
0.39
0.42
0.54
0.75
0.71
0.29
0.47
0.34
0.22
0.12
0.17
0.28
1.09
nt
30
57
54
80
25
67
82
27
40
77
13
100
30
nt
4b
4-NO2
2,4-2F
2-F
4c
4d
4e
2,3-2F
4-Cl
4f
4g
4-Br
4h
3-F-4-Cl
2-Cl
4i
4j
2-OCF3-4-Br
4-CH3
4-H
4k
4l
4m
4-OCH3
IMI
3
62.1
nt
nt
nt
NTN32692
nt
nt
nt
Intriguingly, non-EDG-substituted compounds 4k, 4l, and 4m
maintained high insecticidal activities.
The test showed that all of the synthesized compounds did
not exhibited high activities against armyworm (P. separata
Walker) at the dosage of 100 mg L−1 except for compound 4l
based on the data of Table 1.
Hydrolysis and Photolysis. According to the data of
bioactivities shown in Table 1, typical EWG/EDG-substituted
compounds with high bioactivities, such as compounds 4a, 4b,
4c, 4f, 4g, 4i, 4k, and 4l, were selected to measure their half-life
of hydrolysis. Their degradation kinetics constants were
calculated by the residues of peak area versus time. The
relative concentrations of compounds 4a, 4b, 4c, 4f, 4g, 4i, 4k,
4l, and 3 fitted well to the following pseudo-first-order kinetic
equation:
RESULTS AND DISCUSSION
Synthesis. Two routes were used to synthesize the
■
intermediates 7a−7m. Compounds 7a−7j were synthesized
from furfural and aniline bearing electron-withdrawing groups
(EWGs) via Meerwein reactions. Reactions proceeded
smoothly. The products precipitated in the reaction mixtures
were filtrated and washed with MeCN and CH2Cl2, affording
the pure yellow solids.
Nevertheless, trace products and many byproducts were
obtained during the synthesis of intermediates 7k−7m bearing
EDGs or no substitute via Meerwein reactions. In view of above
results, the Suzuki coupling reaction was used in the synthesis
of intermediates 7k−7m. Because many byproducts would
cause difficult workup, reactions must be carried out under an
argon atmosphere at mild temperatures of 40−80 °C. The yield
and purity of 7k−7m were improved through this attempt.
During the synthesis of target compounds, compounds that
the benzene ring was substituted at the para position had a high
yield, such as the yield of compound 4f of 96%. A lower yield of
ortho-substituted products may be attributed to the increased
steric hindrance.
ln(Ct/C0) = −kt
(1)
where C0 is the initial concentration of compounds 4a, 4b, 4c,
4f, 4g, 4i, 4k, 4l, and 3, Ct is the concentration of compounds
4a, 4b, 4c, 4f, 4g, 4i, 4k, 4l, and 3 at time t, and k is the
observed reaction rate constant [obtained from the slope of the
line in the plot of ln(Ct/C0) versus time]. Figure 2 shows the
Biological Activities. Compounds 4a−4m exhibited
significant insecticidal activities against cowpea aphid (A.
craccivora), cotton aphid (A. gossypii), brown planthopper (N.
lugens), and armyworm (P. separata Walker). The insecticidal
activities were shown in Table 1. The bioactivities of all of the
synthesized compounds against cowpea aphid were better than
that of compound 3 and commercialized IMI. Among the
synthesized compounds, compound 4c showed excellent
insecticidal activities against cowpea aphid, with the LC50
value of 0.33 μmol L−1. Compound 4g exhibited the best
insecticidal activity against cotton aphid, with the LC50 value of
0.42 μmol L−1, while compound 4k showed the best insecticidal
activities against brown planthopper, with the LC50 value of
0.12 μmol L−1. Different substituents did not lead to obvious
change of activities against cowpea aphid. It was also found that
those compounds bearing strong EWGs presented lower
insecticidal activities, such as compounds 4a and 4b. Fluoro
substituted at the ortho and para positions enhanced the
activities of compounds 4c and 4d; however, compound 4e
with difluorine substituted at ortho and meta positions exhibited
an obviously lower activity than compounds 4c and 4d.
Figure 2. Degradation curve of compounds 4a, 4b, 4c, 4f, 4g, 4i, 4k,
4l, IMI, 3, and NTN32692 in water.
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best fit of eq 1 to the observed changes. The data of hydrolysis
rate constants (k), half-lives (t1/2), and linear response (R2) for
compounds are shown in Table 2. In this study, selected
Table 2. Hydrolysis Rate Constants (k), Half-Lives (t1/2),
and Linear Response (R2) for Compounds 4a, 4b, 4f, 4i, 4k,
4l, and 3
compound
k
t1/2 (h)
R2
4a
4b
4c
4f
4g
4i
0.0011836
0.0011997
0.0005763
0.0008598
0.0008720
0.0015173
0.0002679
0.0002459
0.00482
9.8
9.6
0.966
0.952
0.999
0.995
0.999
0.991
0.987
0.987
0.994
20.0
13.4
13.2
7.6
4k
4l
43.0
47.0
2.4
Figure 3. Photolysis rate constants (k), half-lives (t1/2), and linear
responses (R2) for compounds 4c, 4g, 4k, 4l, IMI, 3, and NTN32692
under the irradiation of a 300 W high-pressure mercury lamp.
3
compounds showed significantly improved stability in water.
The half-life of compounds 4k and 4l was longer than other
compounds, whose half-life was 43.0 and 47.0 h, respectively,
while that of compound 3 was only 2.4 h. The stability of
synthesized compounds increased about 18-fold. The stability
of eight selected compounds in water improved significantly,
which means that the molecular design is reasonable and
valuable.
The photodegradation of our synthesized compounds was
also a concern. Compounds 4c, 4g, 4k, and 4l were selected
because of their better stability in water. The photolysis half-life
of compounds 4c, 4g, 4k, 4l, 3, IMI, and NTN32692 were
measured. The photolysis data for compounds were shown in
Table 3, and the degradation curves were shown in Figure 3.
increase the conjugation effect. The bioassays showed that all
13 compounds exhibited excellent insecticidal activities against
cowpea aphid (A. craccivora), cotton aphid (A. gossypii), and
brown planthopper (N. lugens). Hydrolysis and photolysis of
synthesized compounds were also investigated. The results
exhibited that the stabilities of synthesized compounds in water
or after irradiation of mercury lamp improved obviously
compared to leading compound 3. Enhanced bioactivities and
stability suggested that the strategy of molecular design was
significative for further research.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR, infrared (IR), and high-resolution mass
spectrometry (HRMS) data of compounds 4a−4m. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Table 3. Photolysis Rate Constants (k), Half-Lives (t1/2), and
Linear Response (R2) for Compounds 4c, 4g, 4k, and 4l
under the Irradiation of a 300 W High-Pressure Mercury
Lamp
AUTHOR INFORMATION
Corresponding Author
*Telephone: +86-21-64252945. Fax: +86-21-64252603. E-mail:
xyxu@ecust.edu.cn.
■
λmax
t1/2
light source
sample
(nm)
k
(min)
R2
300 W high-pressure
mercury lamp
4c
4g
427
438
420
450
373
270
322
0.0303
0.0163
0.0091
0.0205
0.904
22
0.907
0.930
0.941
0.911
0.988
0.997
0.992
42
4k
76
Funding
4l
34
This work was financial supported by the National Basic
Research Program of China (973 Program, 2010CB126100)
and the National High Technology Research and Development
Program of China (863 Program, 2011AA10A207). This work
was also partly supported by the National Key Technology
R&D Program of China (2011BAE06B01), the National
Natural Science Foundation of China (21272071), Shanghai
Leading Academic Discipline Project (Project B507), and the
Fundamental Research Funds for the Central Universities and
Special Fund for Agro-scientific Research in the Public Interest
(201103007).
3
0.77
10
IMI
0.0669
0.2807
NTN32692
2.47
The half-life of compound 4k was the longest among seven
compounds, which was 76 min. The photostability of
compounds was enhanced significantly in comparison to that
of compound 3, which had a half-life of only 0.77 min. In
comparison to NTN32692, the synthesized compounds after
irradiation of the mercury lamp were also more stable than
NTN32692, with the half-life of 2.47 min.
In addition, we observed that the main product of both
hydrolysis and photolysis of synthesized compounds was the
important intermediate NTN32692. It suggested that these
compounds might be pro-insecticide, and there are more works
being investigated to further verify it.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) Tomizawa, M.; Casida, J. E. Neonicotinoid insecticide toxicology:
Mechanisms of selective action. Annu. Rev. Pharmacol. Toxicol. 2005,
45, 247−268.
A series of novel conjugated neonicotinoids were designed
and synthesized on the basis of enhanced conjugation. The
introduction of the substituted phenyl group was beneficial to
́
(2) Talley, T. T.; Harel, M.; Hibbs, R. E.; Radic, Z.; Tomizawa, M.;
Casida, J. E.; Taylor, P. Atomic interactions of neonicotinoid agonists
10862
dx.doi.org/10.1021/jf403272h | J. Agric. Food Chem. 2013, 61, 10858−10863

Journal of Agricultural and Food Chemistry
Article
with AChBP: Molecular recognition of the distinctive electronegative
pharmacophore. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 7606−7611.
(3) Tomizawa, M.; Maltby, D.; Talley, T. T.; Durkin, K. A.;
Medzihradszky, K. F.; Burlingame, A. L.; Taylor, P.; Casida, J. E.
Atypical nicotinic agonist bound conformations conferring subtype
selectivity. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 1728−1732.
(4) Nauen, R.; Denholm, I. Resistance of insect pests to
neonicotinoid insecticides: Current status and future prospects. Arch.
Insect Biochem. Physiol. 2005, 58, 200−215.
of Ca2+ release from sarcoplasmic reticulum of mouse skeletal muscle.
Biorg. Med. Chem. 2003, 11, 663−673.
(21) Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. Synthesis
of unsymmetrical biaryls using a modified Suzuki cross-coupling: 4-
Biphenylcarboxaldehyde ([1,1′-Biphenyl]-4-carboxaldehyde). Org.
Synth. 1998, 75, 53−59.
(22) Tian, Z.; Jiang, Z.; Li, Z.; Song, G.; Huang, Q. Syntheses and
biological activities of octahydro-1H-cyclopenta[d]pyrimidine deriva-
tives. J. Agric. Food. Chem. 2007, 55, 143−147.
(5) Reyes, M.; Franck, P.; Charmillot, P.-J.; Ioriatti, C.; Olivares, J.;
Pasqualini, E.; Sauphanor, B. Diversity of insecticide resistance
mechanisms and spectrum in European populations of the codling
moth, Cydia pomonella. Pest Manage. Sci. 2007, 63, 890−902.
(6) Zewen, L.; Zhaojun, H.; Yinchang, W.; Lingchun, Z.; Hongwei,
Z.; Chengjun, L. Selection for imidacloprid resistance in Nilaparvata
lugens: Cross-resistance patterns and possible mechanisms. Pest
Manage. Sci. 2003, 59, 1355−1359.
(7) Liu, Z.; Williamson, M. S.; Lansdell, S. J.; Denholm, I.; Han, Z.;
Millar, N. S. A nicotinic acetylcholine receptor mutation conferring
target-site resistance to imidacloprid in Nilaparvata lugens (brown
planthopper). Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 8420−8425.
́
(8) Henry, M.; Beguin, M.; Requier, F.; Rollin, O.; Odoux, J.-F.;
Aupinel, P.; Aptel, J.; Tchamitchian, S.; Decourtye, A. A common
pesticide decreases foraging success and survival in honey bees. Science
2012, 336, 348−350.
(9) Kagabu, S.; Matsuno, H. Chloronicotinyl insecticides. 8. Crystal
and molecular structures of imidacloprid and analogous compounds. J.
Agric. Food. Chem. 1997, 45, 276−281.
(10) Tomizawa, M.; Zhang, N.; Durkin, K. A.; Olmstead, M. M.;
Casida, J. E. The neonicotinoid electronegative pharmacophore plays
the crucial role in the high affinity and selectivity for the Drosophila
nicotinic receptor: An anomaly for the nicotinoid cation−π interaction
model. Biochemistry (Moscow) 2003, 42, 7819−7827.
(11) Tomizawa, M.; Yamamoto, I. Structure−activity relationships of
nicotinoids and imidacloprid analogs. J. Pestic. Sci. 1993, 18, 91−98.
(12) Tomizawa, M.; Talley, T. T.; Maltby, D.; Durkin, K. A.;
Medzihradszky, K. F.; Burlingame, A. L.; Taylor, P.; Casida, J. E.
Mapping the elusive neonicotinoid binding site. Proc. Natl. Acad. Sci.
U. S. A. 2007, 104, 9075−9080.
(13) Wang, Y.; Cheng, J.; Qian, X.; Li, Z. Actions between
neonicotinoids and key residues of insect nAChR based on an ab
initio quantum chemistry study: Hydrogen bonding and cooperative
π−π interaction. Bioorg. Med. Chem 2007, 15, 2624−2630.
(14) Ye, Z.; Xia, S.; Shao, X.; Cheng, J.; Xu, X.; Xu, Z.; Li, Z.; Qian,
X. Design, synthesis, crystal structure analysis, and insecticidal
evaluation of phenylazoneonicotinoids. J. Agric. Food. Chem. 2011,
59, 10615−10623.
(15) Shao, X.; Lee, P. W.; Liu, Z.; Xu, X.; Li, Z.; Qian, X. cis-
Configuration: A New Tactic/Rationale for Neonicotinoid Molecular
Design. J. Agric. Food. Chem. 2010, 59, 2943−2949.
(16) Shao, X.; Li, Z.; Qian, X.; Xu, X. Design, synthesis, and
insecticidal activities of novel analogues of neonicotinoids: Replace-
ment of nitromethylene with nitroconjugated system. J. Agric. Food.
Chem. 2009, 57, 951−957.
(17) Paizs, C.; Tahtinen, P.; Lundell, K.; Poppe, L.; Irimie, F.-D.;
̈
Kanerva, L. T. Preparation of novel phenylfuran-based cyanohydrin
esters: Lipase-catalysed kinetic and dynamic resolution. Tetrahedron:
Asymmetry 2003, 14, 1895−1904.
(18) Mugnaini, C.; Rajamaki, S.; Tintori, C.; Corelli, F.; Massa, S.;
Witvrouw, M.; Debyser, Z.; Veljkovic, V.; Botta, M. Toward novel
HIV-1 integrase binding inhibitors: Molecular modeling, synthesis, and
biological studies. Bioorg. Med. Chem. Lett. 2007, 17, 5370−5373.
(19) Umezawa, K.; Matsui, A.; Nakamura, Y.; Citterio, D.; Suzuki, K.
Bright, color-tunable fluorescent dyes in the vis/NIR region:
Establishment of new “tailor-made” multicolor fluorophores based
on borondipyrromethene. Chem.Eur. J. 2009, 15, 1096−1106.
(20) Hosoya, T.; Aoyama, H.; Ikemoto, T.; Kihara, Y.; Hiramatsu, T.;
Endo, M.; Suzuki, M. Dantrolene analogues revisited: General
synthesis and specific functions capable of discriminating two kinds
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