Cis-nitenpyram analogues containing 1,4-dihydropyridine: Synthesis, insecticidal activities, and molecular docking studies

Article abstract of DOI:10.1002/cjoc.201200165

A novel series of cis-nitenpyram analogues (2a-2p) were designed and prepared by introducing the 1,4-dihydropyridine, with their cis-configuration confirmed by X-ray diffraction. Preliminary bioassays showed that most compounds exhibited good insecticidal activities at 20 mg/L against Aphis medicagini, and analogues 2a and 2d afforded the best activity, and both of them had 100% mortality at 4 mg/L. In addition, molecular docking studies were also performed to model the ligand-receptor complexes, and the results explained the structure-activity relationships observed in vitro, which may provide some useful information for future design of new insecticides. Copyright

Full text of DOI:10.1002/cjoc.201200165

FULL PAPER
DOI: 10.1002/cjoc.201200165
cis-Nitenpyram Analogues Containing 1,4-Dihydropyridine:
Synthesis, Insecticidal Activities, and Molecular Docking
Studies
Sun, Chuanwen*,a(孙传文)
Wu, Yinga(吴颖)
Chen, Yanxiaa(陈艳霞)
Wang, Jinga(王静)
Liu, Tianyana(刘天雁)
Xing, Jiahuab(邢家华)
Fang, Tinga(方庭)
a College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, China
b Bioassay Department, Branch of National Pesticide R&D South Center, Hangzhou, Zhejiang 310023, China
A novel series of cis-nitenpyram analogues (2a—2p) were designed and prepared by introducing the
1,4-dihydropyridine, with their cis-configuration confirmed by X-ray diffraction. Preliminary bioassays showed that
most compounds exhibited good insecticidal activities at 20 mg/L against Aphis medicagini, and analogues 2a and
2d afforded the best activity, and both of them had 100% mortality at 4 mg/L. In addition, molecular docking stud-
ies were also performed to model the ligand-receptor complexes, and the results explained the structure-activity re-
lationships observed in vitro, which may provide some useful information for future design of new insecticides.
Keywords cis-nitenpyram analogue, 1,4-dihydropyridine, synthesis, insecticidal acvitity, molecular docking
Introduction
of resistance and cross-resistance in a range of spe-
cies.[12-15] Besides, the situation of bee pesticide poison-
ing had become worse,[16] some of the NNSs, such as
imidacloprid has been banned or restricted in some
European and American countries, because of its killing
effect on bees and other pollinators. Hence, the devel-
opment of novel neonicotinoids with both good insecti-
cidal activities and less resistance is highly desirable.
According to the literature, changing the configura-
tion of commercial neonicotinoids’ pharmacophore is
one of the effective resistance-management tactics.[17,18]
The nitro groups in all commercialized neonicotinoids
have a trans configuration, on which three proposals
formodes of action are based.[19] However, In the late
1980s, Bayer and Nihon Tokushu Noyaku Seizo Co.
reported that several cis-configuration neonicotinoids
showed high insecticidal activity,[17,18] which implied
that neonicotinoids in the cis-configuration might bind
to the receptor in a different way,[7,20] and their insecti-
cidal activities may benefit from it. In addition, consid-
ering the pharmacophore moieties, these commercial-
ized neonicotinoids can be divided into two groups: the
open-chain compounds and the 5- or 6-membered com-
pounds (Scheme 1), which makes them different in their
molecular characteristics. Until recently, most of the
structural optimization of NNSs are based on cyclic
neonicotinoid insecticides, such as imidacloprid. How-
ever, few studies have been focused on the structural
modification of acyclic NNSs, such as nitenpyram.
In the past decades, neonicotinoid insecticides have
gained worldwide attention for being the fastest grow-
ing class of insecticides in modern crop protection, with
widespread use against most of sucking and certain
chewing pests. As potent agonists, they act selectively
on the insect nicotinic acetylcholine receptors
(nAChRs).[1] The greatest attributes of the neonicoti-
noids include their novel mode of action, low mammal-
ian toxicity, broad insecticidal spectrum, and good sys-
temic properties.[2] Since imidacloprid[3] (IMI) was first
introduced to the market in 1991, many new neonicoti-
noid insecticides (NNSs) are now on the market with
their own prominence. As the second of the chloroni-
cotinyl subclass, nitenpyram,[4] which was brought to
market in 1995, was characterized with much lower
toxicity against the mammals than imidacloprid.[5] Be-
sides, nitenpyram also had higher selectivity[6-8] and
better systemic properties[9,10] against mammals, birds,
aquatic life than insects, due to the differential binding
affinities with the nAChR of their neurosystem.[11]
As a popular saying goes, “everything has two sides”.
On one hand, now the agricultural industry is benefiting
more and more from NNSs. On the other hand, a serious
potential problem facing all insecticides is the develop-
ment of resistance. Although NNSs have a new mode of
insecticidal action, frequent applications of structural
analogues of neonicotinoids have led to the acquisition
* E-mail: willin@shnu.edu.cn; Fax: ＋86-021-64321926
Received February 20, 2012; accepted March 27, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200165.
Chin. J. Chem. 2012, XX, 1—8
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Sun et al.
FULL PAPER
Scheme 1 Seven commercial neonicotinoid insecticides
tro group in cis-configuration (Figure 2, confirmed by
X-ray diffraction). In order to enhance the hydrogen
bond interactions, NH2, COOCH3, COOCH2CH3 and
CN were introduced to the 2-position and 3-position of
this ring. A new series of nitenpyram analogues (2a—
2p) described herein were synthesized by multicom-
ponet reaction (MCRs) and tested. Preliminary bioassay
against Aphis medicagini showed that all these com-
pounds exhibited excellent insecticide activities, and
their structure-activity relationships were discussed. To
further investigate their binding interactions, molecular
docking simulations were carried out. As expected, ac-
tive analogues exhibited significant hydrogen bonding
interactions with the nAChR target. The docking results
explained the structure-activity relationships observed
in vitro, and shed a light on the novel insecticidal
mechanism of these new analogues, which may provide
some useful information for future design of new insec-
ticides.
5- and 6-membered
compounds (Cyclic NNSs)
Cl
Open-chain
compounds (Acyclic NNSs)
H
H
O
N
N
N
N
NH
Me
N
N
NO2
NO2
Dinotefuran
Imidacloprid
4
1
Cl
Cl
Me
N
N
N
S
N
Me
CN
N
N
CN
Acetarniprid
Thiacloprid
5
2
Me
N
O
N
Cl
N
H
N
N
N
Cl
S
Me
Me
N
Ar
NO2
NO2
O2N
N
R
NO2
NH
Nitenpyram
Thiamethoxam
3
6
N
NH2
N
N
H
H
N
Cl
N
Cl
N
N
Cl
S
Nitenpyram
Me
2a - 2p
N
NO2
Figure 2 The target compounds based on nitenpyram (2a—2p).
Clothianidin
7
Experimental
Materials and physical measurements
Unless otherwise noted, reagents and solvents were
of analytical reagent grade or were chemically pure and
used as received without further purification. Melting
O2N
N
R
NO2
NH
N
N
N
points were measured using an uncorrected RK－ mi-
1
Cl
N
Cl
N
1
croscopic melting point apparatus. H NMR spectrum
Nitenpyram
Nitenpyram analogues 1
(CDCl3) was recorded on a Bruker AVANCE-400 MHz
with TMS as an internal standard. Coupling constants (J
values) are in Hertz. The IR spectra were obtained from
Figure 1 Nitenpyram analogues with tetrahydropyrimidine
fixed cis configuration in our group.
KBr discs in the range 4000 to 400 cm－ on a Nicolet
1
5DXFT-IR spectrophotometer. Combustion analyses for
elemental composition were made with a Perkin-Elmer
2400 instrument. All microwave experiments were per-
formed using a YL8023B1 microwave reactor possess-
ing a single-mode microwave cavity producing con-
trolled irradiation at 2.45 GHz.
In our previous work,[21-23] we have focused our at-
tention on designing novel neonicotinoids, in which the
nitenpyam structure was reserved and the different sub-
stituents R were introduced into the lead compound
through forming a 1,2,3,6-tetrahydropyrimidine ring to
fix the nitro group in the cis position (Figure 1). Corre-
spondingly, a series of cis-configuration nitenpyram
analogues 1 (Figure 1) were synthesized by introducing
1,2,3,6-tetrahydropyrimidine, these compounds exhib-
ited good insecticide activities against Nilaparvata
lugens. However, the insecticidal spectra of these com-
pouds are narrow. In order to search for lead compouds
of neonicotinoid insecticides with novel structural fea-
tures, high activity, less resistance and broad insecti-
cidal spectra, based on the above mentioned reports, we
developed a new design strategy by introducing a
1,4-dihydropyridine ring into nitenpyram fixing the ni-
Synthesis of target compounds 2a—2p (exemplified
by 2a)
A mixture of methyl cyanoacetate (12 mmol), ben-
zaldehyde (12 mmol), piperidine (0.1 mmol), and niten-
pyram (10 mmol) in anhydrous alcohol (20 mL) was
heated to 60—75 ℃ for 5 min in a microwave reactor
and stirred for 30 min at the temperature. The reaction
mixture was concentrated under reduced pressure and
treated with 20 mL of water. Then, the solution was
extracted three times with ethyl acetate, and the com-
bined extracts were dried over MgSO4. The organic
2
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—8

cis-Nitenpyram Analogues: Synthesis, Insecticidal Activities, and Molecular Docking Studies
Scheme
2
Synthesis of nitenpyram analogues with
NCH2CH3, 1H), 4.16—4.10 (m, COOCH2CH3, 2H),
4.06 (d, J＝14.8 Hz, NCH2CH3, 1H), 3.27—3.19 (m,
1H), 3.16 (s, NCH3, 3H), 3.10 (dt, J＝13.9, 7.0 Hz, 1H),
1.31 (t, J＝7.0 Hz, COOCH2CH3, 3H), 1.23 (t, J＝7.0
Hz, NCH2CH3, 3H); IR (KBr) vmax: 3327, 3200 (NH2),
1,4-dihydropyridine ring (2a—2p).
CH2Cl
a
CH2NHCH2CH3
b
Cl
Cl
N
N
Cl
N
NO2
NH
2984, 2935, 2870 (C＝O), 1343 (NO2), 1308 (vas,C
C),
— —
O
Cl
－
1
1235 (va,C
C) cm . Anal. calcd for C23H26ClN5O4: C
— —
O
NO2
c
N
N
58.53, H 5.55, N 14.84; found C 58.64, H 5.53, N 14.81.
ESI-MS (M＋H) m/z: 472.17.
Cl
N
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-cyano-1-methyl-5-nitro-4-phenyl-
Ar
O2N
R
1,4-dihydropyridine (2c)
Yellow crystals, yield
86.0%, m.p. 100—102 ℃; 1H NMR (CDCl3) δ: 8.08 (d,
J＝12.4 Hz, Py-H, 1H), 7.34 (d, J＝8.9 Hz, Py-H, 1H),
7.24 (s, PhH, 3H), 7.08 (d, J＝7.8 Hz, Py-H, 1H),
7.05—6.95 (m, PhH, 2H), 5.06 (s, CH, 1H), 4.79 (s,
NH2, 2H), 4.33 (d, J＝14.8 Hz, 1H), 4.06 (d, J＝14.6
Hz, 1H), 3.35—3.20 (m, 1H), 3.17 (s, NCH3, 3H), 3.10
(dd, J＝13.8, 7.3Hz, 1H), 1.33—1.21 (m, NCH2CH3,
3H); IR (KBr) vmax: 2974 (CH3) 3327, 3197 (NH2), 2184
(CN), 1457, 1409 (NO2), 1648, 1614, 1557 (benzene)
d
N
N
NH2
Cl
N
2a Ar = Ph, R = COOCH3; 2b Ar = Ph, R = COOCH2CH3
2c Ar = Ph, R = CN; 2d Ar = 4-Cl-C6H4, R = COOCH3
2e Ar = 4-Cl-C6H4, R = COOCH2CH3; 2f Ar = 4-Cl-C6H4, R = CN
2g Ar = 4-NO2-C6H4, R = COOCH3; 2h Ar = 4-NO2-C6H4, R = CN
2i Ar = 4-F-C6H4, R = COOCH2CH3; 2j Ar = 4-F-C6H4, R = CN
－
1
2k Ar = 4-OCH3-C6H4, R = COOCH3; 2l Ar = 4-OCH3-C6H4, R = CN
2m Ar = 2-Cl-C6H4, R = COOCH3; 2n Ar = 3-Cl-C6H4, R = COOCH3
2o Ar = 4-CH(CH3)2-C6H4, R = CN; 2P Ar = 4-CF3-C6H4, R = CN
cm . Anal. calcd for C21H21ClN6O2: C 59.36, H 4.98,
N 19.78; found C 59.28, H 4.97, N 19.74. ESI-MS (M
＋H) m/z: 425.14.
cis-2-Amino-4-(4-chlorophenyl)-6-[N-(6-chloro-3-
pyridinylmethyl)-N-ethyl]amino-1-methyl-3-meth-
Reagents
and
conditions:
(a)
Ethanamine
(42%).
(b)
1,1,1-Trichloro-2-nitroethane/CHCl3, 2—7 ℃ (65%). (c) Methanamine,
3—7 ℃ (58%). (d) substituted aromatic aldehydes, cyano compounds,
piperidine/anhydrous alcohol, 60—75 ℃ (65.5%—86.0%)
oxycarbonyl-5-nitro-1,4-dihydropyridine
(2d)
1
Yellow crystals, yield 83.2%, m.p. 227—228 ℃; H
NMR (CDCl3) δ: 8.20 (d, J＝16.8 Hz, Py-H, 1H),
7.19—7.09 (m, Ph-H, 4H), 7.04 (d, J＝7.9 Hz, Py-H,
1H), 6.98 (d, J＝7.0 Hz, Py-H, 1H), 6.22 (s, NH2, 2H),
5.73 (d, J＝17.1 Hz, CH, 1H), 4.38 (d, J＝14.8 Hz,
NCH2CH3, 1H), 4.12 (d, J＝14.9 Hz, NCH2CH3, 1H),
3.65 (s, COOCH3, 3H), 3.28 (s, 1H), 3.20 (s, NCH3, 3H),
3.10—3.06 (m, 1H), 1.33 (t, J＝6.8 Hz, NCH2CH3, 3H);
IR (KBr) vmax: 3364, 3278 (NH2), 2981, 2945, 2876
phase was evaporated under reduced pressure, and crude
product was subjected to flash chromatography on silica
gel, eluting with ethyl acetate/petroleum ether (3∶1) to
afford pure products 2a.
The syntheses of 2a—2p were carried out by the
similar method. The analytical data for the compounds
2a—2p were summarized as follows:
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-1-methyl-3-methoxycarbonyl-4-phe-
nyl-5-nitro-1,4–dihydropyridine (2a) Yellow crys-
tals, yield 75.1%, m.p. 217—218 ℃; 1H NMR (CDCl3)
δ: 8.21 (d, J＝15.2 Hz, Py-H, 1H), 7.30—7.02 (m, Ph-H,
4H), 7.10 (d, J＝8.0 Hz, Py-H, 1H), 6.80 (d, J＝7.6 Hz,
Py-H, 1H), 6.32 (s, NH2, 2H), 5.67 (d, J＝17.1 Hz, CH,
1H), 4.40 (d, J＝14.8 Hz, NCH2CH3, 1H), 4.18 (d, J＝
14.9 Hz, NCH2CH3, 1H), 3.58 (s, COOCH3, 3H), 3.30
(s, 1H), 3.21 (s, NCH3, 3H), 3.13—3.08 (m, 1H), 1.33 (t,
J＝6.8 Hz, NCH2CH3, 3H); IR (KBr) vmax: 2923 (CH3),
3335, 3202 (NH2), 1502—1416 (NO2), 1646, 1615,
(C＝O), 1342 (NO2), 1309 (vas,C
C), 1235 (va,C
)
— —
O
— —
O
C
－
1
cm . Anal. calcd for C22H23Cl2N5O4: C 53.67, H 4.71,
N 14.22; found C 53.56, H 4.72, N 14.24. ESI-MS (M
＋H) m/z: 492.11.
cis-2-Amino-4-(2-chlorophenyl)-6-[N-(6-chloro-3-
pyridinylmethyl)-N-ethyl]amino-3-ethoxycarbonyl-1-
methyl-5-nitro-1,4-dihydropyridine (2e)
Yellow
1
crystals, yield 65.5%, m.p. 174—175 ℃; H NMR
(CDCl3) δ: 8.19 (s, Py-H, 1H), 7.81 (s, Py-H, 1H), 7.27
(s, Py-H, 1H), 7.22 (d, J＝6.0 Hz, Ph-H, 1H), 7.14—
7.06 (m, Ph-H, 2H), 7.04 (t, J＝8.2 Hz, Ph-H, 1H), 6.24
(s, NH2, 2H), 5.68 (s, CH, 1H), 4.37 (d, J＝14.5 Hz,
NCH2CH3, 1H), 4.14—4.08 (m, COOCH2CH3, 2H),
4.07—4.03 (m, NCH2CH3, 1H), 3.23 (s, NCH3, 3H),
3.20 (d, J＝7.3 Hz, 1H), 3.11 (dd, J＝13.7, 6.9 Hz, 1H),
1.32 (dd, J＝13.3, 6.2 Hz, COOCH2CH3, 3H), 1.21 (t,
J＝7.1 Hz, NCH2CH3, 3H); IR (KBr) vmax: 3384, 3298
(NH2), 3065, 2981, 2933 (C＝O), 1337 (NO2), 1294
－
1
1592 (benzene) cm . Anal. calcd for C22H24ClN5O4: C
57.70, H 5.28, N 15.29; found C 57.78, H 5.26, N 15.25.
ESI-MS (M＋H) m/z: 458.15.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-ethoxycarbonyl-1-methyl-5-nitro-4-
phenyl-1,4-dihydropyridine (2b) Yellow crystals,
C) cm － 1. Anal. calcd for
1
(vas,C
C), 1267 (va,C
— —
O
— —
O
yield 81.23%, m.p. 167—168 ℃; H NMR (CDCl3) δ:
C23H25Cl2N5O4: C 54.55, H 4.98, N 13.83; found C
54.65, H 4.96, N 13.87. ESI-MS (M＋H) m/z: 506.13.
cis-2-Amino-4-(4-chlorophenyl)-6-[N-(6-chloro-3-
8.08 (s, Py-H, 1H), 7.82 (s, Py-H, 1H), 7.19—7.18 (m,
Ph-H, 3H), 7.05 (s, Ph-H, 2H), 6.98 (s, Py-H, 1H), 6.19
(s, NH2, 2H), 5.49 (s, CH, 1H), 4.32 (d, J＝14.6 Hz,
Chin. J. Chem. 2012, XX, 1—8
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3

Sun et al.
FULL PAPER
pyridinylmethyl)-N-ethyl]amino-3-cyano-1-methyl-5-
nitro-1,4-dihydropyridine (2f) Yellow crystals, yield
85.5%, m.p. 102—104 ℃; 1H NMR (CDCl3) δ: 8.30 (s,
Py-H, 1H), 8.09 (s, Py-H, 1H), 7.78 (s, Py-H, 1H), 7.21
(d, J＝7.3 Hz, PhH, 1H), 7.10 (d, J＝6.8 Hz, PhH, 1H),
7.01 (d, J＝7.8 Hz, PhH, 1H), 6.94 (d, J＝7.5 Hz, PhH,
1H), 5.01 (s, CH, 1H), 4.51 (s, NH2, 2H), 4.33 (d, J＝
14.2 Hz, 1H), 4.10 (dd, J＝16.9, 10.8 Hz, 1H), 3.25—
3.16 (m, 1H), 3.16 (s, NCH3, 3H), 3.14—3.08 (m, 1H),
1.35—1.20 (m, NCH2CH3, 3H); IR (KBr) vmax: 2927
(CH3), 3447, 3319, 3196 (NH2), 2184 (CN), 1485—1413
2929, (C＝O), 1358 (NO2), 1305 (vas,C
C), 1275
— —
O
(va,C
C) cm－1. Anal. calcd for C23H25ClFN5O4: C
— —
O
56.39, H 5.14, N 14.29; found C 55.56, H 5.15, N 14.26.
ESI-MS (M＋H) m/z: 490.16.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-cyano-4-(4-fluorophenyl)-1-methyl-
5-nitro-1,4-dihydropyridine (2j)
Yellow crystals,
1
yield 80.5%, m.p. 202—203 ℃; H NMR (CDCl3) δ:
8.20 (s, Py-H, 1H), 8.12 (s, Py-H, 1H), 7.25 (s, Py-H,
1H), 7.21—6.51 (m, Ph-H, 5H), 5.10 (s, CH, 1H), 4.70
(s, NH2, 2H), 4.32 (d, J＝14.3 Hz, 1H), 4.11 (d, J＝14.8
Hz, 1H), 3.35—3.21 (m, 1H), 3.19 (s, NCH3, 3H), 3.14
(d, J＝6.5 Hz, 1H), 1.35—1.24 (m, NCH2CH3, 3H); IR
(KBr) vmax: 2937 (CH3), 3467, 3326, 3198 (NH2), 2183
(CN), 1504—1343 (NO2), 1653, 1603, 1558 (benzene)
－
1
(NO2), 1648, 1608, 1557 (benzene) cm . Anal. calcd
for C21H20Cl2N6O2: C 54.91, H 4.39, N 18.30; found C
55.01, H 4.38, N 18.24. ESI-MS (M＋H) m/z: 459.10.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-methoxycarbonyl-1-methyl-5-nitro-
4-(4-nitrophenyl)-1,4 -dihydropyridine (2g) Yellow
－
1
cm . Anal. calcd for C21H20ClFN6O2: C 56.95, H 4.55,
N 18.98; found C 57.12, H 4.53, N 19.03. ESI-MS (M
＋H) m/z: 443.13.
1
crystals, yield 78.1%, m.p. 194—195 ℃; H NMR
(CDCl3) δ: 8.13 (d, J＝8.1 Hz, Py-H, 1H), 8.06 (d, J＝
8.3 Hz, Ph-H, 2H), 7.42 (d, J＝8.0 Hz, Py-H, 1H), 7.17
(d, J＝12.5 Hz, Ph-H, 2H), 6.95 (d, J＝8.1 Hz, Py-H,
1H), 6.34 (br, NH2, 2H), 5.48 (s, CH, 1H), 4.35 (d, J＝
14.6 Hz, NCH2CH3, 1H), 3.57 (s, COOCH3, 3H), 4.09
(dd, J＝12.3, 5.3 Hz, NCH2CH3, 1H), 3.38 (dd, J＝13.7,
6.7 Hz, 1H), 3.30 (s, NCH3, 3H), 3.23—3.16 (m, 1H),
1.19 (t, J＝7.1 Hz, NCH2CH3, 3H); IR (KBr) vmax: 3385,
3297 (NH2), 3083, 2980, 2935 (C＝O), 1349 (NO2),
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-methoxycarbonyl-4-(4-methoxyl-
phenyl)-1-methyl-5-nitro-1,4-dihydropyridine (2k)
1
Yellow crystals, yield 78.5%, m.p. 201—202 ℃; H
NMR (CDCl3) δ: 8.19 (s, Py-H, 1H), 7.81 (s, Py-H, 1H),
7.27 (s, Py-H, 1H), 7.22 (d, J＝8.0 Hz, Ph-H, 2H), 7.03
(d, J＝8.0 Hz, Ph-H, 2H), 6.24 (s, NH2, 2H), 5.68 (s,
CH, 1H), 4.36 (d, J＝14.5 Hz, 1H,), 4.07—4.03 (m, 1H),
3.80 (s, OCH3, 3H), 3.65 (s, COOCH3, 3H), 3.23 (s,
NCH3, 3H), 3.19 (d, J＝7.3 Hz, 1H), 3.11 (dd, J＝13.7,
6.9 Hz, 1H), 1.21 (t, J＝7.1 Hz, NCH2CH3, 3H); IR
(KBr) vmax: 2963 (CH3), 3323, 3211 (NH2), 1477, 1413
(NO2), 1652, 1612, 1577 (benzene). Anal. calcd for
C23H26ClN5O5: C 56.62, H 5.37, N 14.35; found C
56.78, H 5.36, N 14.37. ESI-MS (M＋H) m/z: 488.16.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-cyano-4-(4-methoxylphenyl)-1-me-
－
1
1300 (vas,C
C), 1237 (va,C
C) cm . Anal. calcd for
— —
O
— —
O
C22H23ClN6O6: C 52.54, H 4.61, N 16.71; found C
52.64, H 4.60, N 16.74. ESI-MS (M＋H) m/z: 503.14.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-cyano-1-methyl-5-nitro-4-(4-nitro-
phenyl)-1,4-dihydropyridine (2h) Yellow crystals,
1
yield 83.1%, m.p. 133—135 ℃; H NMR (CDCl3) δ:
8.11 (s, Py-H, 1H), 7.78 (s, Py-H, 1H), 7.38 (d, J＝7.5
Hz, Py-H, PhH, 2H), 7.16—6.86 (m, Ph-H, 3H), 5.01 (s,
CH, 1H), 4.60 (s, NH2, 2H), 4.35 (d, J＝13.6 Hz, 1H),
4.09 (d, J＝14.1 Hz, 1H), 3.27 (d, J＝7.2 Hz, 1H), 3.20
(s, NCH3, 3H), 3.08 (d, J＝5.0 Hz, 1H), 1.29 (t, J＝10.7
Hz, NCH2CH3, 3H); IR (KBr) vmax: 2930 (CH3), 3333,
3203 (NH2), 2186 (CN), 1347 (NO2), 1647, 1611, 1518
thyl-5-nitro-1,4-dihydropyridine (2l)
Yellow
1
crystals, yield 80.5%, m.p. 173—175 ℃; H NMR
(CDCl3) δ: 8.30 (s, Py-H, 1H), 8.11 (s, Py-H, 1H), 7.80
(s, Py-H, 1H), 7.12 (d, J＝6.4 Hz, Ph-H, 1H), 7.01 (d,
J＝7.2 Hz, Ph-H, 1H), 6.93 (d, J＝7.5 Hz, Ph-H, 1H),
6.77 (d, J＝8.0 Hz, Ph-H, 1H), 4.98 (s, CH, 1H), 4.45 (d,
J＝22.7 Hz, NH2, 2H), 4.33 (d, J＝14.3 Hz, 1H), 4.07
(d, J＝14.3 Hz, 1H), 3.80 (s, OCH3, 3H), 3.30—3.21 (m,
1H), 3.18 (s, NCH3, 3H), 3.15—3.06 (m, 1H), 1.29 (dd,
J＝17.0, 9.9 Hz, NCH2CH3, 3H); IR (KBr) vmax: 2928
(CH3), 3412, 3330 (NH2), 2184 (CN), 1507, 1417 (NO2),
1653, 1608, 1559 (benzene) cm－1. Anal. calcd for
C22H23ClN6O3: C 58.09, H 5.01, N 18.47; found C
58.26, H 5.02, N 18.43. ESI-MS (M＋H) m/z: 455.15.
cis-2-Amino-4-(2-chlorophenyl)-6-[N-(6-chloro-3-
pyridinylmethyl)-N-ethyl]amino-3-methoxycarbonyl-
1-methyl-5-nitro-1,4-dihydropyridine (2m) Yellow
－
1
(benzene) cm . Anal. calcd for C21H20ClN7O4: C 53.68,
H 4.29, N 20.87; found C 53.84, H 4.30, N 20.89.
ESI-MS (M＋H) m/z: 470.13.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-ethoxycarbonyl-4-(4-fluorophenyl)-
1-methyl--5-nitro-1,4-dihydropyridine (2i) Yellow
1
crystals, yield 81.2%, m.p. 189—191 ℃; H NMR
(CDCl3) δ: 8.12 (s, Py-H, 1H), 7.80 (s, Py-H, 1H), 7.36
(s, Py-H, 1H), 7.33 (d, J＝8.1 Hz, Ph-H, 1H), 7.10 (d,
J＝6.4 Hz, Ph-H, 1H), 7.03 (d, J＝8.1 Hz, Ph-H, 1H),
6.93 (d, J＝6.4 Hz, Ph-H, 1H), 6.06 (br, NH2, 2H), 5.41
(s, CH, 1H), 4.34 (d, J＝14.6 Hz, NCH2CH3, 1H),
4.16—4.12 (m, COOCH2CH3, 2H), 4.09 (d, J＝14.9 Hz,
NCH2CH3, 1H), 3.30 (dd, J＝13.8, 7.0 Hz, 1H), 3.20 (s,
NCH3, 3H), 3.16 (dd, J＝14.0, 7.1 Hz, 1H), 1.33 (t, J＝
7.0 Hz, COOCH2CH3, 3H), 1.21 (t, J ＝7.1 Hz,
NCH2CH3, 3H); IR (KBr) vmax: 3399, 3291 (NH2), 2976,
1
crystals, yield 83.2%, m.p. 227—228 ℃; H NMR
(CDCl3) δ: 8.20 (d, J＝16.8 Hz, Py-H, 1H), 7.19—7.09
(m, Ph-H, 4H), 7.04 (d, J＝7.9 Hz, Py-H, 1H), 6.98 (d,
J＝7.0 Hz, Py-H, 1H), 6.22 (s, NH2, 2H), 5.73 (d, J＝
17.1 Hz, CH, 1H), 4.38 (d, J＝14.8 Hz, NCH2CH3, 1H),
4.12 (d, J＝14.9 Hz, NCH2CH3, 1H), 3.65 (s, COOCH3,
4
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—8

cis-Nitenpyram Analogues: Synthesis, Insecticidal Activities, and Molecular Docking Studies
3H), 3.28 (s, 1H), 3.20 (s, NCH3, 3H), 3.10—3.06 (m,
1H), 1.33 (t, J＝6.8 Hz, NCH2CH3, 3H); IR (KBr) vmax
3364, 3278 (NH2), 2981, 2945, 2876 (C＝O), 1342
dimensions of 0.20 mm×0.20 mm×0.20 mm, which is
:
suitable for singlecrystal X-ray diffraction, was obtained
by slowly evaporating a solution of 2o in mixed acetone
and petroleum at 25 ℃. The crystal was mounted on a
glass fiber for data collection on a Bruker Smart Apex
CCD diffractometer equipped with a graphite-mono-
chromatic Mo Kα radiation (λ＝0.71073 Å). The ψ-ω
scan mode in the range of 1.84°≤θ≤25.00° at 298 K
was used. A total of 14933 reflections were collected
with 4485 unique ones (Rint 0.0280), of which 4485 with
I＞2σ(I) were considered as observed and used in the
subsequent refinements. The structure was refined by
full-matrix least-squares method on F2 with anisotropic
thermal parameters for all nonhydrogen atoms.
－
1
(NO2), 1309 (vas,C
C), 1235 (va,C
C) cm . Anal.
— —
O
— —
O
calcd for C21H20Cl2N6O2: C 54.91, H 4.39, N 18.30;
found C 55.01, H 4.40, N 18.26. ESI-MS (M＋H) m/z:
459.10.
cis-2-Amino-4-(4-chlorophenyl)-6-[N-(6-chloro-3-
pyridinylmethyl)-N-ethyl]amino-3-methoxycarbonyl-
1-methyl-5-nitro-1,4-dihydropyridine (2n) Yellow
1
crystals, yield 81.2%, m.p. 197—198 ℃; H NMR
(CDCl3) δ: 8.13 (d, J＝8.1 Hz, Py-H, 1H), 7.80 (s, Py-H,
1H), 7.34—7.27 (m, Py-H, Ph-H, 2H), 7.16 (d, J＝5.6
Hz, Ph-H, 1H), 7.05 (d, J＝8.0 Hz, Ph-H, 1H), 6.91 (d,
J＝7.0 Hz, Ph-H, 1H), 6.27 (br, NH2, 2H), 5.43 (d, J＝
12.0 Hz, CH, 1H), 4.35 (d, J＝14.5 Hz, 1H), 4.10 (d,
J＝14.8 Hz, 1H), 3.67 (s, COOCH3, 3H), 3.30—3.27 (m,
1H), 3.23 (s, NCH3, 3H), 3.18 (dt, J＝13.7, 6.9 Hz, 1H),
1.32 (t, J＝7.1 Hz, NCH2CH3, 3H); IR (KBr) vmax: 3364,
3278 (NH2), 2981, 2945, 2876 (C＝O), 1342 (NO2),
Crystal data for 2o: space group P21/c with a＝
11.1272(10) Å, b＝13.4939(13) Å, c＝17.1732(16) Å,
V＝2560.0(4) Å3, Dc＝1.212 Mg/m3, F(000)＝984, μ＝
－
1
0.180 mm , Z＝4. The final refinement gave S＝1.137,
R＝0.0816 and w＝1/[σ2( Fo2 )＋(0.0996P)2]＋1.1836P,
where P＝( Fo2 ＋2 F2 )/3. The crystal was analyzed
c
－
1
1309 (vas,C
C), 1235 (va,C
C) cm . Anal. calcd for
— —
O
— —
O
with SHELXTL-97 software package and the structural
plots were drawn with Otrep. Crystall ographic data
(excluding structure factors) for the structure in this pa-
per have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication nos.
CCDC 823444. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax:＋44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
C22H23Cl2N5O4: C 53.67, H 4.71, N 14.22; found C
53.77, H 4.69, N 14.26. ESI-MS (M＋H) m/z: 492.10.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-cyano-4-(4-isopropylphenyl)-1-meth-
yl-5-nitro-1,4-dihydropyridine (2o) Yellow crystals,
1
yield 82.1%, m.p. 117—118 ℃; H NMR (CDCl3) δ:
8.15 (s, Py-H, 1H), 7.35 (s, Py-H, 1H), 7.11 (d, J＝6.6
Hz, Ph-H, 3H), 7.04 (d, J＝7.4 Hz, Py-H, 1H), 6.94 (d,
J＝7.5 Hz, Ph-H, 1H), 5.03 (s, 1H, CH), 4.50 (d, J＝
18.2 Hz, NH2, 2H), 4.35 (d, J＝13.8 Hz, 1H), 4.03 (d,
J＝14.6 Hz, 1H), 3.20 (s, 1H), 3.14 (s, NCH3, 3H),
3.09—2.97 (m, 1H), 2.93—2.82 [m, CH(CH3)2, 1H],
1.32—1.25 (m, NCH2CH3, 3H), 1.23 [d, J＝6.6 Hz,
CH(CH3)2, 6H]; IR (KBr) vmax: 2960 (CH3), 3329, 3194
(NH2) , 2185 (CN), 1461, 1411 (NO2), 1648, 1612,
Result and Discussion
Synthesis
To prepare the title analogues with 1,4-dihydro-
pyridine ring fixing the nitro group in cis-configuration,
an efficient synthesis approach is developed as depicted
in Scheme 2. The target compounds (2a—2p) were
prepared via Knoevenagel reaction, Michael addition
and nucleophilic addition by means of MCRs (multi-
component reactions). The MCRs included three com-
ponents: nitenpyram, substituted aromatic aldehydes
and cyano compounds. This new series of cis-niten-
pyram analogues (2a—2p) were synthesized in good
yields under microwave irradiation.
－
1
1554 (benzene) cm . Anal. calcd for C23H27ClN6O3: C
61.73, H 5.83, N 18.00; found C 61.85, H 5.81, N 18.05.
ESI-MS (M＋H) m/z: 467.19.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-
N-ethyl]amino-3-cyano-1-methyl-5-nitro-4-(4-triflou-
rophenyl)-1,4-dihydropyridine (2p) Yellow crystals,
1
yield 82.1%, m.p. 117—118 ℃; H NMR (CDCl3) δ:
8.30 (s, Py-H, 1H), 8.09 (s, Py-H, 1H), 7.78 (s, Py-H,
1H), 7.21 (d, J＝7.3 Hz, Ph-H, 1H), 7.10 (d, J＝6.8 Hz,
Ph-H, 1H), 7.01 (d, J＝7.8 Hz, Ph-H, 1H), 6.94 (d, J＝
7.5 Hz, Ph-H, 1H), 5.01 (s, CH, 1H), 4.51 (s, NH2, 2H),
4.33 (d, J＝14.2 Hz, 1H), 4.10 (dd, J＝16.9, 10.8 Hz,
1H), 3.25—3.18 (m, 1H), 3.16 (s, NCH3, 3H), 3.14—
3.03 (m, 1H), 1.35—1.20 (m, NCH2CH3, 3H); IR (KBr)
Evaluation of insecticidal activities
The insecticidal activities of these cis-nitenpyram
analogues were evaluated against Aphis medicagini. As
depicted in Table 1 (2a—2p), most of our designed
compounds exhibited good insecticidal activities against
Aphis medicagini, having ＞80% mortality at 100 mg/L.
Among these analogues, 2a and 2d afforded the best in
vitro activity, with 100% mortality at 4 mg/L, and their
LC50 values were close to nitenpyram’s LC50 value.
When different substituents R and Ar were introduced
to the 3-position and 4-position of the 1,4-dihydro-
pyridine ring, their insecticidal activities varied greatly.
As for the substituent R, their insecticidal activities in-
v
max: 2927 (CH3), 3447, 3319, 3196 (NH2), 2184 (CN),
－
1
1485—1413 (NO2), 1648, 1608, 1557 (benzene) cm .
Anal. calcd for C22H20ClF3N6O2: C 53.61, H 4.09, N
17.05; found C 53.71, H 4.10, N 17.08. ESI-MS (M＋H)
m/z: 493.13.
Crystal growth and X-ray data for crystal structure
of 2o
Yellow crystal of compound 2o with approximate
Chin. J. Chem. 2012, XX, 1—8
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Sun et al.
FULL PAPER
creased in the order cyano group (2c)＜ethyl ester group
(2b)＜methyl ester group (2a), while the Ar group is the
same (Ph). In addition, as the substituent Ar is con-
cerned, this series of compounds demonstrated good
activities with either electron-withdrawing or electron-
donating groups. Moreover, the substituent position on
the phenyl groups also caused changes in the insecti-
cidal activities, and their inhibitory potency decreased in
the order 4-position (2d)＞2-position (2m)＞3-position
(2n), which may be related to their different affinities to
the nAChR target, such as the number of hydrogen
bondings.
ingly, the bond lengths of C—C on the 1,4-dihydro-
pyridine are obviously shorter than the pure C—C sin-
gle bond (1.54 Å),[25] such as C(16)—C(12), C(12)—
C(11), C(11)—C(15) and C(12)—C(13) being 1.520(7)
Å, 1.521(4) Å, 1.406(4) Å and 1.507(4) Å, respectively.
Similarly, the bond lengths of C—N on the 1,4-dihydro-
pyridine are obviously shorter than the pure C—N sin-
gle bond (1.47 Å),[25] such as C(10)—N(4), C(9)—N(3),
and C(13)—N(6), their lengths are 1.341(4), 1.377(3),
and 1.371(4) Å, respectively. On the contrary, the bond
lengths [1.355(4) Å, 1.402(4) Å, respectively] of the
C(11)＝C(10) and C(13)＝C(9) are longer than the pure
C＝C bond (1.34 Å).[25] The bond lengths of C(15)≡
N(5) is 1.135(4) Å, a bit shorter than pure C≡N bond
(1.15 Å).[25] Based on these data, we can presume that
there is a homo conjugation effect on the 1,4-dihydro-
pyridine ring in the compound 2o. As all the modes of
action were put forward based on trans-configuration,
this unique cis-configuration may confer some new
properties onto the compounds.
Table 1 Insecticidal activities of nitenpyram analogues 2a—2p
against Aphis medicagini
Ar
O2N
N
R
N
NH2
Cl
N
2a - 2p
Mortality (%) at
different concentra-
tions (mg/L)
Compd.
2a
Ar
R
500 100 20
4
Ph
Ph
Ph
COOCH3
100 100 100 90
2b
2c
COOCH2CH3 100 90 80 70
CN
100 80 70 65
100 100 100 100
2d
2e
4-Cl-C6H4
2-Cl-C6H4
4-Cl-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-F-C6H4
COOCH3
COOCH2CH3 100 100 50 40
2f
CN
100 90 40 30
95 90 60 30
90 50 40 20
2g
COOCH3
CN
2h
2i
COOCH2CH3 100 100 100 20
2j
4-F-C6H4
CN
90 50 30
n.t.
2k
2l
4-OCH3-C6H4
4-OCH3-C6H4
COOCH3
CN
100 100 80 50
80 60 50 15
100 100 100 55
100 90 80 40
100 90 70 25
2m 2-Cl-C6H4
COOCH3
COOCH3
2n
2o
3-Cl-C6H4
4-CH(CH3)2-C6H4CN
4-CF3-C6H4 CN
2p
95 50 30
n.t.
Nitenpyram
100 100 100 100
n.t.＝not tested.
Single-crystal structure of compound 2o
To confirm the cis-configuration with precise three-
dimensional information, the single-crystal structure of
compound 2o was investigated and determined by X-ray
diffraction analysis (CCDC Number: 823444). As com-
pared with the trans configuration of nitro in the crystal
structure of nitenpyram,[24] the nitro group in 2o is ob-
viously in the cis configuration as anticipated. In addi-
tion, the 1,4-dihydropyridine ring of the compound 2o
adopts a skew boat conformation (Figure 3). Interest-
Figure 3 Molecular structure of compound 2o (Number CCDC
823444) with atom-labeling and packing diagram.
Molecular docking study
To further explore the structural features for better
activities, models of these new inhibitors-receptor com-
plexes were investigated by docking studies with
AutoDock version 4.0.[26] Since the amino acids form-
6
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—8

cis-Nitenpyram Analogues: Synthesis, Insecticidal Activities, and Molecular Docking Studies
ing the active sites are both structurally and functionally
consistent in the diverse nAChRs and AchBPs, and
none of the insect nAChRs has been published until
now, the crystal structure of a Lymnaea stagnalis-
AChBP (Ls-AChBP) co-crystallized with imidacloprid
(PDB ID: 2zju)[27] was used as the template of receptor.
The docking was carried out through the graphical user
interface AUTODOCKTOOLS (ADT 1.4.6). The only
modification was the number of docking runs that was
set to 300 (previously 100) for more accuracy.
As a result, the scoring function of the docking pro-
gram ranked the compounds in the same general order
observed experimentally (data not shown), and all active
analogues exhibited significant hydrogen bonding in-
teractions with the nAChR target. As expected, the most
potent compound 2d is nicely accommodated within the
subunit interfacial binding pocket between the two faces
of adjacent subunits (Figure 4 a, b). Its binding confor-
mation exhibited two important hydrogen bonds be-
tween its nitro and H—O of Tyr192 (Figure 4b), and the
O30 of its ester group hydrogen-bonds the H—O of
Tyr185, while its chloropyridine interacts primarily with
the side chain of Glu190, and its chlorophenyl also hy-
drogen-bonds the side chain of Gln55. Moreover, 2d
also showed the important additional H bonding interac-
tions with Trp143 at the interface of two adjacent
nAChR subunits (Figure 4c). In addition, due to the
novel structure of compound 2d, all these interactions
above may greatly enhance the binding affinity of in-
hibitor 2d, and account for its high inhibitory potency.
Hence, the observations herein have also explained the
structure-activity relationships observed in vitro.
a
b
Furthermore, most of the other active analogues (2a,
2j) shared a similar binding mode with 2d, and many of
them exhibited more than four hydrogen bonds with
different amino acids of the active pocket between the
nAChR subunits (unpublished result), which is consis-
tent with their high insecticidal activities. Since these
amino acids (Gln55, Trp 143, Tyr185, Glu190, and
Tyr192) of the active site residues were different from
the ones that interacted with nitenpyram, the above re-
c
sults suggested a novel mechanism of their insecticidal
effects. Thereby, compared with nitenpyram, the newly
introduced substituents of the designed analogues pre-
sumably played important roles in ligand recognition
and binding interactions, which may enhance their ac-
tivities and contribute to the selectivity as well. Based
on these, further inhibitory tests on special insect
nAChR target(s) and advanced insecticide design are
underway.
Figure 4 Modeling of the docking results of compounds 2d in
the extracellular domain of insect nAChR. (a) 2d nestled in the
interfacial agonist-binding pocket between the (＋)-face (primary,
cyan) and (－)-face (complementary, purple) subunits of the
Ls-AChBP (PDB ID: 2zju), as a structural surrogate of the insect
nAChR. The second structure of the protein is represented as
solid ribbon; (b) nAChR-2d binding site interactions (zoomed-in),
and the corresponding subunits which are also colored cyan and
purple, respectively; (c) The hydrogen-bonding between 2d and
the active site residues of nAChR.
Conclusions
the 1,4-dihydropyridine ring. All the target compounds
presented good insecticidal activity against Aphis medi-
cagini at 100 mg/L. Among these analogues, 2a and 2d
afforded the best activity, and had 100% mortality at 4
mg/L. The most active analogue was 2d with LC50 val-
ues of 0.136 mg/L, although less than nitenpyram. The
In this paper, in order to search for lead compounds
of neonicotinoid insecticides with novel structural fea-
tures, high activity, less resistance and broad insecti-
cidal spectra, a new series of cis-nitenpyram analogues
(2a—2p) were designed and synthesized by introducing
Chin. J. Chem. 2012, XX, 1—8
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7

Sun et al.
FULL PAPER
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revealed a unique binding mode other than nitenpyram,
and the docking scores were in good agreement with
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the structure-activity relationships observed in vitro.
Further researches are underway to verify their molecu-
lar nAChR target and evaluate the inhibitory activities
against resistant insect species. The study herein has
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cis-configuration neonicotinoid analogues, and may
facilitate receptor structure-guided design of novel in-
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This work was supported by the National Natural
Science Foundation of China (21042010, 21102092 and
30870560), the Key Scientific "Twelfth Five-Year" Na-
tional Technology Support Program (2011BAE06B01-
17), the Innovation Project of Shanghai Education
Commission (12YZ078), the Leading Academic Disci-
pline Project of Shanghai Normal University (DZL808),
Shanghai Key Laboratory of Rare Earth Functional Ma-
terials, Shanghai Normal University (07dz22303). We
are also grateful for the support from Branch of Na-
tional Pesticide R&D South Center.
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