Facile three-component synthesis, insecticidal and antifungal evaluation of novel dihydropyridine derivatives

Article abstract of DOI:10.3390/molecules23102422

In an attempt to find the neonicotinoid insecticides, twenty novel dihydropyridine derivatives were designed, "green" synthesized via one pot facile three-component reaction and evaluated for their bioactivities against Tetranychus cinnabarinus, Myzus per

Full text of DOI:10.3390/molecules23102422

molecules
Article
Facile Three-Component Synthesis, Insecticidal
and Antifungal Evaluation of Novel
Dihydropyridine Derivatives
1
,†
1,2,†
1
1
1
Guan-Zhou Yang , Xiao-Fei Shang
, Pi-Le Cheng , Xiao-Dan Yin , Jia-Kai Zhu ,
1
,
3,
1,
Ying-Qian Liu *, Jing Zhang * and Zhi-Jun Zhang *
1
School of Pharmacy, Lanzhou University, Lanzhou 730000, China; yanggzh2016@lzu.edu.cn (G.-Z.Y.);
shangxiaofei@caas.cn (X.-F.S.); chengpile@hopelife.cn (P.-L.C.); yinxd14@lzu.edu.cn (X.-D.Y.);
zhujk17@lzu.edu.cn (J.-K.Z.)
Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences,
2
Lanzhou 730000, China
3
Environment and Plant Protection Institute, Chinese Academy of Tropical Agricultural Sciences,
Haikou 571010, China
*
Correspondence: yqliu@lzu.edu.cn (Y.-Q.L.); zh-jing99@163.com (J.Z.); zhangzhijun198803@163.com (Z.-J.Z.);
Tel.: +86-898-66969260 (Y.-Q.L., J.Z. & Z.-J.Z.)
†
These authors contributed equally to this work.
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 2 September 2018; Accepted: 19 September 2018; Published: 21 September 2018
Abstract: In an attempt to find the neonicotinoid insecticides, twenty novel dihydropyridine
derivatives were designed, “green” synthesized via one pot facile three-component reaction and
evaluated for their bioactivities against Tetranychus cinnabarinus, Myzus persicae, Brevicoryne brassicae,
Fusarium oxysporum f. sp. vasinfectum, Magnaporthe oryzae, Sclerotinia sclerotiorum and Botrytis cinereal.
All of the tested compounds showed potent insecticidal activity, and some were much better in
comparison with imidacloprid (IMI). Especially, compounds 3d (LC : 0.011 mM) and 5c (LC :
50
50
0
.025 mM) were 12.2- and 5.4-fold more active than IMI (LC : 0.135 mM) against T. cinnabarinus,
50
respectively. Moreover, out of all the derivatives, compound 3d (LC : 0.0015 mM) exhibited the
50
strongest insecticidal activity against B. brassicae and compound 3i (LC : 0.0007 mM) displayed the
50
strongest insecticidal activity against M. persicae. Surprisingly, when the concentration of compound
was 50 mg/L, the inhibition rate against F. oxysporum and S. sclerotiorum reached 45.00% and 65.83%,
4
respectively. The present work indicated that novel dihydropyridine derivatives could be used as
potential lead compounds for developing neonicotinoid insecticides and agricultural fungicides.
Keywords: neonicotinoid; insecticide; fungicide; dihydropyridine derivatives; three-component reaction
1
. Introduction
Neonicotinoid insecticides are one of the most important chemical classes of insecticides
introduced to global markets due to their broad spectrum of biological activities, favorable safety profile
and unique mechanism of action [ ], which have been registered globally in more than 120 countries
for more than 25% of global insecticide market [ ]. However, the great success of commercialization
and the widespread and frequent use of these insecticides have inevitably led to the occurrence of
resistance and cross-resistance [ ]. In addition, reports of the toxicity of neonicotinoid insecticides
on honey bees have raised concerns about whether the ecological balance has been destroyed [ ].
1
2,3
1,4–6
7,8
Therefore, it is of great significance to seek a novel structure that is more efficient and less toxic as a
potential candidate for future pest control.
Molecules 2018, 23, 2422; doi:10.3390/molecules23102422
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2422
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Representative generation of commercial neonicotinoid insecticides is shown in Figure 1.
The common molecular structural features of neonicotinoids consist of four sections: (i) aromatic
heterocycle, (ii) flexible linkage, (iii) hydroheterocyle or guanidine/amidine and (iv) electron-withdrawing
segment [9,10] Through our previous work on pesticides [11–14] and other reported structure
activity relationships for neonicotinoid insecticides [10], it has been found that pesticides containing
dihydropyridine or dihydropyran rings have relatively low non-target organisms and environmental
risks, high target specificity and a wide range of biological uses [15,16]. Furthermore, in recent years,
multi-component reactions (MCRs) have become powerful tools for the synthesis of target molecules
in organic chemistry, which are efficient, convenient, economical, practical and avoid purification
and measurement of intermediate structures during the synthesis process [17,18]. On this basis,
minimizing the amount of toxic waste and by-products and performing the reaction in the absence of
non-environmental organic solvents is one of the goals that participated with green chemistry and
green pesticides, as they were usually used in large quantities [19]. Thus, a series of derivatives
with dihydropyridine as the core structure were designed and “green” synthesized by one-pot
and three-component reactions and evaluated for their activity against T. cinnabarinus, M. persicae,
B. brassicae, and four kinds of phytopathogens (Figure 2).
Figure 1. Representative generation of commercial neonicotinoid insecticides.
Figure 2. The molecular design of target compounds.

Molecules 2018, 23, 2422
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2
. Results and Discussion
2
.1. Chemistry
MCRs provide an efficient, economical, and rapid approach towards the efficient synthesis of
diverse compounds and compound libraries. The combination of MCR-type chemistry-planning
with evolutionary in vitro prediction of drug potential or biological properties is a new and powerful
tool in drug discovery [20]. The derivatives of 3a
–3j, 4a and 5a–5i were prepared according to the
synthetic Scheme 1. Compounds 3a 3j were produced by the three-component one-pot reaction of
–
dimedone (1), aromatic aldehydes (2), and 2-cyanothioacetamide in the presence of morpholine under
ethanol conditions at reflux temperature, and then further replaced by iodoalkane. Compound 4a
was produced by the one-pot three-component reaction of dimedone (1), aromatic aldehydes (2),
and ethyl propionate under acetic acid conditions at room temperature. The reaction conditions
of the 5a
–
5i were substantially the same as those of 3a
–3j except that 2-cyanothioacetamide was
replaced with and 2-(nitromethylene) imidazolidine. The structures of synthesized 3a
–
3j and 5a 5i
,
4
–
1
13
1
13
were characterized by melting point, H-NMR, C-NMR and MS. The H and C NMR spectra of
representative compounds can be found in the supplementary materials. The obtained results showed
consistency with the expected structures and formulas of the targeted products. According to the
reaction route, the reaction could occur under the conditions of ethanol and acetic acid as a solvent, in
line with the importance of economical and green transformations in green chemistry.
Scheme 1. General synthetic procedure for target compounds 3a
conditions: ( ) Et N, EtOH, reflux; ( ) CH I or CH ICO C H , EtOH, reflux; (
EtOH, reflux.
–
3j
,
4
and 5a
–
5i. Reagents and
) Et N,
a
b
c) HOAc, rt; (d
3
3
2
2
2
5
3
2
.2. Evaluation of Insecticidal Activity
Based on the methodology in Scheme 1, with twenty derivatives 3a
examined their acaricidal activities against T. cinnabarinus and the results were summarized in Table 1.
Next, we selected the five most active compounds (3c 3d 3i 5c and 5e) to evaluate their insecticidal
–3j, 4a and 5a–5i in hand, we
,
,
,
activities against M. persicae and B. brassicae and the results were shown in Tables 2 and 3. IMI were
tested under the same conditions as a comparison compound.
As indicated in Table 1, all new compounds exhibited potent acaricidal activity against
T. cinnabarinus, with LC50 values ranging from 0.011 to 0.523 mM. Almost all of the derivatives
showed significant acaricidal activities against T. cinnabarinus, and even half of the compounds were
more than that of imidacloprid (0.135 mM). In particular, compounds 3c, 3d, 3i, 5c and 5e showed
pronounced acaricidal activities with respective LC50 values of 0.057, 0.011, 0.033, 0.025 and 0.064 mM,
respectively, higher than that of imidacloprid (IMI) (0.135 mM). The activities of these compounds in

Molecules 2018, 23, 2422
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Table 1 varied drastically, depending upon the types and patterns of substitution on the phenyl ring
and dihydropyridinecore.
For the effect of substituents at phenyl ring in the series of 3a–3i compounds, it was observed
that compounds with electron-donating is favorable for high activities from data analysis present,
the introduction of electron-donating groups, like 3d (0.011 mM), 3e (0.282 mM), 3f (0.122 mM), 3g
(0.076 mM) and 3i (0.033 mM), resulted in higher acaricidal potency than the corresponding analog
with electron-withdrawing group, such as 3a (0.473 mM) and 3b (0.523 mM). Unexpectedly, the activity
was found to increase rapidly when chlorine group was simultaneously introduced at the 2,4-position
of the phenyl ring (3c, 0.057 mM), and its activity was nearly 10 times higher than that of the 3b
(
0.523 mM), which introduced the chlorine group only at the 4-position the phenyl ring. Furthermore,
the insecticidal activity of compound 3j (0.079 mM) with an ethyl acetate group quadrupled compared
to 3e (0.282 mM) containing a methylthio group. In order to explore the effect of ester group on
acaricidal activity, we replaced cyano group (3a, 0.473 mM) with ethyl formate (4a, 0.204 mM) and
found that the activity was doubled. Of course, this may be due to the replacement of thiomethyl with
ethyl. To identify more potent acaricidal activity, the effect of different phenyl groups on the insecticidal
activity of the 5a
derivatives was completely different from that of 3a
exhibited significant acaricidal activity against T. cinnabarinus, with LC50 values of 0.096, 0.025 and
.064 mM, respectively. This indicated that the change in activity of the compound series depended
–
5j derivatives was investigated. However, the structure activity relationship of 5a
–5i
–
3j. Remarkably, compounds 5a 5c and 5e
,
0
5
not only on the type of electronic effect of the substituent group on the benzene ring, but also on
the number and position of the substituents. By summarizing the structure activity relationship
of all compounds, the results clearly underlined that the acaricidal difference could be ascribed to
combination of factors, like nature of the substitutes (which may depend on electronic characteristics
of substitutes, the position of substitutes, and other factors) or by a different interaction at the site.
Table 1. Insecticidal activities of compounds 3a–3j, 4a and 5a–5i and imidacloprid (IMI) against T.
Cinnabarinus.
Mortality (%) a,b
Compd.
2
50 mg/L
100 mg/L
50 mg/L
10 mg/L
1 mg/L
LC50 (mM) c
3
a
63
63
100
100
60
90
97
90
97
93
90
87
90
100
80
97
80
70
100
90
90
◦
37
37
60
97
50
58
87
50
70
80
40
60
53
67
43
80
57
30
33
47
60
30
23
53
93
40
45
43
33
63
37
27
47
43
57
40
60
53
20
23
30
33
23
13
37
57
27
21
17
23
50
27
17
30
20
43
23
20
30
17
20
23
30
10
7
17
30
10
8
10
17
20
7
0.473
0.523
0.057
0.011
0.282
0.122
0.076
0.159
0.033
0.079
0.204
0.096
0.132
0.025
0.191
0.064
0.107
0.404
0.184
0.173
0.135
3
b
3
c
3
3
d
e
3
f
3
g
3
h
3
3
i
j
4
5
a
a
7
13
13
33
20
12
10
3
13
10
27
5
b
5
c
5
5
d
e
5
f
5
g
5
h
5
IMI
i
a
b
Temperature: 25
±
2 C; room humidity (RH): 65–80%; photoperiod: light/dark = 12/12 h. Experimental size:
c
1
0 insects per group, three groups. LC50 calculations were determined by Probit analysis using a maximum
quasi-likelihood curve fitting algorithm.

Molecules 2018, 23, 2422
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Subsequently, 3c
,
3d
,
3i
,
5c and 5e with the most acaricidal activities against T. cinnabarinus
among of tested compounds, were selected to evaluate the insecticidal activity against M. persicae
and B. brassicae. As to the insecticidal activities, from Tables 2 and 3, it was surprising that all of the
target compounds showed strong insecticidal activities against M. persicae and B. oleracea, and the
activity of 3i (0.0007 and 0.0025 mM) was even better than or equal to that of imidacloprid (0.0010 and
0
.0006 mM). This result indicated that the series of compounds not only have good acaricidal activities,
but also have extremely strong aphicidal activities. These encouraging results would prompt us to
study the dihydropyridine derivatives as insecticidal agent in future.
Table 2. Insecticidal activities of compounds 3c
,
3d
,
3i
,
5c,
5e and imidacloprid (IMI) against M. persicae.
Mortality (%) a,b
Compd.
24 h
1 mg/L
48 h
1 mg/L
5
0 mg/L 10 mg/L
0.1 mg/L
50 mg/L 10 mg/L
0.1 mg/L
LC50 (mM) c
3
c
63
53
57
40
40
40
39
27
30
33
33
23
◦
30
17
20
20
20
6
17
13
10
10
7
87
93
90
70
87
43
63
83
50
57
87
37
40
70
40
43
70
30
33
37
27
23
37
0.0077
0.0033
0.0007
0.0111
0.0053
0.0010
3
d
3
5
i
c
5
e
IMI
3
100
a
2 C; RH: 65–80%; photoperiod: light/dark = 12/12 h. b Experimental size: 10 insects per
Temperature: 25
±
c
group, three groups. LC50 calculations were determined by Probit analysis using a maximum quasi-likelihood
curve fitting algorithm.
Table 3. Insecticidal activities of compounds 3c
,
3d
,
3i
,
5c,
5e and imidacloprid (IMI) against B. brassicae.
Mortality (%) a,b
Compd.
24 h
1 mg/L
48 h
1 mg/L
5
0 mg/L 10 mg/L
0.1 mg/L
50 mg/L 10 mg/L
0.1 mg/L
LC50 (mM) c
3
c
37
67
60
30
53
93
30
40
43
20
37
77
◦
20
33
30
13
23
43
13
17
17
7
13
10
70
90
83
60
67
97
63
70
67
50
57
90
40
60
57
33
37
77
20
33
27
13
23
43
0.0087
0.0015
0.0025
0.0291
0.0125
0.0006
3
d
3
5
i
c
5
e
IMI
a
2 C; RH: 65–80%; photoperiod: light/dark = 12/12 h. b Experimental size: 10 insects per
Temperature: 25
±
c
group, three groups. LC50 calculations were determined by Probit analysis using a maximum quasi-likelihood
curve fitting algorithm.
2
.3. Evaluation of Antifungal Activity
Plant fungal diseases are increasingly becoming a food security threat, and fungicides are widely
used to control the development of phytopathogenic fungi. Inspired by the excellent insecticidal
activities of this series of compounds, all compounds were evaluated for fungicidal activities against
phytopathogenic fungi and it would inspire us to find a wider range of biologically active uses.
Surprisingly, as shown in Table 4, although compound 4a exhibited moderate insecticidal activity,
it showed significant antifungal activity against F. oxysporum and S. sclerotiorum in vitro, and the
inhibition rate reached 45.00% and 65.85% at 50 mg/L, respectively. The conversion of cyano group
(3a) to ester groups (4a) could significantly increase the activities against phytopathogenic fungi,
which provides a reference for our search to discovery the promising candidates with insecticidal and
antifungal activities.

Molecules 2018, 23, 2422
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Table 4. Antifungal activities of compounds 3a–j, 4, 5a–i and azoxystrobin against F. oxysporum,
M. oryzae, S. sclerotiorum, B. cinerea at 50 mg/L.
Inhibition (%)
Compd.
F. oxysporum
M. oryzae
S. sclerotiorum
B. cinerea
3
a
5.00
23.33
17.92
5.42
0.00
11.67
7.87
0.00
12.45
5.42
45.00
0.00
5.42
5.83
0.00
0.00
2.92
0.00
0.00
7.08
52.50
8.75
12.50
4.17
11.67
3.75
11.25
10.56
0.00
0.00
7.08
24.17
0.00
0.00
6.25
7.32
8.33
7.52
10.83
65.83
0.00
0.00
0.00
11.67
9.24
6.25
6.25
10.83
0.00
74.58
6.25
5.00
11.25
0.00
0.00
0.00
0.00
0.00
6.27
6.25
18.33
7.78
0.00
32.50
0.00
0.00
0.00
0.00
0.00
0.00
42.08
3
b
3
c
3
3
d
e
3
f
3
g
3
h
3
3
4
5
i
j
4.56
10.83
21.67
6.45
0.00
0.00
9.58
7.56
16.25
5.83
9.58
a
5
b
5
c
5
d
5
5
e
f
5
g
5
h
5
i
5.42
88.48
azoxystrobin
3
. Experimental Section
3
.1. Chemicals and Instruments
All reactions were performed with commercially available reagents without further purification.
All reactions were monitored by thin-layer chromatography (TLC) and preparative thin-layer
chromatography (PTLC) were performed with silica gel plates using silica gel 60 GF254 (Qingdao
Haiyang Chemical Co., Ltd., Qingdao, China). Melting points were determined in an open capillary
using WRS-2U melting point apparatus (Shanghai Precision Instrument Co., Ltd., Shanghai, China)
and are uncorrected. Mass spectra were recorded on a Bruker Daltonics APEXII49e spectrometer
1
13
(
Bruker Daltonics Inc., Billerica, MA, US.) with ESI source as ionization. H and C-NMR spectra
were recorded at 400 and 100 MHz on a Bruker AM-400 (Bruker Company, Billerica, MA, US.)
spectrometer using TMS as reference. The commercial insecticide imidacloprid and fungicides
azoxystrobin (analytical grade, 98% purity) (Jiangsu Bailing Agrochemical Co., Ltd., Jiangying, China)
was used as a positive control in vitro experiment. Tetranychus Cinnabarinus, Myzus persicae, Brevicoryne
brassicae, Fusarium oxysporum f. sp. vasinfectum, Magnaporthe oryzae, Sclerotinia sclerotiorum and Botrytis
cinereal were obtained from the Institute of Plant Protection, Gansu Academy of Agricultural Science,
Lanzhou, China.
3
.2. Synthesis
3
.2.1. General Synthetic Procedure for Target Compounds 3a–3j
A 0.5 L round-bottom flask fitted with an overhead stirrer was charged with the corresponding
aromatic aldehyde (0.1 mol), cyanothioacetamide 10 (10.0 g, 0.10 mol) and EtOH (100 mL).
◦
Triethylamine (0.8
−
1.0 mL) was added, and the mixture was stirred for 1 h at 20 C (yellow/orange
crystalline may precipitate from the solution). Then dimedone (15.0 g, 0.104 mol) and N-methylmorpholine
16.5 mL, 0.15 mol) were added, and the solution was refluxed for 2 4 h, The mixture of salt was added
(
−

Molecules 2018, 23, 2422
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iodomethane (0.1 mol) or ethyl iodoacetate (0.1 mol) in 80% ethanol (15 mL) and boiled for 2 min and then
filtered through paper (Scheme 1). The solid was recrystallized from EtOH to afford the pure products [21].
◦
1
3
a
: Yellow solid; yield 56%; m.p. 192–194 C; H-NMR (400 MHz, DMSO-d )
δ: 9.75 (s, 1H, br, NH),
6
8
.19 (d, 2H, J = 8 Hz, Ar-H), 7.44 (d, 2H, J = 8 Hz, Ar-H), 4.76 (s, 1H, CH), 2.54 (s, 3H, -SCH ), 2.42
3
(
(
d, 2H, J = 16 Hz, CH ), 2.21 (d, 1H, J = 16 Hz, CH), 2.09–1.99 (m, 1H, CH), 1.03 (s, 3H, -CH ), 0.90
2
3
s, 3H, -CH3). 13C-NMR (100 MHz, DMSO-d6)
δ
194.1, 149.5, 148.3, 144.9, 144.4, 127.0, 127.0, 123.5,
1
23.5, 118.6, 111.9, 104.5, 51.2, 39.6, 32.8, 31.3, 29.7, 26.7, 17.1. HRMS: calcd. for C H N O S [2M +
19 19 3 3
Na]: 761.2192, found: 761.2195.
◦
1
3
b
: Yellow solid; yield 53%; m.p. 201–203 C; H-NMR (400 MHz, DMSO-d )
δ: 9.66 (s, 1H, br, NH),
6
7
.36 (d, 2H, J = 8 Hz, Ar-H), 7.16 (d, 2H, J = 8 Hz, Ar-H), 4.49 (s, 1H, -CH), 2.52 (s, 3H, SCH ), 2.43–2.46
3
(
m, 2H, CH ), 2.20 (d, 1H, J = 16 Hz, CH), 2.01 (t, 1H, J = 16 Hz, CH), 1.02 (s, 3H, CH ), 0.89 (s, 3H,
2
3
CH3). 13C-NMR (100 MHz, DMSO-d6)
δ
194.6, 152.1, 145.5, 140.2, 131.3, 131.4, 131.4, 128.8, 128.8, 118.6,
1
11.9, 104.5, 51.2, 39.6, 32.8, 31.3, 29.7, 26.7, 17.1. HRMS: calcd. for C H ClN OS [2M + Na]: 739.1711,
19 19 2
found: 739.1720.
◦
c: Yellow solid; yield 48%; m.p. 243–245 C; H-NMR (400 MHz, DMSO-d ) δ: 9.67 (s, 1H, br, NH),
6
1
3
7
2
.54 (s, 1H, Ar-H), 7.39 (dd, 1H, J = 8 Hz, J = 4 Hz, Ar-H), 7.24 (d, 1H, J = 8 Hz, Ar-H), 4.99 (s, 1H, CH),
.50 (s, 3H, -SCH ), 2.44–2.40 (m, 2H, CH ), 2.18 (d, 1H, J = 16 Hz, CH), 1.97–2.09 (m, 1H, CH), 1.03
3
2
13
(
s, 3H, CH ), 0.93 (s, 3H, -CH ). C-NMR (100 MHz, DMSO-d6)
δ
194.6, 152.1, 145.5, 140.2, 131.3, 131.4,
3
3
131.4, 129.5, 127.5, 118.6, 111.9, 104.5, 51.2, 39.6, 32.8, 31.3, 29.7, 26.7, 17.1. MS-ESI m/z: 807.0 [2M+Na]
HRMS: calcd. for C H Cl N OS [2M + Na]: 807.0931, found: 807.0935.
19
19
2
2
◦
1
3
d
: Yellow solid; yield 52%; m.p. 189–191 C; H-NMR (400 MHz, DMSO-d )
δ: 9.59 (s, 1H, br, NH),
6
7
.05 (d, 2H, J = 8 Hz, Ar-H), 6.85 (d, 2H, J = 8 Hz, Ar-H), 4.40 (s, 1H, CH), 3.71 (s, 3H, -OCH ), 2.50
3
(
s, 3H, -SCH ), 2.38–2.45 (m, 2H, CH ), 2.19 (d, 1H, J = 16 Hz, CH), 1.99–2.09 (m, 1H, CH), 1.02 (s, 3H,
3 2
13
-
CH ), 0.90 (s, 3H, -CH ). C-NMR (100 MHz, DMSO-d6)
δ
194.5, 157.8, 148.5, 146.2, 136.2, 133.3, 133.3,
18.6, 118.4, 118.4, 111.9, 104.5, 59.2, 52.7, 39.6, 32.8, 31.3, 29.7, 26.7, 17.1. MS-ESI m/z: 731.1 [2M + Na]
HRMS: calcd. for C H N O S [2M + Na]:731.2702, found: 731.2710.
3
3
1
20
22
2
2
◦
1
3
7
2
e
: Yellow solid; yield 55%; m.p. 197–199 C; H-NMR (400 MHz, DMSO-d )
δ
: 9.63 (s, 1H, br, NH),
6
.18 (d, 1H, J = 12 Hz, Ar-H), 7.08 (t, 2H, J = 8 Hz, Ar-H), 4.42 (s, 1H, CH), 2.44 (m, 5H, CH , SCH ),
.50 (s, 3H, SCH ), 2.20 (d, 1H, J = 16 Hz, CH), 2.09–2.00 (m, 1H, CH), 1.03 (s, 3H, CH ), 0.90 (s, 3H,
2
3
3
3
13
CH3). C-NMR (100 MHz, DMSO-d6)
δ
194.5, 148.5, 146.2, 142.8, 140.3, 130.3, 130.3, 128.9, 128.9, 118.6,
1
11.9, 104.5, 52.7, 39.6, 32.8, 31.3, 29.7, 26.7, 17.1, 14.8. MS-ESI m/z: 763.0 [2M + Na] HRMS: calcd. for
C H N OS [2M + Na]: 763.2245, found: 763.2251.
20
22
2
2
◦
1
3
f
: Yellow solid; yield 48%; m.p. 195–199 C; H-NMR (400 MHz, DMSO-d )
δ: 9.54 (s, 1H, br, NH),
6
6
.89 (d, 1H, J = 8 Hz, Ar-H), 6.73 (dd, 1H, J = 8 Hz, J = 4 Hz, Ar-H), 6.52 (d, 1H, J = 4 Hz, Ar-H), 4.80
(
s, 1H, CH), 3.73 (s, 3H, OCH ), 3.64 (s, 3H, OCH ), 2.46 (s, 3H, -SCH ), 1.04 (s, 3H, CH ), 2.44–2.40
3 3 3 3
13
(
m, 2H, CH ), 2.19 (d, 1H, J = 16 Hz, CH), 2.09–1.98 (m, 1H, CH), 0.96 (s, 3H, CH ). C-NMR (100 MHz,
2
3
DMSO-d6)
δ
194.5, 152.8, 151.2, 150.5, 146.2, 123.3, 118.6, 116.5, 112.8, 111.9, 106.5, 56.6, 55.9, 52.7, 39.6,
3
7
2.8, 29.7, 26.7, 25.3 17.1. MS-ESI m/z: 792.3 [2M + Na] HRMS: calcd. for C H N O S [2M + Na]:
91.2913, found: 791.2918.
21
24
2
3
◦
1
3
g
: Light yellow solid; yield 55%; m.p. 221–223 C; H-NMR (400 MHz, DMSO-d )
δ: 9.66 (s, 1H, br,
6
NH), 6.40 (s, 1H, Ar-H), 4.42 (s, 1H, CH), 3.71 (s, 6H, OCH ), 3.67 (s, 3H, OCH ), 2.50 (s, 3H, SCH )
3
3
3
2
(
.45–2.41 (m, 2H, CH ), 2.23 (d, 1H, J = 16 Hz, CH), 2.09–1.99 (m, 1H, CH), 1.05 (s, 3H, CH ), 0.98
2
3
s, 3H, CH3). 13C-NMR (100 MHz, DMSO-d6)
δ
194.5, 152.8, 152.8, 150.5, 138.5, 137.2, 118.6, 111.9, 106.5,
1
06.5, 104.5, 61.6, 56.8, 56.8, 52.7, 39.6, 32.8, 31.9, 29.7, 26.7, 25.3 17.1. HRMS: calcd. for C H N O S
22 26 2 4
[2M + Na]: 851.3124, found: 851.3129.

Molecules 2018, 23, 2422
8 of 12
◦
1
3
h
: Light yellow solid; yield 58%; m.p. 201–203 C; H-NMR (400 MHz, DMSO-d )
δ
: 9.77 (s, 1H, br,
6
NH), 7.18 (d, 1H, J = 12 Hz, Ar-H), 7.08 (t, 2H, J = 8 Hz, Ar-H), 4.43 (s, 1H, CH) 4.04 (q, 2H, J = 8 Hz,
CH ), 3.84 (dd, 2H, J = 16 Hz, J = 44 Hz, CH ), 2.37–2.41 (m, 5H, CH , SCH ), 2.22–2.18 (d, 1H, J = 16 Hz,
2
2
2
3
13
CH), 2.00–2.09 (m, 1H, CH), 1.13 (t, 3H, J = 4 Hz, CH ), 1.02 (s, 3H, CH ), 0.91 (s, 3H, CH ). C-NMR
3
3
3
(100 MHz, DMSO-d6)
δ 194.5, 150.5, 146.2, 140.2, 137.7, 134.2, 131.2, 130.8, 127.6, 118.6, 111.9, 106.5,
5
4.6, 39.6, 32.8, 31.6, 29.7, 26.7, 19.1, 18.8, 17.1. HRMS: calcd. for C H N OS [2M + Na]: 727.3116,
21
24
2
found: 727.3120.
◦
1
3
i
: Light yellow solid; yield 51%; m.p. 195–197 C; H-NMR (400 MHz, DMSO-d )
δ: 9.60 (s, 1H, br,
6
NH), 6.82 (d, 1H, J = 8 Hz, Ar-H), 6.06 (t, 2H, J = 8 Hz, Ar-H), 5.07 (s, 2H, CH ), 4.39 (s, 1H, CH), 2.50
2
(
s, 3H, -SCH ), 2.44 (d, 2H, J = 4 Hz, CH ), 2.19 (d, 1H, J = 16 Hz, CH), 2.02–2.09 (m, 1H, CH) 1.02
3
2
13
(
s, 3H, CH ), 0.91 (s, 3H, CH ). C-NMR (100 MHz, DMSO-d6)
δ
194.5, 150.5, 148.7, 145.8, 144.4, 135.5,
3
3
122.6, 118.6, 115.9, 112.3, 111.9, 106.5, 101.5, 54.6, 39.6, 32.8, 31.6, 29.7, 26.7, 17.1. HRMS: calcd. for
C H N O S [2M + Na]: 759.2287, found: 759.2290.
20
20
2
3
◦
1
3
j
: Yellow solid; yield 57%; m.p. 213–215 C; H-NMR (400 MHz, DMSO-d )
δ: 9.57 (s, 1H, br, NH),
6
7
.04 (d, 1H, J = 8 Hz, Ar-H), 6.84 (m, 2H, Ar-H), 4.36 (s, 1H, CH), 2.50 (s, 3H, SCH ), 2.43–2.46 (m, 2H,
3
13
CH ), 2.17–2.15 (m, 6H, CH ), 2.09–1.99 (m, 2H, CH ), 1.03 (s, 3H, CH ), 0.91 (s, 3H, CH ). C-NMR
2
3
2
3
3
(100 MHz, DMSO-d6) δ 194.5, 169.9, 150.5, 145.8, 139.8, 139.2, 130.5, 130.5, 128.6, 128.6, 118.6, 111.9,
106.5, 62.8, 54.6, 39.6, 34.2, 32.8, 31.6, 29.7, 26.7, 14.8, 14.1. HRMS: calcd. for C H N O S [2M + Na]:
23 26 2 3 2
9
07.2667, found: 907.2672.
3
.2.2. General Synthetic Procedure for Target Compounds 4
In a dry 50 mL flask, arylaldehyde (1 mmol), ethyl propionylacetate (1 mmol), dimedone (1 mmol)
and excessive ammonium acetate and HOAc (10 mL) were mixed and then stirred at room temperature
for 8–10 h. After completion of the reaction, as indicated by thin layer chromatography (TLC), the
reaction mixture was poured into water, then the solid product was collected and purified by flash
column chromatography (Scheme 1) [22].
◦
1
4
8
2
3
: Yellow solid; yield 56%; m.p. 223–225 C; H-NMR (400 MHz, DMSO-d )
δ
: 9.22 (s, 1H, br, NH),
.09 (d, 2H, J = 8 Hz, Ar-H), 7.40 (d, 2H, J = 8 Hz, Ar-H), 4.97 (s, 1H, CH), 3.94 (q, 2H, J = 8 Hz, CH2),
.76–2.67 (m, 2H, CH ), 2.32–2.18 (m, 2H, CH ), 2.09–1.95 (m, 2H, CH ), 1.13–1.09 (m, 6H, CH ), 1.01 (s,
6
2
2
2
3
13
H, CH ), 0.80 (s, 3H, CH ). C-NMR (100 MHz, DMSO-d6)
δ
194.5, 169.9, 152.6, 150.5, 149.5, 145.8,
27.8, 127.8, 124.6, 124.6, 111.9, 102.5, 62.8, 54.6, 42.4, 40.3, 32.8, 29.7, 26.7, 23.8, 14.2, 12.9. HRMS: calcd.
for C H N O [2M + Na]: 819.3581, found: 819.3583.
3
3
1
22
26
2
5
3
.2.3. General Synthetic Procedure for Target Compounds 5a–5i
-(nitromethylene) imidazolidine (0.5 mmol), aldehydes (0.5 mmol), dimedone (0.5 mmol) and
2
EtOH (10 mL) and Et N (0.25 mmol) were added into a 25 mL flask and the mixture was stirred for
3
◦
the appropriate reaction time at 80 C in an oil bath until the 2-(nitromethylene) imidazolidine was
completely consumed. The solid mixture was washed with EtOH (2
recrystallized from EtOH to afford the pure products (Scheme 1) [23].
×
5 mL). The crude residue was
◦
1
5
a
: Dark yellow solid; yield 56%; m.p. 264–267 C; H-NMR (400 MHz, DMSO-d )
δ
9.52 (s, 1H, br,
NH), 8.14–7.97 (m, 2H, Ar-H), 7.63–7.42 (m, 2H, Ar-H), 5.16 (s, 1H, CH), 4.26–4.14 (m, 1H, CH), 4.05
q, J = 9.5 Hz, 1H, CH), 3.91–3.77 (m, 2H, CH ), 2.62 (d, J = 17.7 Hz, 1H, CH ), 2.55 (s, 1H, CH ), 2.21 (d,
6
(
2
2
2
1
3
J = 16.1 Hz, 1H, CH ), 2.00 (d, J = 16.1 Hz, 1H, CH ), 1.05 (s, 3H, CH ), 0.84 (s, 3H, CH ). C-NMR
2
2
3
3
(
3
100 MHz, DMSO-d6)
δ
194.7, 160.8, 148.3, 146.5, 144.9, 134.2, 131.5, 128.89, 126.7, 111.9, 94.0, 52.2, 50.5,
+
9.9, 40.9, 33.1, 30.1, 29.7, 26.7. HRMS: calcd. for C H N O [M + H] : 385.1512, found: 385.1518.
19
20
4
5

Molecules 2018, 23, 2422
9 of 12
◦
1
5
b
: Yellow solid; yield 56%; m.p. 295–296 C; H-NMR (400 MHz, DMSO-d )
δ
9.45 (s, 1H, br, NH),
6
7.34–7.14 (m, 4H, Ar-H), 5.50 (s, 1H, CH), 4.17 (dd, J = 10.0, 6.7 Hz, 1H, CH), 4.03(q, J = 9.5 Hz, 1H,
CH ), 3.87–3.78 (m, 2H, CH ), 2.65 (d, J = 20.0 Hz, 1H, CH ), 2.58 (s, 1H, CH ), 2.20 (d, J = 16.1 Hz,
2
2
2
2
13
1
H, CH ), 2.00 (d, J = 16.3 Hz, 1H, CH ), 1.05 (s, 3H, CH ), 0.85 (s, 3H, CH ). C-NMR (100 MHz,
2 2 3 3
DMSO-d6)
δ
193.7, 151.9, 150.0, 140.5, 134.3, 134.2, 131.5, 128.89, 126.7, 112.1, 106.7, 45.2, 43.9, 39.9, 38.8,
+
3
7.4, 32.1, 29.7, 26.7. HRMS: calcd. for C H ClN O [M + Na] : 396.1091, found: 396.1095.
19
20
3
3
◦
1
5
c
: Yellow solid; yield 56%; m.p. 284–287 C; H-NMR (400 MHz, DMSO-d )
δ
9.47 (s, 1H, br, NH),
6
7.48–7.33 (m, 2H, Ar-H), 7.26 (dd, J = 8.4, 2.2 Hz, 1H, Ar-H), 5.28 (s, 1H, CH), 4.19 (t, J = 9.0 Hz, 1H,
CH), 4.08 (s, 1H, CH ), 3.84 (s, 2H, CH ), 2.60 (d, J = 17.6 Hz, 1H, CH ), 2.46 (s, 1H, CH ), 2.18 (d,
2
2
2
2
13
J = 16.1 Hz, 1H, CH ), 1.98 (s, 1H, CH ), 1.05 (s, 3H, CH ), 0.87 (s, 3H, CH ). C-NMR (100 MHz,
2
2
3
3
DMSO-d6)
δ
193.7, 151.9, 150.0, 140.5, 134.3, 134.2, 131.5, 128.89, 126.7, 112.1, 106.7, 45.2, 43.9, 39.9, 38.8,
+
3
7.4, 32.1, 29.7, 26.7. HRMS: calcd. for C H Cl N O [M + Na] : 430.0701, found: 430.0731.
19
19
2
3
3
◦
1
5
d
: Yellow solid; yield 56%; m.p. 310–311 C; H-NMR (400 MHz, DMSO-d )
δ
9.38 (s, 1H, br, NH),
6
7
.22–7.05 (m, 2H, Ar-H), 6.86–6.63 (m, 2H, Ar-H), 5.02 (s, 1H, CH), 4.17 (s, 1H, CH ), 4.02 (d, J = 9.6 Hz,
2
1
H, CH ), 3.83 (t, J = 9.9 Hz, 2H, CH ), 3.68 (s, 3H, CH ), 2.65 (d, J = 21.3 Hz, 1H, CH ), 2.58 (s, 1H,
2 2 3 2
CH ), 2.19 (d, J = 16.1 Hz, 1H, CH ), 1.99 (d, J = 16.1 Hz, 1H, CH ), 1.05 (s, 3H, CH ), 0.86(s, 3H, CH ).
2
2
2
3
3
1
3
C-NMR (100 MHz, DMSO-d ) δ 198.5, 162.7, 156.8, 153.9, 141.7, 134.2, 134.0, 119.1, 119.1, 118.2, 94.0,
0.1, 54.7, 50.0, 48.6, 43.4, 41.4, 37.0, 34.6, 31.4. HRMS: calcd. for C H N O [M + H] : 370.1767,
6
+
6
20
23
3
4
found: 370.1771.
◦
1
5
7
4
e
: Yellow solid; yield 56%; m.p. 279–281 C; H-NMR (400 MHz, DMSO-d )
δ
9.42 (s, 1H, br, NH),
6
.19–7.13 (m, 2H, Ar-H), 7.09 (d, J = 8.3 Hz, 2H, Ar-H), 5.03 (s, 1H, CH), 4.19 (q, J = 8.7 Hz, 1H, CH2),
.03 (q, J = 9.6 Hz, 1H, CH ), 3.84 (d, J = 9.9 Hz, 2H, CH ), 2.58 (d, J = 17.0 Hz, 1H, CH ), 2.53 (s, 1H,
2
2
2
CH ), 2.41 (s, 3H, CH ), 2.20 (d, J = 16.0 Hz, 1H, CH ), 2.00 (d, J = 16.1 Hz, 1H, CH ), 1.05 (s, 3H, CH ),
2
3
2
2
3
13
0
.86 (s, 3H, CH3). C-NMR (100 MHz, DMSO-d6)
δ 193.7, 152.1, 149.7, 141.6, 135.8, 128.9, 128.9, 126.0,
1
26.0, 114.0, 107.7, 49.9, 45.3, 43.9, 38.7, 37.2, 32.3, 29.8, 26.6, 15.3. HRMS: calcd. for C H N O S
20
24
3
3
+
[M + H] : 386.1538, found: 386.1540.
◦
1
5
6
3
f
: Yellow solid; yield 56%; m.p. 278–279 C; H-NMR (400 MHz, DMSO-d )
δ
9.42 (s, 1H, br, NH),
6
.97 (d, J = 5.2 Hz, 3H, Ar-H), 5.02 (s, 1H, CH), 4.25–4.16 (m, 1H, CH ), 4.02 (q, J = 9.6 Hz, 1H, CH ),
.83 (t, J = 8.6 Hz, 2H, CH ), 3.77 (s, 3H, CH ), 2.60 (d, J = 17.7 Hz, 1H, CH ), 2.54 (s, 1H, CH ), 2.18
2
2
2
3
2
2
13
(
s, 1H, CH ), 2.03 (s, 1H, CH ), 1.05 (s, 3H, CH ), 0.87 (s, 3H, CH ). C-NMR (100 MHz, DMSO-d ) δ
2 2 3 3 6
1
3
93.8, 152.0, 149.5, 145.7, 124.3, 124.2, 115.7, 115.5, 113.7, 113.4, 107.5, 56.4, 45.3, 43.9, 40.5, 38.7, 36.9,
+
2.3, 29.8, 26.6. HRMS: calcd. for C H FN O [M + H] : 388.1673, found: 388.1675.
20
22
3
4
◦
g: Yellow solid; yield 56%; m.p. 279–280 C; H-NMR (400 MHz, DMSO-d ) δ 9.47 (s, 1H, br, NH), 7.62
6
1
5
(
d, J = 2.3 Hz, 1H, Ar-H), 7.51 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.19 (d, J = 8.7 Hz, 1H, Ar-H), 5.04 (s, 1H,
CH), 4.19 (td, J = 9.5, 6.9 Hz, 1H, CH), 4.08–3.94 (m, 1H, CH ), 3.85 (d, J = 10.8 Hz, 5H, CH , CH ),
2
3
2
2
.61 (d, J = 17.7 Hz, 1H, CH ), 2.55 (s, 1H, CH ), 2.21 (d, J = 16.1 Hz, 2H, CH ), 2.01 (d, J = 16.1 Hz, 2H,
2
2
2
13
CH ), 1.06 (s, 3H, CH ), 0.88 (s, 3H, CH ). C-NMR (100 MHz, DMSO-d6)
δ
193.8, 151.8, 150.8, 150.0,
2
3
3
1
39.1, 137.3, 134.4, 124.1, 113.9, 113.0, 107.2, 57.0, 49.8, 45.3, 43.9, 38.7, 37.2, 32.3, 29.8, 26.6. HRMS: calcd.
+
for C H N O [M + H] : 415.1618, found: 415.1621.
20
22
4
6
◦
1
5
6
7
h
: Yellow solid; yield 56%; m.p. 240–242 C; H-NMR (400 MHz, DMSO-d )
δ
9.40 (s, 1H, br, NH),
.46 (s, 2H, Ar-H), 5.09 (s, 1H, CH), 4.28–4.13 (m, 1H, CH), 4.02(q, J = 9.6 Hz, 1H, CH), 3.83 (dd, J = 10.2
.2 Hz, 2H, CH ), 3.70 (s, 6H, CH , CH ), 3.60 (s, 3H, CH ), 2.63 (d, J = 17.7 Hz, 1H, CH ), 2.58 (s, 1H,
6
,
2
3
3
3
2
CH ), 2.23 (d, J = 16.2 Hz, 1H, CH ), 2.05(d, J = 16.1 Hz, 1H, CH ), 1.07 (s, 3H, CH ), 0.94 (s, 3H, CH ).
2
2
2
3
3
1
3
C-NMR (100 MHz, DMSO-d6)
4.0, 65.1, 61.0, 61.0, 54.7, 48.6, 43.5, 42.0, 37.0, 34.8, 31.2. HRMS: calcd. for C H N O [M + H] :
30.1978, found: 430.1985.
δ
198.6, 157.5, 156.8, 154.6, 157.5, 144.9, 141.3, 118.6, 112.3, 110.4, 110.4,
+
9
4
22
27
3
6

Molecules 2018, 23, 2422
10 of 12
◦
1
5
i
: Yellow solid; yield 56%; m.p. 345–356 C; H-NMR (400 MHz, DMSO-d )
δ
9.13 (s, 1H, br, NH),
6
6
.74–6.65 (m, 3H, Ar-H), 5.91 (d, J = 3.8 Hz, 2H, CH ), 4.25 (d, J = 10.8 Hz, 1H, CH), 3.75–3.57 (m, 4H,
2
CH ), 2.59 (d, J = 17.4 Hz, 1H, CH ), 2.44 (s, 1H, CH ), 2.11 (d, 1H, CH ), 1.92 (d, J = 14.2 Hz, 1H, CH ),
2
2
2
2
2
13
1
.04 (s, 3H, CH ), 1.01 (s, 3H, CH ). C-NMR (100 MHz, DMSO-d6)
δ
204.8, 157.6, 146.7, 145.3, 139.1,
3
3
1
35.5, 121.4, 109.4, 108.6, 107.8, 100.9, 85.6, 54.3, 46.3, 43.3, 36.6, 35.3, 33.3, 32.3, 28.1. HRMS: calcd. for
+
C H N O [M + H] : 384.1559, found: 384.1565.
20
23
3
6
3
.3. Insecticidal Activity
◦
2 C
Bioassays on representative test organisms reared in the laboratory were carried out at 25
±
apropos to statistical standards. Series concentrations of 250.0, 100.0, 50.0, 10.0, 1.0 and 0.1 mg/L for
bioassays were obtained by dissolving all the synthesized dihydropyridine analogues in acetone and
diluted with water containing Tween-20 (0.1 mg/L). The control imidacloprid was tested under the
same experimental conditions.
3
.3.1. Acaricidal Assay against T. Cinnabarinus.
Slide immersion method recommended by FAO [13] was employed to evaluate the acaricidal
activity of all the synthesized agents. All the test compounds were prepared in acetone at a
concentration of 250 mg/L and diluted to the required concentration with distilled water containing
TW-80. Using a small brush, thirty adult spider mites were fixed dorsally to a strip of double-sided
tape attached to the slide. The slide was immersed diluted solution of the test compounds and shaken
◦
for 3 s. The treated slides with the mites were kept at 25
±
2 C in a covered dish with wet filter
paper after the excessive solution was removed. After 24 h treatment, the number of demised mites
was recorded. Each treatment was repeated with triplicate experiments and each replicate involved
3
0 adult mites. Control groups were tested with only acetone.
3
.3.2. Insecticidal Assay Against M. Persicae and B. Brassicae.
The insecticidal activities of five compounds 3c, 3d, 3i, 5c, 5e and imidacloprid against M. persicae
and B. brassicae were evaluated according to the reported procedure [24].
3
.4. Antifungal Activity
The effects of 3a–j, 4a, 5a–i and azoxystrobin on the mycelial growth against F. oxysporum,
M. oryzae, S. sclerotiorum and B. cinerea were assessed using Poison Food Technique in solid media [25].
After completely covered the Petri dishes of the fungal, the mycelial growth diameters were measured
and inhibition percentages relative to the control with DMSO were calculated using the formula from
Agarwal: I(%) = ([(C
−
d)
−
(T
−
d)])/((C
−
d))
×
100, where d is diameter of the cut fungus (5 mm), I
is the inhibition (%), and C and T are the average colony diameters of the mycelium of the control and
treatment, respectively.
4
. Conclusions
In summary, a series of novel dihydropyridine derivatives were designed, “green” synthesized
via one pot facile three-component reaction and their structures were characterized by melting point,
1
13
H-NMR, C-NMR and EI-MS. The bioactivities were evaluated against T. cinnabarinus, M. persicae,
B. brassicae, F. oxysporum, M. oryzae, S. sclerotiorum and B. cinereal. In particular, Compound 3d (LC :
5
0
0
.011 and 0.0015 mM) exhibited the strongest insecticidal activity against T. cinnabarinus and B. brassicae
in all of the derivatives we prepared. Compound 3i (LC : 0.0007 mM) exhibited the strongest
50
insecticidal activity against M. persicae, and, surprisingly, when the concentration of compound
4
a
was 50 mg/L, the inhibition rate against F. oxysporum and S. sclerotiorum reached 45.00% and
6
5.83%. SARs clearly indicated that variations of R groups in the position of benzene ring markedly
affected the insecticidal activity. When cyano group was replaced by ethyl acetate at the 3-position of

Molecules 2018, 23, 2422
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dihydropyridine core, the biological activity spectrum was markedly affected. These results provide
a reference for searching for neonicotinoid insecticides and agricultural fungicide candidates in
the future.
Supplementary Materials: The representative compounds H and 13C NMR spectra are available online.
1
Author Contributions: G.-Z.Y. and P.-L.C. performed the chemical synthesis; X.-D.Y. and J.-K.Z. carried out the
insecticidal and antifungal activity evaluation; X.-F.S. contributed to the practical aspects of the research work and
Y.-Q.L. and J.Z. supervised the research and prepared the manuscript.
Funding: This research was funded by the National Natural Science Foundation of China (31371975, 21672092),
and the National Key Research and Development Program of China (2017YFD0201404). Funding was also
supplied by the Fundamental Research Funds for the Central Universities (lzujbky-2016-147, lzujbky-2017-k23).
Acknowledgments: My heart-felt gratitude goes to all the students in the laboratory for their immense
contributions to this the success of this research work, specially Raymond Kobla Lawoe for thoroughly reviewing
this article. At the same time, I thank. W.J. Gao for her continuous encouragement and support.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
5.
Bass, C.; Denholm, I.; Williamson, M.S.; Nauen, R. The global status of insect resistance to neonicotinoid
insecticides. Pestic. Biochem. Physiol. 2015, 121, 78–87. [CrossRef] [PubMed]
Nauen, R.; Jeschke, P.; Copping, L. In focus: Neonicotinoid insecticides. Pest Manag. Sci. 2008, 64, 1081.
[CrossRef] [PubMed]
Jeschke, P.; Nauen, R.; Beck, M.E. Nicotinic acetylcholine receptor agonists: A milestone for modern crop
protection. Angew. Chem. 2013, 52, 9464–9485. [CrossRef] [PubMed]
Crossthwaite, A.J.; Rendine, S.; Stenta, M.; Slater, R. Target-site resistance to neonicotinoids. J. Chem. Biol.
2
014, 7, 125–128. [CrossRef] [PubMed]
Gorman, K.; Devine, G.; Bennison, J.; Coussons, P.; Punchard, N.; Denholm, I. Report of resistance to the
neonicotinoid insecticide imidacloprid in trialeurodes vaporariorum (hemiptera: Aleyrodidae). Pest Manag. Sci.
2
007, 63, 555–558. [CrossRef] [PubMed]
6.
7.
8.
9.
Gorman, K.; Liu, Z.; Denholm, I.; Bruggen, K.U.; Nauen, R. Neonicotinoid resistance in rice brown
planthopper, nilaparvata lugens. Pest Manag. Sci. 2008, 64, 1122–1125. [CrossRef] [PubMed]
Raine, N.E.; Gill, R.J. Ecology: Tasteless pesticides affect bees in the field. Nature 2015, 521, 38–40. [CrossRef]
[PubMed]
Fairbrother, A.; Purdy, J.; Anderson, T.; Fell, R. Risks of neonicotinoid insecticides to honeybees.
Environ. Toxicol. Chem. 2014, 33, 719–731. [CrossRef] [PubMed]
Tian, Z.; Shao, X.; Li, Z.; Qian, X.; Huang, Q. Synthesis, insecticidal activity, and qsar of novel nitromethylene
neonicotinoids with tetrahydropyridine fixed cis configuration and exo-ring ether modification. J. Agric.
Food Chem. 2007, 55, 2288–2292. [CrossRef] [PubMed]
1
1
0. Bakhite, E.A.; Abd-Ella, A.A.; El-Sayed, M.E.A.; Abdel-Raheem, S.A.A. Pyridine derivatives as insecticides.
Part 2: Synthesis of some piperidinium and morpholinium cyanopyridinethiolates and their insecticidal
activity. J. Saudi Chem. Soc. 2017, 21, 95–104. [CrossRef]
1. Zhang, J.; Nan, X.; Yu, H.T.; Cheng, P.L.; Zhang, Y.; Liu, Y.Q.; Zhang, S.Y.; Hu, G.F.; Liu, H.; Chen, A.L.
Synthesis, biological activities and structure-activity relationships for new avermectin analogues. Eur. J.
Med. Chem. 2016, 121, 422–432. [CrossRef] [PubMed]
1
1
1
2. Liu, Y.-Q.; Yang, L.; Zhao, Y.-L.; Li, H.-Y. Synthesis of novel derivatives of camptothecin as potential
insecticides. Pestic. Biochem. Physiol. 2010, 98, 219–223. [CrossRef]
3. Wang, M.-J.; Nan, X.; Feng, G.; Yu, H.-T.; Hu, G.-F.; Liu, Y.-Q. Design, synthesis and bioactivity evaluation of
novel acylthiourea derivatives of cantharidin. Ind. Crops Prod. 2014, 55, 11–18. [CrossRef]
4. Liu, Y.-Q.; Zhao, Y.-L.; Yang, L.; Zhou, X.-W.; Feng, G. Design, semisynthesis and insecticidal activity of
novel podophyllotoxin derivatives against brontispa longissima in vivo. Pestic. Biochem. Physiol. 2012, 102,
1
1–18. [CrossRef]
1
5. Xia, Q.; Dong, J.; Li, L.; Wang, Q.; Liu, Y.; Wang, Q. Discovery of glycosylated genipin derivatives as novel
antiviral, insecticidal, and fungicidal agents. J. Agric. Food Chem. 2018, 66, 1341–1348. [CrossRef] [PubMed]

Molecules 2018, 23, 2422
12 of 12
1
6. Schade, D.; Lanier, M.; Willems, E.; Okolotowicz, K.; Bushway, P.; Wahlquist, C.; Gilley, C.; Mercola, M.;
Cashman, J.R. Synthesis and sar of b-annulated 1,4-pyridines define cardiomyogenic compounds as novel
inhibitors of tgf-β signaling. J. Med. Chem. 2012, 55, 9946–9957. [CrossRef] [PubMed]
1
7. Elnagdi, M.H.; Moustafa, M.S.; Al-Mousawi, S.M.; Mekheimer, R.A.; Sadek, K.U. Recent developments in
utility of green multi-component reactions for the efficient synthesis of polysubstituted pyrans, thiopyrans,
pyridines, and pyrazoles. Mol. Divers. 2015, 19, 625–651. [CrossRef] [PubMed]
1
1
2
2
8. Kaur, R.; Chaudhary, S.; Kumar, K.; Gupta, M.K.; Rawal, R.K. Recent synthetic and medicinal perspectives of
dihydropyrimidinones: A review. Eur. J. Med. Chem. 2017, 132, 108–134. [CrossRef] [PubMed]
9. Nikoofar, K.; Yielzoleh, F.M. A concise study on dimedone: A versatile molecule in multi-component
reactions, an outlook to the green reaction media. J. Saudi Chem. Soc. 2017, 22, 715–741. [CrossRef]
0. Weber, L. Multi-component reactions and evolutionary chemistry. Drug Discov. Today 2002, 7, 143–147.
[CrossRef]
1. Shestopalov, A.M.; Yakubov, A.P.; Tsyganov, D.V.; Emel’yanova, Y.M.; Nesterov, V.N. Synthesis of
Substituted 6-Amino-4-aryl-5-cyano-2H,4H-pyrano[2,3-c]pyrazoles (IV). Crystal and Molecula Structure of
0
0 0
6
2
-Amino-5-cyano-3-methyl-4-(2 ,4 ,6 -triethylphenyl)-2H,4H-pyrano[2,3-c]pyrazole. Chem. Heterocycl. Compd.
002, 38, 1180–1189. [CrossRef]
2
2. Yao, C.S.; Wang, C.H.; Jiang, B.; Tu, S.J. One-pot combinatorial synthesis of 4-aryl-1h-thiopyrano[3,4-b]pyridine-
-one derivatives. J. Comb. Chem. 2010, 12, 472–475. [CrossRef] [PubMed]
5
2
3. Wen, L.R.; Sun, Q.C.; Zhang, H.L.; Li, M. A new rapid multicomponent domino heteroannulation of
heterocyclic ketene aminals: Solvent-free regioselective synthesis of functionalized benzo[g]imidazo[1,2-a]
quinolinediones. Org. Biomol. Chem. 2013, 11, 781–786. [CrossRef] [PubMed]
2
4. Zhao, Q.; Li, Y.; Xiong, L.; Wang, Q. Design, synthesis and insecticidal activity of novel phenylpyrazoles
containing a 2,2,2-trichloro-1-alkoxyethyl moiety. J. Agric. Food Chem. 2010, 58, 4992–4998. [CrossRef]
[PubMed]
2
5. Zhang, J.; Yan, L.T.; Yuan, E.L.; Ding, H.X.; Ye, H.C.; Zhang, Z.K.; Yan, C.; Liu, Y.Q.; Feng, G. Antifungal
activity of compounds extracted from cortex pseudolaricis against colletotrichum gloeosporioides. J. Agric.
Food Chem. 2014, 62, 4905–4910. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds 3a–3j, 4a and 5a–5i are available from the authors.
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