Ovicidal and insecticidal activities of pyriproxyfen derivatives with an oxime ester group

Article abstract of DOI:10.3390/molecules22060958

Based on the structural framework of a pyriproxyfen metabolite, nineteen oxime ester derivatives were synthesized via reaction of the carboxylic acids with 4-(2-(2-pyridinyloxy) ethoxy)benzaldehyde oxime. The corresponding structures were comprehensively

Full text of DOI:10.3390/molecules22060958

molecules
Article
Ovicidal and Insecticidal Activities of Pyriproxyfen
Derivatives with an Oxime Ester Group
Guo-Shao Sun, Xin Xu, Shu-Hui Jin *, Le Lin and Jian-Jun Zhang *
Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China;
guoshaosun@163.com (G.-S.S.); lijinming0711@cau.edu.cn (X.X.); linlel@163.com (L.L.)
* Correspondence: shuhuij@cau.edu.cn (S.-H.J.); zhangjianjun@cau.edu.cn (J.-J.Z.);
Tel.: +86-10-6273-3003 (S.-H.J.); +86-10-6273-2219 (J.-J.Z.)
Received: 12 May 2017; Accepted: 7 June 2017; Published: 8 June 2017
Abstract: Based on the structural framework of a pyriproxyfen metabolite, nineteen oxime
ester derivatives were synthesized via reaction of the carboxylic acids with 4-(2-(2-pyridinyloxy)
ethoxy)benzaldehyde oxime. The corresponding structures were comprehensively characterized by
1H-nuclear magnetic resonance (NMR), 13C-NMR, and electrospray ionization high-resolution mass
spectrometry (ESI-HRMS). All of the compounds were screened for their insecticidal activities against
Plutella xylostella and Myzus persicae, and for their ovicidal activities against Helicoverpa armigera
eggs. The results obtained show that most of the oxime ester derivatives displayed moderate to
high insecticidal activities and ovicidal activities at a concentration of 600
µg/mL. In particular,
the ovicidal activity of compounds 5j 5o 5p 5q, and 5s was determined to be 100%. Importantly,
,
,
,
some of the compounds presented even higher biological activities than the reference compound
pyriproxyfen. For example, compound 5j displayed an insecticidal activity value of 87.5% against
Myzus persicae, whereas the activity value of pyriproxyfen was 68.3% at a concentration of 600
Among the synthesized compounds 5j and 5s exhibited broad biological activity spectra.
µg/mL.
Keywords: pyriproxyfen metabolite; oxime ester derivatives; insecticidal activity; ovicidal activity
1. Introduction
In the 1930s, various research groups reported that prontosil exhibits a suitable therapeutic effect
in mice infected with different bacterial strands. However, the results were deemed abnormal with
respect to the antibacterial activity of prontosil being absent in vitro
sulfanilamide, exhibited a strong antibacterial activity in vivo, indicating that the antibacterial activity
of prontosil could mainly be attributed to this metabolite [ ]. Since then, dozens of sulfonamide
[1]. The metabolite of prontosil,
1,2
species have been developed and used for the treatment of bacterial diseases. Furthermore, the use
of drug metabolites as lead compounds has become one of the new drug development approaches
widely used in the pharmaceutical industry. For example, norastemizole (Figure 1), stemming from
astemizole (Figure 1), was found to increase selectivity in the process of targeting receptors [3].
Concurrently, pesticides also generate a series of pesticide metabolites in organisms through
a variety of metabolic pathways. In some cases, these pesticide metabolites may exhibit a good
biological activity. For example, malaoxon (Figure 1) represents the metabolite of malathion (Figure 1).
However, the inhibitory effect of malaoxon to acetylcholinesterase was found to be increased compared
to malathion [
insecticidal activity compared to clothianidin (Figure 1), which is generated by degradation of
thiamethoxam [ ]. In our previous studies, a series of diamide derivatives were designed and
synthesized based on a benalaxyl metabolite and the target compounds showed excellent fungicidal
4]. A more common example is thiamethoxam (Figure 1) that demonstrates a poor
5,6
activities against Phytophthora capsici and Rhizoctonia solani [
7
]. From these findings, it can be
Molecules 2017, 22, 958; doi:10.3390/molecules22060958
www.mdpi.com/journal/molecules

Molecules 2017, 22, 958
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hypothesized that the chemical structure of the pesticide metabolites may also provide critical
information for the future development of pesticide lead compounds.
Figure 1. Chemical structures of malathion, malaoxon, thiamethoxam, clothianidin, astemizole,
and norastemizole.
Pyriproxyfen, a juvenile hormone analogue, proves to be highly selective for target organisms
with lower mammalian toxicity, and has been clinically used to control the spread of a wide range of
arthropods [
(metabolite B, Figure 2), and 3-(pyridin-2-yloxy)butan-1-ol (metabolite C, Figure 2) were generated
from degradation of pyriproxyfen ex vivo, as well as in animals and plants in vivo 10 13]. Metabolite
8,9]. 4-(2-(pyridin-2-yloxy)propoxy)-phenol (metabolite A, Figure 2), 4-phenoxyphenol
[
–
A was synthesized and demonstrated a moderate insecticidal activity as well as ovicidal activity.
4-(2-(2-pyridinyloxy)ethoxy)benzaldehyde, a metabolite A analogue, retained the structural skeleton
of pyriproxyfen but exhibited potent ovicidal activities against Plutella xylostella, Myzus persicae,
and Helicoverpa armigera eggs, with overall activity values of 40.2%, 32.5%, and 75.2%, respectively.
Therefore, we hypothesize that 4-(2-(2-pyridinyloxy)ethoxy) benzaldehyde may be used as a lead
compound for further studies.
In 1963, tranid, the first oxime ester insecticide, was developed. Thereafter, oxime carbamate
insecticides (e.g., methomyl) and oxime phosphate insecticides (e.g., phoxim) have been developed.
These oxime ester compounds have attracted considerable attention in the scientific community due to
their broad-spectrum biological activities as plant virucides [14], fungicides [15,16], insecticides [17–19],
and herbicides [20]. In our group, oleanolic acid and avermectin oxime ester derivatives were
synthesized and exhibited suitable biological activities, providing further incentive to study the
oxime ester group in more detail [16,21]. Continuing this work, nineteen novel oxime ester derivatives
were synthesized (cf. Scheme 1) and their ovicidal activities against Plutella xylostella, Myzus persicae,
and Helicoverpa armigera eggs were evaluated.
Figure 2. Molecular structure of the target compounds.

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2. Results and Discussion
2.1. Chemistry
As shown in Scheme 1, nineteen oxime ester derivatives were synthesized. Compound
2
was prepared by reacting commercially available 4-hydroxybenzaldehyde with 2-bromoethanol in
N,N-dimethylformamide as previously reported in the literature [22]. A subsequent reaction with
2-fluoropyridine in the presence of sodium hydride led to the formation of intermediate
addition of sodium hydride, the mixture was placed in an ice bath due to the release of a large amount
of heat as the reaction progressed. Next, intermediate was directly converted to the key intermediate,
, by treatment with hydroxylamine hydrochloride [24]. Finally, the corresponding target oxime esters
5a 5s) were obtained via intermediate and reactions with carboxylic acid functionalities in the
3 [23]. Upon
3
4
(
–
4
presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). The physical
1
data of the target compounds 5a
–
5s are given in Table 1. H- and 13C-NMR spectra of all compounds
are presented in the Supplementary Materials.
Since the oxime group can exist both in the E- or Z-configuration, it was necessary to determine
the geometries of all the oxime target compounds 5a–5s. Attempts to obtain X-ray quality single
crystals of the oxime intermediates or target products proved unsuccessful in this study. However, the
oxime geometry was considered to be in the E-configuration, an assumption that is in agreement with
published data [24].
Scheme 1. General synthetic route for target compounds. Reagents and conditions: (a) BrCH2CH2OH,
K2CO3, dimethylformamide (DMF), 100 ◦C, 12 h; (b) i. NaH, DMF, 0–5 ◦C; ii. 2-fluoropyridine,
DMF, 55 ◦C, 6 h; (c) NH2OH/NaOH, EtOH/H2O, r.t.;
(d) substituted carboxylic acid,
dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), dichloromethane (DCM).
Table 1. Physical data for compounds 5a–5s.
◦
Compound
R
Formula
Status
m.p./ C
Yield (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
Ph-
4-OCH3-Ph-
2-F-Ph-
4-OCH3-Ph-CH2-
4-CH3-Ph-CH2-
4-OC2H5-Ph-
C21H18N2O4
C22H20N2O5
C21H17FN2O4
C23H22N2O5
C23H22N2O4
C23H22N2O5
C22H18Cl2N2O4
C26H22N2O4
C25H25ClN2O4
C19H16N2O5
C23H22ClF3N2O4
C20H16ClN3O4
C20 H15Cl2N3O4
C24H28N2O4
C18H20N2O4
C16H16N2O4
C19H16N2O4S
C20H17N3O4
C22H26N2O4
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
Pale yellow solid
White solid
Yellow solid
White solid
Yellow solid
White solid
White solid
White solid
White solid
White solid
Yellow solid
102–104
101–103
107–109
97–99
102–104
103–105
102–104
112–114
75–77
130–132
141–143
133–135
88–90
99–101
71–73
87
91
91
90
88
83
71
94
85
92
86
90
87
85
93
96
88
90
89
2,4-Cl-Ph-CH2-
β-Naphthyl-CH2-
2-(4-chlorophenyl)-3-methylpropyl-
2-furyl-
3-(2-Cl-3,3,3-F-1-propenyl)-2,2-Me-cycloproyl-
3-(2-Cl-Py)-
2-(3,6-Cl-Py)-
2,2-Me-3-(2-Me-1-propenyl)-cycloproyl-
CH3CH2CH2-
CH3-
2-thienyl-
3-Py-
85–87
132–134
163–165
91–93
5s
2,2,3,3-Me-cyclopropyl-

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2.2. Biological Activities
2.2.1. Insecticidal Activities
As highlighted in Table 2, the insecticidal activities of all target compounds against Myzus
persicae and Plutella xyllostella were evaluated. With the substituent being a phenyl group, the results
indicated that compounds 5a
at a concentration of 600 g/mL, demonstrating that the substituent species and the position of
the phenyl ring had no significant effect on the insecticidal activity. Compounds 5l, 5 , and 5
showed 49.4%, 58.1%, and 25.9% insecticidal activities against Myzus persicae at a concentration of
600 g/mL. As the substituent was changed to a pyridine group, compounds 5l and 5m, but not
compound 5r, exhibited improved insecticidal activities compared to compounds 5a 5i. Compounds
–5i possessed 3.6% to 15.7% insecticidal activities against Myzus persicae
µ
m
s
µ
–
5o and 5p, bearing an alkyl substituent, displayed moderate activity against Myzus persicae. Some
of the synthesized compounds exhibited higher insecticidal activities than the reference compound
pyriproxyfen. For instance, the activity rates of compounds 5j
87.5%, 73.6%, and 72.8% at 600 g/mL, respectively, whereas pyriproxyfen featured a value no higher
than 70% at the same concentration. Moreover, some of the compounds exhibited moderate insecticidal
activities against Myzus persicae upon reduction of the concentration to 200 g/mL; for example,
compounds 5j 5q, and 5s showed insecticidal activities of 53.8%, 36.4%, and 43.1%, respectively,
, 5q and 5s against Myzus persicae were
µ
µ
,
further suggesting that the futyl, thienyl and 2,2,3,3-Me-cyclopropyl groups exhibit a great influence
on the activities. Many of the synthesized compounds exhibited no to moderate insecticidal activities
against Plutella xyllostella at a concentration of 600 µg/mL. Compounds 5b, 5e, 5f, 5g, 5l, 5n, 5o,
and 5p showed no or very weak insecticidal activities against Plutella xyllostella. The activity rates
of compounds 5j and 5s were 68.7% and 57.1%, respectively. Considering Plutella xyllostella, any
structure–activity relationships were not obvious.
Table 2. Insecticidal and ovicidal activities of oxime ester derivatives (activity provided in %).
Myzus persicae
Plutella xyllostella
Helicoverpa armigera Eggs
Compound
600 µg/mL
200 µg/mL
600 µg/mL
600 µg/mL
200 µg/mL
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
3.6 ± 0.7 a
13.3 ± 1.6
12.6 ± 2.1
8.7 ± 1.5
41.7± 1.9
7.7 ± 2.1
38.5 ± 3.0
20.0 ± 1.3
0 ± 0.0
20.9 ± 0.7
23.2 ± 0.8
28.8 ± 1.1
15.3 ± 0.4
47.6 ± 0.1
9.2 ± 1.8
11.3 ± 0.4
15.7 ± 0.2
11.6 ± 1.0
6.7 ± 0.4
10.0 ± 2.5
0 ± 0.0
55.7 ± 3.1
51.6 ± 3.3
45.7 ± 1.7
100.0 ± 0.0
67.6 ± 3.3
62.4 ± 3.1
28.5 ± 0.8
43.3 ± 3.5
100.0 ± 0.0
100.0 ± 0.0
100.0 ± 0.0
73.4 ± 5.1
100.0 ± 0.0
100.0 ± 0.0
40.0 ± 2.0
33.3 ± 1.9
68.7 ± 3.6
26.7 ± 1.8
15.4 ± 0.4
34.3 ± 1.0
15.1 ± 0.8
9.6 ± 2.1
12.8 ± 1.3
43.1 ± 3.3
27.7 ± 1.0
57.1 ± 1.4
76.0 ± 5.3
11.3 ± 0.4
87.5 ± 5.3
45.2 ± 2.6
49.4 ± 5.7
58.1 ± 1.9
39.6 ± 2.7
57.7 ± 0.4
53.2 ± 3.6
73.6 ± 2.9
25.9 ± 2.2
72.8 ± 1.2
68.3 ± 4.7
53.8 ± 4.5
36.4 ± 2.1
45.3 ± 2.7
67.8 ± 5.2
79.5 ± 4.2
37.1 ± 1.6
5q
5r
5s
41.3 ± 2.4
38.5 ± 1.3
64.3 ± 2.0
54.8 ± 1.7
Pyriproxyfen
a
Each value represents the mean ± the standard error of the mean (SEM) of three replicates.

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2.2.2. Ovicidal Activities
Besides insecticidal activities, the ovicidal activities of the new compounds against Helicoverpa
armigera eggs were also explored. As shown in Table 2, most of the target compounds exhibited
moderate to excellent ovicidal activities against Helicoverpa armigera eggs at a concentration of
600
with activity values of less than 30%. Compounds 5j
at 600 g/mL. At a concentration of 200 g/mL, compounds 5o,
µ
g/mL. Compounds 5a
,
5b
,
5c
,
5d
,
5f, and 5m showed limited ovicidal activities at 600
5o 5p 5q, and 5s all featured 100% activity
5p, and 5s still exhibited ovicidal
µg/mL,
,
,
,
µ
µ
activities of 67.8%, 79.5%, and 64.3% against Helicoverpa armigera eggs, values that prove to be higher
than that of pyriproxyfen (i.e., 54.8%). Compound 5j featured an ovicidal activity value of 45.3% against
Helicoverpa armigera eggs. Similar to that of insecticidal activities against Myzus persicae, compounds
5j, 5q, and 5s exhibited more potent ovicidal activities against Helicoverpa armigera eggs. However,
compounds 5o and 5p with moderate insecticidal activities against Myzus persicae, showed the best
ovicidal activities against Helicoverpa armigera eggs. The latter finding may indicate that the presence
of alkyl groups could improve the overall ovicidal activity.
3. Materials and Methods
3.1. Chemistry
3.1.1. General Information
All reagents used were of analytical grade and the solvents were dried according to standard
procedures. 1H-NMR and 13C-NMR spectra were recorded on a Bruker Avance (Bruker Co.,
Karlsruhe, Germany) 300 spectrometer (300 MHz, 1H; 75 MHz, 13C) in CDCl3 as a solvent and with
tetramethylsilane as the internal standard. High-resolution mass spectra (ESI-HRMS) were recorded
on a Bruker Daltonics Bio-TOF-Q III mass spectrometer (Bruker Co., Karlsruhe, Germany). The
melting points were measured on a YRT-3 apparatus and the values are shown in the uncorrected form.
Column chromatographic purification was carried out using 200–300 mesh silica gel. The reactions
were monitored by analytical thin-layer chromatography (TLC) carried out on silica gel GF/UV 254
TLC plates.
3.1.2. Synthesis of 4-(2-Hydroxyethoxy)benzaldehyde (2)
To a solution of 4-hydroxybenzaldehyde (10.0 g, 82.0 mmol) in dry DMF (80 mL), K2CO3 (22.6 g,
163.8 mmol) and 2-bromoethanol (12.3 g, 98.3 mmol) were added. The reaction mixture was heated
to 100 ◦C for 12 h with monitoring by TLC. The resulting solution was extracted with ethyl acetate
(3
×
80 mL) and dried over anhydrous Na2SO4. The solvents of the combined organic layer were
removed under reduced pressure and the residue was purified by flash chromatography on silica gel
(200–300 mesh) using petroleum ether and ethyl acetate (v/v = 8:1) as eluents to afford compound
2
1
as a pale yellow liquid (11.3 g, 83%). H-NMR (300 MHz, CDCl3)
δ 9.86 (s, 1H, PhCHO), 7.74–7.90
(m, 2H, Ar-H), 6.92–7.10 (m, 2H Ar-H), 4.13–4.20 (m, 2H, PhOCH2), 3.95–4.04 (m, 2H, C H2OH).
3.1.3. Synthesis of 4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde (3)
To an ice-cooled solution of compound
2 (5.0 g, 30.1 mmol) in DMF (40 mL), 60% sodium
hydride (1.4 g, 36.1 mmol) was slowly added within 10 min. After stirring for an additional 30 min,
2-fluoropyridine (3.5 g, 36.1 mmol) was added. The resulting mixture was then heated to 55 ◦C and
allowed to react for another 6 h. The reaction was quenched by addition of ice water and the resulting
crude product was extracted with ethyl acetate (3
combined organic layers were concentrated in vacuo and then purified by flash chromatography on
×
50 mL) and dried over anhydrous Na2SO4. The
silica gel (200–300 mesh) using petroleum ether and ethyl acetate (v/v = 10:1) as eluent to provide
1
compound
3
as a white solid (6.4 g, 88%). H-NMR (300 MHz, CDCl3):
δ
9.86 (s, 1H, PhCHO), 8.11–8.17

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(m, 1H, Ar-H), 7.78–7.86 (m, 2H, Ar-H), 7.52–7.60 (m, 1H, Ar-H), 6.99–7.08 (m, 2H Ar-H), 6.84–6.92
(m, 1H Ar-H), 6.74–6.80 (m, 1H Ar-H), 4.58–4.78 (m, 2H, PyOCH2), 4.31–4.45 (m, 2H, PhOCH2).
3.1.4. Synthesis of 4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde oxime (4)
Hydroxylamine hydrochloride (1.5 g, 26.1 mmol) was dissolved in water (10 mL) and neutralized
with aqueous sodium hydroxide solution (10%). A solution of compound
3 (4.4 g, 18.1 mmol) in
ethanol was slowly added to this mixture. The resulting suspension was stirred at room temperature
with monitoring by TLC. After reaction completion, the solvent ethanol was removed in vacuo. The
resulting solution was extracted with ethyl acetate (3
×
30 mL) and dried over anhydrous Na2SO4.
The solvent of the combined organic layers was removed in vacuo to provide a residue which was then
purified by silica gel (200–300 mesh) column chromatography using petroleum ether and ethyl acetate
(v/v = 6:1) as eluents to afford compound
(300 MHz, CDCl3) 8.19 (dd, J = 5.0 Hz, 1.6 Hz, 1H, Ar-H), 8.12 (s, 1H, CH=N), 7.58–7.67 (m, 1H,
4
as a white solid (4.2 g, 90%). m.p.: 81–83 ◦C; 1H-NMR
δ
Ar-H), 7.51–7.57 (m, 2H, Ar-H), 7.48 (s, 1H, NOH), 6.96–7.03 (m, 2H Ar-H), 6.89–6.96 (m, 1H Ar-H),
6.84 (d, J = 8.4 Hz, 1H, Ar-H), 4.65–4.84 (m, 2H, PyOCH2), 4.26–4.51 (m, 2H, PhOCH2). 13C-NMR
(75 MHz, CDCl3): 163.18, 159.96, 149.44, 146.49, 138.79, 128.31, 125.03, 116.95, 114.78, 111.40, 66.43,
64.11; HRMS (ESI) calcd. for C14H15N2O4 (M + H)+ 275.1032, found 275.1031.
3.1.5. General Procedure for the Synthesis of 4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde oxime ester
derivatives (5a–5s)
A solution of the appropriate carboxylic acid (7.5 mmol) and DCC (7.5 mmol) was stirred in DCM
(20 mL) in the presence of DMAP (100 mg). Compound 4 (5.8 mmol) was added to the reaction mixture
upon stirring and stirring was continued for another 10 h with monitoring by TLC. The resulting
liquid was collected by filtration and evaporated under reduced pressure. The resulting residue was
purified by column chromatography on silica (200–300 mesh) using petroleum ether and ethyl acetate
(v/v = 4:1~16:1) as eluents.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-benzoyl-oxime (5a). H-NMR (300 MHz, CDCl3)
δ 8.50 (s, 1H,
CH=N), 8.24–8.01 (m, 3H, Ar-H), 7.84–7.68 (m, 2H, Ar-H), 7.65–7.54 (m, 2H, Ar-H), 7.49 (t, J = 7.5 Hz,
2H, Ar-H), 7.05–6.96 (m, 2H, Ar-H), 6.87–6.93 (m, 1H, Ar-H), 6.80 (d, J = 8.4 Hz, 1H, Ar-H), 4.76–4.66
(m, 2H, PyOCH2), 4.45–4.33 (m, 2H, PhOCH2); 13C-NMR (75 MHz, CDCl3)
δ 163.31, 161.70, 156.30,
146.73, 138.73, 133.28, 130.23, 129.68, 128.85, 128.52, 122.83, 117.10, 115.08, 111.37, 66.69, 63.86; HRMS
(ESI) calcd. for C21H19N2O4 (M + H)+ 363.1339, found 363.1341.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(4-methoxybenzoyl)-oxime (5b). H-NMR (300 MHz, CDCl3)
δ
8.47 (s, 1H, CH=N), 8.16 (dd, J = 5.0 Hz, 1.5 Hz, 1H, Ar-H), 8.02–8.12 (m, 2H, Ar-H), 7.75 (d, J = 8.8 Hz,
2H, Ar-H), 7.66–7.52 (m, 1H, Ar-H), 7.07–6.87 (m, 5H, Ar-H), 6.80 (d, J = 8.4 Hz, 1H, Ar-H), 4.75–4.65
(m, 2H, PyOCH2), 4.43–4.30 (m, 2H, PhOCH δ 163.84,
2), 3.87 (s, 3H, OCH3); 13C-NMR (75 MHz, CDCl3)
163.66, 163.30, 161.58, 155.92, 146.70, 138.71, 131.74, 130.14, 122.97, 121.03, 117.07, 115.03, 113.84, 111.34,
66.66, 63.86, 55.44; HRMS (ESI) calcd. for C22H21N2O5 (M + H)+ 393.1445, found 393.1444.
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(2-fluorobenzoyl)-oxime (5c). 1H-NMR (300 MHz, CDCl3)
δ
8.48 (s, 1H, CH=N), 8.22–8.011 (m, 1H, Ar-H), 8.07–7.95 (m, 1H, Ar-H), 7.80–7.67 (m, 2H, Ar-H),
7.66–7.51 (m, 2H, Ar-H), 7.26–7.14 (m, 2H, Ar-H), 7.07–6.95 (m, 2H, Ar-H), 6.86–6.92 (m, 1H, Ar-H), 6.80
(d, J = 8.4 Hz, 1H, Ar-H), 4.64–4.78(m, 2H, PyOCH2), 4.33–4.42 (m, 2H, PhOCH2); 13C-NMR (75 MHz,
CDCl3)
δ 163.29, 161.75, 156.69, 146.71, 138.71, 134.81, 132.30, 130.27, 124.18, 122.67, 117.13, 116.83,
115.07, 111.34, 66.67, 63.83; HRMS (ESI) calcd. for C21H18FN2O4 (M + H)+ 381.1245, found 381.1243.
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(2-(4-methoxyphenyl)acetyl)-oxime (5d) 1H-NMR (300 MHz,
CDCl3)
δ 8.27 (s, 1H, CH=N), 8.20–8.09 (m, 1H, Ar-H), 7.72–7.61 (m, 2H, Ar-H), 7.61–7.51 (m, 1H,
Ar-H), 7.30–7.23 (m, 2H, Ar-H), 7.02–6.93 (m, 2H, Ar-H), 6.92–6.85 (m, 3H, Ar-H), 6.78 (d, J = 8.4 Hz,
1H, Ar-H), 4.75–4.62 (m, 2H, PyOCH2), 4.45–4.26 (m, 2H, PhOCH2), 3.79 (s, 3H, OCH3), 3.73 (s, 2H,

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PhCH2CO); 13C-NMR (75 MHz, CDCl3)
δ
169.27, 163.21, 161.54, 158.77, 155.74, 146.64, 138.66, 130.25,
130.02, 125.31, 122.63, 117.02, 114.95, 114.03, 111.25, 66.58, 63.77, 55.17, 39.05; HRMS (ESI) calcd. for
C23H23N2O5 (M + H)+ 407.1601, found 407.1601.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(2-(4-methylphenyl)acetyl)-oxime (5e). H-NMR (300 MHz,
CDCl3)
δ 8.27 (s, 1H, CH=N), 8.15 (dd, J = 4.9 Hz, 1.6 Hz, 1H, Ar-H), 7.66 (d, J = 8.8 Hz, 2H, Ar-H),
7.54–7.62 (m, 1H, Ar-H), 7.30–7.18 (m, 2H, Ar-H), 7.15 (d, J = 7.9 Hz, 2H, Ar-H), 6.97 (d, J = 8.8 Hz, 2H,
Ar-H), 6.86–6.94 (m, 1H, Ar-H), 6.79 (d, J = 8.3 Hz, 1H, Ar-H), 4.84–4.60 (m, 2H, PyOCH2), 4.44–4.28
(m, 2H, PhOCH2), 3.77 (s, 2H, PhCH2CO), 2.34 (s, 3H, PhCH3); 13C-NMR (75 MHz, CDCl3)
δ 16919,
163.29, 161.61, 155.78, 146.72, 138.71, 136.88, 130.26, 130.10, 129.34, 129.13, 122.72, 117.08, 115.01, 111.34,
66.65, 63.83, 39.64, 21.06; HRMS (ESI) calcd. for C23H23N2O4 (M + H)+ 391.1652, found 391.1653.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(4-ethoxybenzoyl)-oxime (5f). H-NMR (300 MHz, CDCl3)
δ
8.47 (s, 1H, CH=N), 8.16 (dd, J = 5.1 Hz, 1.3 Hz, 1H, Ar-H), 8.06–7.98 (m, 2H, Ar-H), 7.79–7.71 (m, 2H,
Ar-H), 7.64–7.51 (m, 1H Ar-H), 7.06–6.84 (m, 5H, Ar-H), 6.80 (d, J = 8.3 Hz, 1H, Ar-H), 4.77–4.60 (m, 2H,
PyOCH2), 4.33–4.42 (m, 2H, PhOCH2), 4.09 (q, J = 7.4 Hz, 2H, OCH2CH3), 1.45 (t, J = 7.4 Hz, 3H,
OCH2CH3); 13C-NMR (75 MHz, CDCl3)
δ 163.90, 163.32, 163.10, 161.59, 155.89, 146.72, 138.73, 131.75,
130.15, 117.08, 115.04, 114.27, 111.37, 66.68, 63.88, 63.76, 14.65; HRMS (ESI) calcd. for C23H23N2O5
(M + H)+ 407.1601, found 407.1604.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(2-(2,4-dichlorobenzoyl))acetyl)-oxime (5g). H-NMR (300 MHz,
CDCl3) δ 8.27 (s, 1H, CH=N), 8.14–8.17 (m, 1H, Ar-H), 7.64–7.68 (m, 2H, Ar-H), 7.57–7.61 (m, 1H, Ar-H),
7.28–7.32 (m, 3H, Ar-H), 7.02–6.94 (m, 2H, Ar-H), 6.93–6.86 (m, 1H, Ar-H), 6.85–6.69 (m, 1H, Ar-H),
4.76–4.62 (m, 2H, PyOCH2), 4.42–4.29 (m, 2H, PhOCH2), 3.75 (s, 2H, PhCH2CO); 13C-NMR (75 MHz,
CDCl3)
δ 168.63, 163.26, 161.70, 155.96, 146.69, 138.72, 130.64, 130.12, 128.79, 122.51, 117.08, 115.05,
111.32, 66.65, 63.82, 39.29; HRMS (ESI) calcd. for C22H20ClN2O4 (M + H)+ 411.1106, found 411.1107.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(2-(2-naphthalenyl)acetyl)-oxime (5h). H-NMR (300 MHz,
CDCl3)
δ
8.20 (s, 1H, CH=N), 8.12–8.17 (m, 1H, Ar-H), 8.06 (d, J = 8.4 Hz, 1H, Ar-H), 7.93–7.75
m, 2H, Ar-H), 7.43–7.64 (m, 7H, Ar-H), 6.95 (d, J = 8.8 Hz, 2H, Ar-H), 6.91–6.84 (m, 1H, Ar-H), 6.75-6.81
m, 1H, Ar-H), 4.58–4.67 (m, 2H, PyOCH2), 4.40–4.30 (m, 2H, PhOCH2), 4.24 (s, 2H, PhCH2CO);
168.95, 163.29, 161.63, 155.90, 146.71, 138.71, 130.10, 128.73, 128.24,
(
(
13C-NMR (75 MHz, CDCl3)
δ
128.02, 126.48, 125.84, 125.46, 123.78, 117.08, 115.01, 111.34, 66.64, 63.83, 37.88; HRMS (ESI) calcd. for
C26H23N2O4 (M + H)+ 427.1652, found 427.1651.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(2-(4-chlorophenyl)-3-methyl-1-oxobutyl)-oxime (5i). H-NMR
(300 MHz, CDCl3)
δ 8.26 (s, 1H, CH=N), 8.13 (dd, J = 1.9 Hz, 5.0 Hz, 1H, Ar-H), 7.64 (s, 1H, Ar-H),
7.61 (s, 1H, Ar-H), 7.50–7.55 (m, 1H, Ar-H), 7.26–7.35 (m, 4H, Ar-H), 6.95 (s, 1H, Ar-H), 6.92 (s, 1H,
Ar-H), 6.82–6.86 (m, 1H, Ar-H), 6.75 (d, J = 8.3 Hz, 1H, Ar-H), 4.56–4.88 (m, 2H, PyOCH2), 4.11–4.50
(m, 2H, PhOCH2), 3.26 (d, J = 10.4 Hz, 1H, C
H
CO), 2.29–2.45 (m, 1H, C
H
(CH3)2), 1.11 (d, J = 6.5 Hz,
170.66, 163.03, 161.45,
3H, CHCH3), 0.74 (d, J = 6.7 Hz, 3H, CHCH3); 13C-NMR (75 MHz, CDCl3)
δ
155.89, 146.54, 138.51, 136.12, 133.08, 129.96, 129.74, 128.53, 122.44, 116.90, 114.82, 111.08, 66.44, 63.63,
57.55, 31.95, 21.20, 19.95; HRMS (ESI) calcd. for C25H26ClN2O4 (M + H)+ 453.1576, found 453.1575.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(2-furanylcarbonyl)-oxime (5j). H-NMR (300 MHz, CDCl3)
δ
8.44 (s, 1H, CH=N), 8.15 (dd, J = 1.3 Hz, 5.1 Hz, 1H, Ar-H), 7.69–7.73 (m, 2H, Ar-H), 7.61–7.67 (m, 1H,
Ar-H), 7.50–7.61 (m, 1H, Ar-H), 7.30 (dd, J = 0.7 Hz, 3.5 Hz, 1H, Ar-H), 7.00 (s, 1H, Ar-H), 6.98 (s, 1H,
Ar-H), 6.86–6.90 (m, 1H, Ar-H), 6.78 (d, J = 8.4 Hz, 1H, Ar-H), 6.55 (dd, J = 1.7 Hz, 3.5 Hz, 1H, Ar-H),
4.44–4.91 (m, 2H, PyOCH2), 4.09–4.46 (m, 2H, PhOCH2); 13C-NMR (75 MHz, CDCl3) δ 163.13, 161.59,
156.31, 156.16, 146.72, 146.60, 142.85, 138.57, 130.09, 122.44, 118.62, 116.95, 114.92, 111.89, 111.14, 66.53,
63.68.; HRMS (ESI) calcd. for C19H17N2O5 (M + H)+ 353.1132, found 353.1133.
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-((3-(2-chloro-3,3,3-trifluoro-1-propen-1-yl)-2,2-dimethylcyclop
ropyl)carbonyl)-oxime (5k). 1H-NMR (300 MHz, CDCl3)
δ 8.28 (s, 1H, CH=N), 8.12 (dd, J = 1.9 Hz,

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5.1 Hz, 1H, Ar-H), 7.59–7.75 (m, 2H, Ar-H), 7.52–7.57 (m, 1H, Ar-H), 6.94–7.01 (m, 3H, Ar-H), 6.81–6.89
(m, 1H, ArH), 6.76 (d, J = 8.4 Hz, 1H, CH=C), 4.58–4.79 (m, 2H, PyOCH2), 4.22–4.49 (m, 2H, PhOCH2),
2.26 (t, J = 8.9 Hz, 1H, C
H
-CH=C), 2.06 (d, J = 8.3 Hz, 1H, CHCO), 1.34, 1.32 (2s, 6H, (CH3)2C);
167.76, 163.19, 161.60, 155.45, 146.62, 138.61, 130.00, 129.64, 122.58,
13C-NMR (75 MHz, CDCl3)
δ
118.51, 116.99, 114.96, 111.20, 66.57, 63.72, 31.16, 30.98, 29.10, 28.17, 14.75; HRMS (ESI) calcd. for
C23H23ClF3N2O4 (M + H)+ 483.1293, found 483.1290.
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-((2-chloro-3-pyridinyl)carbonyl)-oxime (5l). 1H-NMR (300 MHz,
CDCl3)
δ 8.55 (dd, J = 1.9 Hz, 4.8 Hz, 1H, Ar-H), 8.46 (s, 1H, CH=N), 8.06–8.24 (m, 2H, Ar-H), 7.71–7.75
(m, 2H, Ar-H), 7.55–7.61 (m, 1H, Ar-H), 7.37 (dd, J = 4.8 Hz, 7.7 Hz, 1H, Ar-H), 7.00–7.04 (m, 2H,
Ar-H), 6.87–6.91 (m, 1H, Ar-H), 6.79 (d, J = 8.4 Hz, 1H, Ar-H), 4.57–4.83 (m, 2H, PyOCH2), 4.02–4.54
(m, 2H, PhOCH2); 13C-NMR (75 MHz, CDCl3)
δ 163.17, 162.38, 161.86, 157.06, 151.95, 149.65, 146.63,
139.99, 138.63, 130.26, 126.21, 122.13, 122.06, 117.00, 115.05, 111.19, 66.61, 63.70; HRMS (ESI) calcd. for
C20H17ClN3O4 (M + H)+ 398.0902, found 398.0906.
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-((3,6-dichloro-2-pyridinyl)carbonyl)-oxime(5m). 1H-NMR
(300 MHz, CDCl3)
δ 8.48 (s, 1H, CH=N), 8.15 (dd, J = 1.9 Hz, 5.1 Hz, 1H, Ar-H), 7.80 (d, J = 8.5 Hz,
1H, Ar-H), 7.63–7.75 (m, 2H, Ar-H), 7.52–7.62 (m, 1H, Ar-H), 7.44 (d, J = 8.5 Hz, 1H, Ar-H), 6.98–7.02
(m, 2H, Ar-H), 6.83–6.94 (m, 1H, Ar-H), 6.78 (d, J = 8.4 Hz, 1H, Ar-H), 4.68–4.71 (m, 2H, PyOCH2),
4.36–4.39 (m, 2H, PhOCH2); 13C-NMR (75 MHz, CDCl3)
δ 163.11, 161.79, 160.67, 157.34, 148.90, 146.58,
146.51, 140.96, 138.59, 130.24, 129.88, 127.47, 122.03, 116.97, 114.99, 111.14, 66.56, 63.67; HRMS (ESI)
calcd. for C20H16Cl2N3O4 (M + H)+ 432.0512, found 432.0510.
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-((2,2-dimethyl-3-(2-methyl-1-propen-1-yl)cyclopropyl)carbony
l)-oxime (5n). 1H-NMR (300 MHz, CDCl3)
(
δ
8.27 (s, 1H, CH=N), 8.07–8.14 (m, 1H, Ar-H), 7.64
d, J = 8.8 Hz, 2H, Ar-H), 7.44–7.58 (m, 1H, Ar-H), 6.93 (d, J = 8.8 Hz, 2H, Ar-H), 6.80–6.87 (m, 1H,
Ar-H), 6.70–6.79 (m, 1H, Ar-H), 4.80–5.03 (m, 1H, C =C(CH3)2), 4.51–4.74 (m, 2H, PyOCH2), 4.14–4.42
(m, 2H, PhOCH2), 2.07–2.23 (m, 1H, C -CH=C), 1.69 (s, 6H, C=C(CH3)2), 1.47 (d, J =5.3 Hz, 1H,
CHCO), 1.31, 1.16 (2s, 6H, (CH3)2C); 13C-NMR (75 MHz, CDCl3)
169.94, 163.14, 161.31, 154.76, 146.57,
H
H
δ
138.54, 135.84, 129.85, 122.95, 120.63, 116.91, 114.83, 111.15, 66.48, 63.69, 33.11, 32.89, 29.18, 25.40, 21.97,
20.25, 18.38; HRMS (ESI) calcd. for C24H29N2O4 (M + H)+ 409.2122, found 409.2122.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(1-oxobutyl)-oxime (5o). H-NMR (300 MHz, CDCl3)
δ
8.29
(s, 1H, CH=N), 8.13–8.16 (m, 1H, Ar-H), 7.62–7.75 (m, 2H, Ar-H), 7.50–7.61 (m, 1H, Ar-H), 6.93–7.05
(m, 2H, Ar-H), 6.86–6.90 (m, 1H, Ar-H), 6.79 (d, J = 8.4 Hz, 1H, Ar-H), 4.57–4.84 (m, 2H, PyOCH2),
4.24–4.53 (m, 2H, PhOC
H
2), 2.44 (t, J = 7.4 Hz, CH2CO), 1.71–1.79 (m, 2H, CH3C
H2), 1.01 (t, J = 7.4 Hz,
3H, CH3CH2); 13C-NMR (75 MHz, CDCl3)
δ
171.10, 163.18, 161.45, 155.33, 146.61, 138.61, 129.94,
122.78, 116.98, 114.90, 111.20, 66.55, 63.73, 34.60, 18.27, 13.56; HRMS (ESI) calcd. for C18H21N2O4
(M + H)+ 329.1496, found 329.1500.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-acetyl-oxime (5p). H-NMR (300 MHz, CDCl3) δ 8.29 (s, 1H,
CH=N), 8.06–8.22 (m, 1H, Ar-H), 7.62–7.73 (m, 2H, Ar-H), 7.55–7.61 (m, 1H, Ar-H), 6.93–7.04 (m, 2H,
Ar-H), 6.87–6.91 (m, 1H, Ar-H), 6.79 (d, J = 8.4 Hz, 1H, Ar-H), 4.56–4.80 (m, 2H, PyOCH2), 4.18–4.45
(
m, 2H, PhOCH2), 2.21 (s, 3H, COCH3); 13C-NMR (75 MHz, CDCl3)
δ 168.66, 163.17, 161.49, 155.30,
146.59, 138.63, 129.94, 122.67, 116.98, 114.93, 111.20, 66.56, 63.74, 19.47; HRMS (ESI) calcd. for
C16H17N2O4 (M + H)+ 301.1183, found 301.1186.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(2-thienylcarbonyl)-oxime (5q). H-NMR (300 MHz, CDCl3)
δ
8.46 (s, 1H, CH=N), 8.15–8.18 (m, 1H, Ar-H), 7.94 (dd, J = 1.2 Hz, 3.8 Hz, 1H, Ar-H), 7.68–7.80
(m, 2H, Ar-H), 7.49–7.68 (m, 2H, Ar-H), 7.16 (dd, J = 3.8 Hz, 5.0 Hz, 1H, Ar-H), 6.95–7.04 (m, 2H, Ar-H),
6.86–6.95 (m, 1H, Ar-H), 6.81 (d, J = 8.4 Hz, 1H, Ar-H), 4.55–4.94 (m, 2H, PyOCH2), 4.20–4.53 (m, 2H,
PhOCH2); 13C-NMR (75 MHz, CDCl3)
δ 163.16, 161.57, 159.68, 156.08, 146.61, 138.61, 134.06, 132.87,
131.32, 130.11, 127.78, 122.56, 116.98, 114.95, 111.20, 66.55, 63.72; HRMS (ESI) calcd. for C19H17N2O4S
(M + H)+ 369.0904, found 369.0906.

Molecules 2017, 22, 958
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1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-(3-pyridinylcarbonyl)-oxime (5r). H-NMR (300 MHz, CDCl3)
9.31–9.36 (m, 1H, Ar-H), 8.85 (dd, J = 4.9 Hz, 1.7 Hz, 1H, Ar-H), 8.53 (s, 1H, CH=N), 8.39–8.43
δ
(m, 1H, Ar-H), 8.17–8.19 (dd, J = 1.3 Hz, 5.1 Hz, 1H, Ar-H), 7.75–7.80 (m, 2H, Ar-H), 7.58–7.64 (m, 1H,
Ar-H), 7.47 (dd, J = 4.9 Hz, 8.0 Hz, 1H, Ar-H), 6.97–7.15 (m, 2H, Ar-H), 6.87–6.95 (m, 1H, Ar-H), 6.82
(
d, J = 8.4 Hz, 1H, Ar-H), 4.64–4.80 (m, 2H, PyOCH2), 4.33–4.45 (m, 2H, PhOCH2); 13C-NMR (75 MHz,
CDCl3)
δ 163.25, 162.74, 161.85, 156.80, 153.68, 150.70, 146.69, 138.68, 137.11, 130.28, 124.93, 123.41,
122.39, 117.05, 115.10, 111.28, 66.67, 63.77; HRMS (ESI) calcd. for C20H18N3O4 (M + H)+ 364.1292,
found 364.1294.
1
4-(2-(2-Pyridinyloxy)ethoxy)benzaldehyde-O-((2,2,3,3 tetramethylcyclopropyl)carbonyl)-oxime (5s). H-NM
R (300 MHz, CDCl3) δ 8.30 (s, 1H, CH=N), 8.16 (dd, J = 1.5 Hz, 5.1 Hz, 1H, Ar-H), 7.63–7.76 (m, 2H,
Ar-H), 7.53–7.62 (m, 1H, Ar-H), 6.95–7.01 (m, 2H, Ar-H), 6.85–6.93 (m, 1H, Ar-H), 6.80 (d, J = 8.4 Hz,
1H, Ar-H), 4.59–4.85 (m, 2H, PyOCH2), 4.18–4.54 (m, 2H, PhOCH2), 1.33 (s, 6H, C(CH3)2), 1.29 (s, 1H,
CHCO), 1.25 (s, 6H, C(CH3)2); 13C-NMR (75 MHz, CDCl3)
δ 169.36, 163.21, 161.28, 154.41, 146.62,
138.61, 129.84, 123.21, 116.97, 114.86, 111.24, 66.54, 63.78, 33.80, 30.97, 23.42, 16.46; HRMS (ESI) calcd.
for C22H27N2O4 (M + H)+ 383.1965, found 383.1968.
3.2. Biological Evaluation
3.2.1. Insecticidal Activity against Plutella xylostella
The test samples were dissolved in acetone and then diluted with water to obtain a final
concentration of 600 µg/mL. Pyriproxyfen was used as a positive control whereas acetone was
used as a negative control. Cabbage leaves were dipped into the obtained solutions for 5 s. The larvae
of P. xyllostella were fed with the discs. Cohorts of about 15 P. xyllostella were treated each time and
bioassays were repeated in triplicate. After 72 h, the numbers of knocked down larvae were counted
and recorded [25,26].
3.2.2. Insecticidal Activity against Myzus persicae
The test samples were dissolved in N,N-dimethylformamide and then diluted to the required
concentration with water. Peach leaves with about 40 Myzus persicae were dipped for 5 s into a solution
with compound concentrations ranging from 200 to 600 µg/mL. After removing any excess solution
on the leaves, Myzus persicae were raised in the leaves at 25 ◦C and 85% relative humidity for 48 h.
Each experiment for every compound was repeated in triplicates [26].
3.2.3. Ovicidal Activity against Helicoverpa armigera Eggs
The test samples were dissolved in N,N-dimethylformamide and then diluted with water to final
concentrations of 600 µg/mL and 200 µg/mL. Pieces of gauze with about 60 Helicoverpa armigera eggs
were dipped into a corresponding solution for 10 s. After drying, the gauzes were moved into disks.
The disks were then kept at 25 ◦C in plastic Petri dishes with moist filter paper. The number of eggs
hatched in the control and treatment samples were recorded and the percentage of ovicidal activity
was calculated.
4. Conclusions
In summary, nineteen oxime ester derivatives, 5a–5s, were synthesized. A preliminary evaluation
of the ovicidal and insecticidal activities of the target compounds was performed. The bioassay results
demonstrated that most of the synthesized compounds displayed moderate insecticidal activities and
high ovicidal activities at a concentration of 600
5o and 5p bearing alkyl groups, exhibited respective ovicidal activities of 67.8% and 79.5% against
Helicoverpa armigera eggs at a lower concentration of 200 g/mL, higher than that of the reference
compound, pyriproxyfen. Among the synthesized compounds, compounds 5j and 5s demonstrated
µg/mL. Some derivatives, including compounds
µ

Molecules 2017, 22, 958
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broad biological activity spectra, with potential insecticidal activities against P. xylostella and Myzus
persicae, and satisfactory ovicidal activities against Helicoverpa armigera eggs. Encouraged by the
results described above, our laboratory is currently studying similar derivatives based on pesticide
metabolites. A report of these advanced studies is currently being written up and will be published in
due course.
Supplementary Materials: Supplementary materials are available online. 1H- and 13C-NMR spectra of all
compounds are presented in the Supporting Information section.
Acknowledgments: This work was supported by the National Natural Science Foundation of China (21172257)
and the Program for Innovation and Entrepreneurship of College Students (201710019231).
Author Contributions: Design, Synthesis, experimental work and writing of the manuscript were performed
by Guo-Shao Sun, Xin Xu, Le Lin, and Jian-Jun Zhang. Biological evaluations were performed by Le Lin and
Shu-Hui Jin. Jian-Jun Zhang supervised the entire project. All authors reviewed and approved the final version of
the manuscript before submission.
Conflicts of Interest: All authors declare no conflicts of interest.
References
1.
2.
3.
Wainwright, M.; Kristiansen, J.E. On the 75th anniversary of Prontosil. Dyes Pigments 2010, 88, 231–234.
[CrossRef]
Bentley, R. Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin (hence β-lactams). J. Ind.
Microbiol. Biot. 2009, 36, 775–786. [CrossRef] [PubMed]
Zhou, Z.; Vorperian, V.R.; Gong, Q.; Zhang, S.; January, C.T. Block of HERG potassium channels by
the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J. Cardiovasc.
Electrophysiol. 1999, 10, 836–843. [CrossRef] [PubMed]
4.
5.
Krstic, D.; Colovic, M.; Krinulovic, K.; Djuric, D.; Vasic, V. Inhibition of AChE by single and simultaneous
exposure to malathion and its degradation products. Gen. Physiol. Biophys. 2007, 26, 247–253. [PubMed]
Karmakar, R.; Bhattacharya, R.; Kulshrestha, G. Comparative metabolite profiling of the insecticide
thiamethoxam in plant and cell suspension culture of tomato. J. Agric. Food Chem. 2009, 57, 6369–6374.
[CrossRef] [PubMed]
6.
Cavallaro, M.C.; Morrissey, C.A.; Headley, J.V.; Peru, K.M.; Liber, K. Comparative chronic toxicity of
imidacloprid, clothianidin, and thiamethoxam to Chironomus dilutus and estimation of toxic equivalency
factors. Environ. Toxicol. Chem. 2017, 36, 372–382. [CrossRef] [PubMed]
7.
8.
Sun, G.S.; Wang, L.N.; Jin, S.H.; Dong, Y.H.; Lu, H.Z.; Zhang, J.J. Synthesis and fungicidal activity of diamide
compounds based on the metabolite of benalaxyl. Chinese J. Org. Chem. 2017, 37, 157–165. [CrossRef]
Sihuincha, M.; ZamoraPerea, E.; OrellanaRios, W.; Stancil, J.D.; LopezSifuentes, V.; VidalOre, C.; Devine, G.J.
Potential use of pyriproxyfen for control of Aedes aegypti (Diptera: Culicidae) in Iquitos, Peru. J. Med. Entomol.
2005, 42, 620–630. [CrossRef] [PubMed]
9.
Shah, R.M.; Shad, S.A.; Abbas, N. Mechanism, stability and fitness cost of resistance to pyriproxyfen in
the house fly, Musca domestica L. (Diptera: Muscidae). Pestic. Biochem. Phys. 2015, 119, 67–73. [CrossRef]
[PubMed]
10. Zhang, C.T.; Liu, H.; Liu, D.H.; Wang, L.Y.; Gao, J.; Zhou, Z.Q.; Wang, P. Enantiomeric separations of
pyriproxyfen and its six chiral metabolites by high-performance liquid chromatography. Chirality 2016, 28,
245–252. [CrossRef] [PubMed]
11. Kodaka, R.; Swales, S.E.; Lewis, C.; Katagi, T. Effect of illumination on degradation of pyriproxyfen in
water-sediment system. J. Pestic. Sci. 2011, 36, 33–40. [CrossRef]
12. Fukushima, M.; Fujisawa, T.; katagi, T. Tomato metabolism and porphyrin-catalyzed oxidation of
pyriproxyfen. J. Agric. Food Chem. 2005, 53, 5353–5358. [CrossRef] [PubMed]
13. Yoshino, H.; Kaneko, H.; Nakatsuka, I.; Yamada, H. Metabolism of pyriproxyfen. 3. in vitro metabolism in
rats and mice. J. Agric. Food Chem. 1996, 44, 1578–1581. [CrossRef]
14. Ouyang, G.P.; Chen, Z.; Cai, X.J.; Song, B.A.; Bhadury, P.S.; Yang, S.; Jin, L.H.; Xue, W.; Hu, D.Y.;
Zeng, S.; et al. Synthesis and antiviral activity of novel pyrazole derivatives containing oxime esters group.
Bioorg. Med. Chem. 2008, 16, 9699–9707. [CrossRef] [PubMed]

Molecules 2017, 22, 958
11 of 11
15. Attia, M.I.; Zakaria, A.S.; Almutairi, M.S.; Ghoneim, S.W. In vitro anti-candida activity of certain new
3-(1H-Imidazol-1-yl)propan-1-one oxime esters. Molecules 2013, 18, 12208–12221. [CrossRef] [PubMed]
16. Zhao, H.Q.; Zhou, M.J.; Duan, L.F.; Wang, W.; Zhang, J.J.; Wang, D.Q.; Liang, X.M. Efficient synthesis and
anti-fungal activity of oleanolic acid oxime esters. Molecules 2013, 18, 3615–3629. [CrossRef] [PubMed]
17. Mondal, A.; Walia, S.; Shrivastava, C.; Kumar, B.; Kumar, J. Synthesis and insecticidal activity of karanj
ketone oxime and its ester derivatives against the mustard aphid (Lipaphis erysimi). Pestic. Res. J. 2010, 22,
39–43.
18. Ma, J.A.; Huang, R.Q.; Chai, Y.X. Synthesis and insecticidal activities of new pyrethroid acid oxime ester
derivatives. Prog. Nat. Sci. 2002, 12, 271–277.
19. Yu, X.; Shi, D.F.; Zhi, X.Y.; Li, Q.; Yao, X.J.; Xu, H. Synthesis and quantitative structure-activity relationship
(QSAR) study of C7-oxime ester derivatives of obacunone as insecticidal agents. RSC Adv. 2015, 5,
31700–31707. [CrossRef]
20. Li, T.G.; Liu, J.P.; Han, J.T.; Fu, B.; Wang, D.Q.; Wang, M.A. Synthesis and herbicidal activity of
α-phenylsulfonylcyclododecanone oxime esters. Chin. J. Org. Chem. 2009, 29, 898–903.
21. Liu, X.G.; Wu, J.P.; Liang, X.M.; Wang, D.Q. Synthesis and insecticidal activity of 5-acyloxyimino-
5-deoxyavermectin B1 derivatives. Pest Manag. Sci. 2004, 6, 697–702.
22. Chandrika, N.T.; Shrestha, S.K.; Ngo, H.X.; Garneau-Tsodikova, S. Synthesis and investigation of novel
benzimidazole derivatives as antifungal agents. Bioorg. Med. Chem. 2016, 24, 3680–3686. [CrossRef]
[PubMed]
23. Sundriyal, S.; Viswanad, B.; Ramarao, P.; Chakraborti, A.K.; Bharatam, P.V. New PPARc ligands based on
barbituric acid: Virtual screening, synthesis and receptor binding studies. Bioorg. Med. Chem. Let. 2008, 18,
4959–4962. [CrossRef] [PubMed]
24. Schwarz, L.; Girreser, U.; Clement, B. Synthesis and characterization of para-Substituted N,N0-
Dihydroxybenzamidines and their derivatives asmodel compounds for a class of prodrugs. Eur. J. Org. Chem.
2014, 2014, 1961–1975. [CrossRef]
25. Sun, J.L.; Zhou, Y.M. Design, synthesis and insecticidal activity of novel phenylurea derivatives. Molecules
2015, 20, 5050–5061. [CrossRef] [PubMed]
26. Dai, H.; Chen, J.; Li, H.; Dai, B.J.; He, H.B.; Fang, Y.; Shi, Y.J. Synthesis and bioactivities of novel pyrazoleoxime
derivatives containing a 5-trifluoromethylpyridyl moiety. Molecules 2016, 21, e276. [CrossRef] [PubMed]
Sample Availability: Samples of compounds 5a–5s are available from the authors.
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