Design, Synthesis, Acaricidal/Insecticidal Activity, and Structure-Activity Relationship Studies of Novel Oxazolines Containing Sulfone/Sulfoxide Groups Based on the Sulfonylurea Receptor Protein-Binding Site

Article abstract of DOI:10.1021/acs.jafc.6b00645

Enormous compounds containing sulfone/sulfoxide groups have been used in a variety of fields, especially in drug and pesticide design. To search for novel environmentally benign and ecologically safe pesticides with unique modes of action, a series of 2,4-diphenyl-1,3-oxazolines containing sulfone/sulfoxide groups as chitin synthesis inhibitors (CSIs) were designed and synthesized on the basis of the sulfonylurea receptor protein-binding site for CSIs. Their structures were characterized by ¹H and ¹³C nuclear magnetic resonance and high-resolution mass spectrometry. The acaricidal and insecticidal activities of the new compounds were evaluated. It was found that most of the target compounds displayed wonderful acaricidal activities against spider mite (Tetranychus cinnabarinus) larvae and eggs. Especially compounds I-4, II-3, and II-4 displayed higher activities than commercial etoxazole at a concentration of 2.5 mg L^-1. Some target compounds exhibited insecticidal activities against lepidopteran pests. The present work demonstrated that these compounds containing sulfone/sulfoxide groups could be considered as potential candidates for the development of novel acaricides in the future.

Full text of DOI:10.1021/acs.jafc.6b00645

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Article
Design, Synthesis, Acaricidal/Insecticidal Activity, and Structure-Activity
Relationship (SAR) Studies of Novel Oxazolines Containing Sulfone/
Sulfoxide Groups Based on the Sulfonylurea Receptor Protein Binding Site
Xiuling Yu, Yu-xiu Liu, Yongqiang Li, and Qingmin Wang
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.6b00645 • Publication Date (Web): 05 Apr 2016
Downloaded from http://pubs.acs.org on April 7, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of Agricultural and Food Chemistry is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 27
Journal of Agricultural and Food Chemistry
Design, Synthesis, Acaricidal/Insecticidal Activity, and StructureꢀActivity
Relationship (SAR) Studies of Novel Oxazolines Containing
Sulfone/Sulfoxide Groups Based on the Sulfonylurea Receptor Protein
Binding Site
1
1
1
1,2
Xiuling Yu , Yuxiu Liu ,* Yongqiang Li and Qingmin Wang *
1
State Key Laboratory of ElementoꢀOrganic Chemistry, Research Institute of ElementoꢀOrganic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China.
2
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071,
People’s Republic of China.
Eꢀmail: liuyuxiu@nankai.edu.cn, wangqm@nankai.edu.cn
*
Corresponding authors. Tel: +86ꢀ(0)22ꢀ23503952; Fax: +86ꢀ(0)22ꢀ23503952; Qingmin Wang,
Eꢀmail: wangqm@nankai.edu.cn Yuxiu Liu, Eꢀmail: liuyuxiu@nankai.edu.cn
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 2 of 27
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
ABSTRACT
Enormous compounds containing sulfone/sulfoxide groups have been used in a
variety of fields, especially in drug and pesticide design. To search for novel
environmentally benign and ecologically safe pesticides with unique modes of action,
a series of 2,4ꢀdiphenylꢀ1,3ꢀoxazolines containing sulfone/sulfoxide groups as chitin
synthesis inhibitors (CSI) were designed and synthesized, on the basis of sulfonylurea
1
receptor protein (SUR) binding site for CSI. Their structures were characterized by H
1
3
NMR, C NMR and HRMS. The acaricidal and insecticidal activities of the new
compounds were evaluated. It was found that most of the target compounds displayed
wonderful acaricidal activities against spider mite (Tetranychus cinnabarinus) larvae
and eggs. Especially Iꢀ4, IIꢀ3 and IIꢀ4 displayed higher activities than commercial
1
1
1
1
1
1
1
1
1
1
2
2
2
ꢀ1
etoxazole at a concentration of 2.5 mg L . And some target compounds exhibited
insecticidal activities against lepidopteran pests. The present work demonstrated that
these compounds containing sulfone/sulfoxide groups could be considered as
potential candidates for the development of novel acaricides in the future.
KEYWORDS: 2,4ꢀdiphenylꢀ1,3ꢀoxazoline, sulfone, sulfoxide, acaricidal/insecticidal
activity, structureꢀactivity relationship
ACS Paragon Plus Environment

Page 3 of 27
Journal of Agricultural and Food Chemistry
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
INTRODUCTION
In the future human is still facing the problem of food, one of the most serious
problems. In order to get the most food production, we have been trying our best to
prevent and control the threats from weeds, pests, and diseases. Among these threats,
the control of mites and insects is of extremely importance. Mites are small in size
and have extremely short life cycle, powerful reproductive potential, wide hosts, and
1
ꢀ3
are easy to develop resistance, so mites are very difficult to prevent and control. To
cope with the serious challenge of insect resistance and stricter environmental
regulation, scientists have been dedicated in innovating novel potent insecticides with
new mechanisms of action and ecoꢀfriendly properties. The use of pesticides can
bring numerous benefits and make a significant contribution to the lifestyles we have
come to expect.
Sulfonylurea receptor (SUR) protein is one of the families of ATPꢀbinding cassette
4
transporter (ABC transporter). So far, the crystal structure of SUR protein has not
been parsed out. Antidiabetics glibenclamide and glipizide containing sulfone
functional groups, are the second generation of sulfonylurea receptor inhibitor,
defined a bipartite binding site in SUR (A site and B site). Of the molecules the
sulfonylurea group was speculated to interact with site A, while the amide group
associated with site B, presenting a “L” shape of the molecular conformation. The
amino acid residues of SUR could possibly form hydrogen bonds with functional
5
groups of the molecules, therefore SUR acts as hydrogen bond donors (Figure 1). In
2004, Matsumura and coꢀworkers by isotope labeling experiments found that the
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 4 of 27
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
benzoylurea insecticide diflubenzuron and antidiabetic glibenclamide both targeted
SUR protein in Drosophila melanogaster and Blattella germanica; such binding made
6
,7
chitin not be biosynthesized normally. In 2012, Leeuwen et al also utilized the
technology of calcofluor white (CFW) staining to demonstrate that etoxazole indeed
8
inhibited chitin biosynthesis in T. urticae. According to the similarity in the action
mechanism of the 2,4ꢀdiphenylꢀ1,3ꢀoxazolines and benzoylureas, both belonging to
9,10
chitin synthesis inhibitors (CSI), our research group preliminarily determined the
binding affinity of etoxazole and oxazoline derivatives to SUR in vitro by
fluorescence polarization method, and found that the trend of their binding affinity
was almost consistent with their acaricidal activities against T. cinnabarinus in vivo.
Therefore, it was verified that oxazoline derivatives including etoxazole could bind
11
with SUR then resulting in the inhibition of chitin biosynthesis in mite body. We
speculated the interaction between oxazoline derivatives and SUR was carried out
possible by forming hydrogen bonds.
Most of sulfone/sulfoxide compounds possess a broad spectrum of bioactivities,
12
13,14
15,16
17,18
19
such as insecticidal, antifungal,
herbicidal,
antitumor,
antiꢀHIVꢀ1 and
20,21
antitubercular
activities et al, especially in the field of pesticides. For example,
Aventis Company developed a sulfoxide insecticide named as fipronil (Figure 1)
which possesses a broad spectrum of bioactivity against Myzus persicae, Empoasca,
Musca domestica, larvae of lepidopteran and hymenopteran pests; Japanese Pesticide
Co., Ltd. and Bayer Crop Science Company jointly developed a new
sulfoneꢀcontaining insecticide flubendiamide (Figure 1) as the first ryanodinne
ACS Paragon Plus Environment

Page 5 of 27
Journal of Agricultural and Food Chemistry
6
6
6
7
7
7
7
7
7
7
7
7
7
8
8
8
8
8
8
8
8
8
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
receptor inhibitor which gave excellent larvicidal activity on lepidopteran pests, such
as cotton bollworm. Sulfone/sulfoxide groups containing oxygen atom(s) which are
good hydrogen bond acceptor. From this point, the introduction of sulfone/sulfoxide
groups into certain insecticides might increase the binding property between the
insecticide and potent receptor. Inspired by the above viewpoints, based on the
molecular mechanism of action of oxazolines acaricides, we developed an idea that
introducing sulfone/sulfoxide groups to oxazolines acaricides to increase the binding
ability, then a series of 2,4ꢀdiphenylꢀ1,3ꢀoxazolines containing sulfone/sulfoxide
group at the para position of 4ꢀphenyl were designed and synthesized. The
acaricidal/insecticidal activities of these novel compounds were evaluated to test the
idea, and the structureꢀactivity relationships were analyzed.
MATERIALS AND METHODS
Instruments. Reaction progress was monitored by thinꢀlayer chromatography on
silica gel GF254 with ultraviolet (UV) detection. Melting points were obtained using
an Xꢀ4 binocular microscope melting point (mp) apparatus and are uncorrected.
1
13
Yields were not optimized. HꢀNMR spectra and CꢀNMR spectra were recorded
utilizing a Bruker AV400 spectrometer with CDCl as solvent and tetramethylsilane as
3
internal standard. Chemical shifts (δ) were given in parts per million (ppm).
Highꢀresolution mass spectra (HRMS) data were obtained with a Fourier transform
ion cyclotron resonance mass spectrometry (FTICRꢀMS) spectrometer (ionspec,
7.0T).
General Synthesis. The reagents were all analytically or chemically pure
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 6 of 27
8
9
9
9
9
9
9
0
1
2
3
4
purchased from commercial sources and were used as received. All anhydrous
solvents were dried and distilled by standard techniques just before use. All the
sulfides
were
prepared
by
the
reaction
of
Nꢀ(1ꢀ(4ꢀ(bromomethyl)phenyl)ꢀ2ꢀchloroethyl)ꢀ2,6ꢀdifluorobenzamide with thiophenol
2
2
or mercaptan according to the literature method. The synthetic route is given in
Figure 2.
9
9
9
9
9
5
6
7
8
9
General Synthetic Procedure for the Target Compounds Iꢀ1
IIꢀ1 IIꢀ9 (Figure 2).
−
Iꢀ13 and
−
Synthesis
of
2ꢀ(2,6ꢀdifluorophenyl)ꢀ4ꢀ(4ꢀ((naphthalenꢀ2ꢀylsulfonyl)methyl)phenyl)ꢀ4,5ꢀdihydrooxa
zole (Iꢀ1). To solution of
a
1
1
1
1
1
1
1
1
1
1
1
00
01
02
03
04
05
06
07
08
09
10
2ꢀ(2,6ꢀdifluorophenyl)ꢀ4ꢀ(4ꢀ((naphthalenꢀ2ꢀylthio)methyl)phenyl)ꢀ4,5ꢀdihydrooxazole
(0.5 g, 1.16 mmol) in 20 mL dichloromethane was successively added trifluoroacetic
acid (1.25 mL) and 30% hydrogen peroxide (0.5 mL, 3.94 mmol) at room temperature.
The progress of the reaction was monitored by TLC until the reaction was complete.
The reaction mixture was added sodium hydrogen sulfite (1.5 g, 14.42 mmol) and
stirred for 1 h at room temperature to decompose excess hydrogen peroxide. The
aqueous phase was separated and then extracted with dichloromethane twice. The
combined organic layer was washed with saturated brine, dried over anhydrous
sodium sulfate, filtered. After the solvent was removed in vacuo, the residue was
purified by column chromatography on silica gel and eluted with petroleum ether and
2
3
ethyl acetate (v/v = 4:1) to give the target compound Iꢀ1.
ACS Paragon Plus Environment

Page 7 of 27
Journal of Agricultural and Food Chemistry
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Compounds Iꢀ2−Iꢀ13 were prepared according to the method used for compound
Iꢀ1. The physical data in detail are included in the Supporting Information.
Synthesis
2ꢀ(2,6ꢀdifluorophenyl)ꢀ4ꢀ(4ꢀ((naphthalenꢀ2ꢀylsulfinyl)methyl)phenyl)ꢀ4,5ꢀdihydrooxa
zole (IIꢀ1). To solution of
of
a
2ꢀ(2,6ꢀdifluorophenyl)ꢀ4ꢀ(4ꢀ((naphthalenꢀ2ꢀylthio)methyl)phenyl)ꢀ4,5ꢀdihydrooxazole
(0.42 g, 0.97 mmol) in dichloromethane (20 mL) under stirring was successively
added glacial acetic acid (1.05 mL) and 30% hydrogen peroxide (0.4 mL, 3.15 mmol).
The reaction mixture was monitored by TLC. Excess hydrogen peroxide was
destroyed by adding 1.5 g sodium hydrogen sulfite and stirred for 1 h at room
temperature. Then the organic phase was separated, and the aqueous phase was
extracted by dichloromethane (2 ×20 mL). The organic layer was washed with
saturated brine and dried with anhydrous sodium sulfate, then filtered. After the
solvent was removed under reduced pressure, the residue was purified by column
chromatography on silica gel and eluted with petroleum ether and ethyl acetate (v/v =
2
4
1:1) to give the target compound IIꢀ1.
Synthesis
of
2ꢀ(2,6ꢀdifluorophenyl)ꢀ4ꢀ(4ꢀ(pꢀtolylsulfinylmethyl)phenyl)ꢀ4,5ꢀdihydrooxazole (IIꢀ2).
To solution of
a
2ꢀ(2,6ꢀdifluorophenyl)ꢀ4ꢀ(4ꢀ(pꢀtolylthiomethyl)phenyl)ꢀ4,5ꢀdihydrooxazole (0.43 g,
1.09 mmol) in 15 mL acetonitrile was added DessꢀMartin Periodinane (0.46 g, 1.09
mmol). Then the reaction mixture was stirred at 0 °C for 0.5 h and slowly warmed to
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 8 of 27
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
room temperature. The progress of the reaction was monitored by TLC. The resulting
mixture was added water, extracted with ethyl acetate (3 ×15 mL), the combined
organic phase was washed with dilute hydrochloric acid, an aqueous sodium
carbonate solution and saturated brine successively. The organic layer was dried over
anhydrous sodium sulfate, filtered, and the solvent was removed under reduced
pressure. The residue was purified by recrystallization using petroleum ether and ethyl
acetate to give the target compound IIꢀ2.
Compounds IIꢀ3−IIꢀ9 were synthesized by a method similar to that used for
compound IIꢀ1. Their physical data are included in the Supporting Information.
25ꢀ30
Biological Assay. Detailed bioassay procedures for spider mites
and various
31ꢀ34
insects
were discribed in published literature and are also included in the
Supporting Information. According to statistical requirements each bioassay was
repeated at least three times. The error of the experimments was 5%. Assessments
were made on a dead/alive basis, and mortality rates were corrected using Abbott’s
formula. Evaluation were based on a percentage scale of 0−100, where 0 equals no
activity and 100 equals total kill. For comparative purpose, etoxazole was tested under
the same conditions.
50 RESULT AND DISCUSSION
51
52
53
54
Chemistry
Synthesis. Sulfides were obtained by the reaction of the key intermediate
Nꢀ(1ꢀ(4ꢀ(bromomethyl)phenyl)ꢀ2ꢀchloroethyl)ꢀ2,6ꢀdifluorobenzamide with thiophenol
or mercaptan on the basis of the previous report. Both sulfones Iꢀ1–Iꢀ13 and
ACS Paragon Plus Environment

Page 9 of 27
Journal of Agricultural and Food Chemistry
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
sulfoxides IIꢀ1–IIꢀ9 were synthesized from corresponding sulfides by oxidation with
2 2
H O but in the presence of different acid. Sulfone compounds (Iꢀ1–Iꢀ13) were
23
2 2 3
prepared by oxidation of sulfides with H O /CF COOH; the reaction occured at
room temperature, and the raw material was disappeared quickly once hydrogen
peroxide was added. Sulfoxide compounds (IIꢀ1–IIꢀ9) were prepared from sulfides by
oxidation with H
need for the whole night to complete. The reaction required 3 equivalent of H
oxidant and CH COOH as catalyst to prevent overꢀoxidation; when using
2
O
2
/CH
3
COOH; H
2
O
2
was added under the ice bath, and the reaction
2
O
2
as
3
1,2ꢀdichloroethane as solvent, very little sulfone compound was detected by TLC
when raw material was consumed completely. II could also be prepared by oxidation
of corresponding sulfide with DeissꢀMartin oxidant, but the yield of the reaction (IIꢀ2
as an example) was not high.
1
Structure. There has a “prochirality” concept in HꢀNMR spectra of sulfoxide
compounds IIꢀ1–IIꢀ9. That is to say, sulfoxide compound contains a lone pair of
electrons on the sulfur atom, so it is a chiral compound. Therefore the two hydrogen
2
atoms on the CH linked to sulfoxide group are chemical nonꢀequivalent atoms and
should give differnet chemical shift. To be specific, the CH
2
connected to sulfoxide
1
group of IIꢀ2 displays two duplicate peaks at 3.98 and 4.08 ppm in HꢀNMR spectrum,
with a coupling constant of 12.4 Hz. Correspondingly, this compound exhibits two set
1
3
of peaks in CꢀNMR spectrum. In contrast, there is no such situation in sulfone
compounds. The CH
2
connected to sulfone group of Iꢀ2 shows only a single peak in
1
13
HꢀNMR, and one set of peaks occur in CꢀNMR spectrum.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 10 of 27
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
77
Biological Activity and StructureꢀActivity Relationship. Activities
78 against Spider Mite (T. cinnabarinus) Larvae. The acaricidal activities of the
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
target compounds Iꢀ1–Iꢀ13, IIꢀ1–IIꢀ9 and commercial etoxazole as the contrast
compound against the eggs and larvae of spider mite (T. cinnabarinus) were evaluated.
The results (Table 1) indicated that most of the target sulfones or sulfoxides possessed
excellent activities against T. cinnabarinus larvae. To be specific, compounds with a
4ꢀhalophenyl sulfonyl (Iꢀ3, Iꢀ4, Iꢀ5) or a sulfinyl (IIꢀ3, IIꢀ4, IIꢀ5) at the para site of
the 4ꢀphenyl of 2,4ꢀdiphenylꢀ1,3ꢀoxazolines all had good acaricidal activities;
componds Iꢀ7 and IIꢀ7 which had a 2ꢀbromophenyl sulfonyl and a 2ꢀbromophenyl
sulfinyl moiety, respectively, also had higher activities than 2ꢀmethoxyphenyl sulfonyl
and sulfinyl compounds Iꢀ6 and IIꢀ6. Tertiary butyl sulfonyl derivative Iꢀ8 and
tertiary butyl sulfinyl derivative IIꢀ8 had higher activities than benzyl sulfonyl
compound Iꢀ9 and benzyl sulfinyl compound IIꢀ9, although the substituents were all
alkyl moieties. Compounds with heterocyclic aryl sulfonyl at the para site of the
4ꢀphenyl moiety of 2,4ꢀdiphenylꢀ1,3ꢀoxazolines (Iꢀ10–Iꢀ13) did not have good
acaricidal activities against spider mite larvae at most concentrations, but Iꢀ11
ꢀ1
exhibited comparable acaricidal activity as etoxazole at 1 mg L . In all, compounds
Iꢀ2, Iꢀ3, IIꢀ5, Iꢀ8 and IIꢀ8 showed activities as high as etoxazole, whereas compounds
IIꢀ3, Iꢀ4, IIꢀ4, Iꢀ5 and IIꢀ7 exhibited a little higher activities. The LC , LC values
5
0
90
of compounds IIꢀ3 and IIꢀ4 are given in Table 2. Both compounds showed lower
concentrations than commercial etoxazole.
Activities against Spider Mite (T. cinnabarinus) Eggs. The results of
ACS Paragon Plus Environment

Page 11 of 27
Journal of Agricultural and Food Chemistry
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
99
00
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
19
20
acaricidal activities given in Table 1 indicated that most of the target sulfone or
sulfoxide compounds possessed moderate to excellent activities against T.
cinnabarinus eggs. Compounds Iꢀ1, IIꢀ1, Iꢀ2, IIꢀ3, IIꢀ4, Iꢀ5, IIꢀ5, IIꢀ7, Iꢀ8, IIꢀ8, IIꢀ9,
Iꢀ10 and Iꢀ11 showed the same level of mortality of T. cinnabarinus eggs as etoxazole,
and compound Iꢀ4 bearing a 4ꢀfiuorophenyl sulfonyl at the para site of the 4ꢀphenyl
moiety exhibited higher activity than etoxazole: the mortality of Iꢀ4 was 100%, 82%
ꢀ1
ꢀ1
at 2.5 mg L and 1 mg L , respectivily, but etoxazole gave only 90% and 63% at the
same concentrations. Whatever for larvae or eggs, when the subsitiuents attached to
sulfonyl or sulfinyl were the same, some sulfones exhibited better acaricidal activities
than sulfoxides, but some were on the contrary; no rules to follow. Among the
compounds bearing heterocyclic aryl sulfonyl groups, Iꢀ11 (bearing a benzothiazole
sulfonyl) was the only compound whose activity was excellent against spider mite
eggs. Then, the LC50, LC90 values of compound Iꢀ4 were tested and are given in Table
3, which showed the LC value of Iꢀ4 was about two times lower than etoxazole.
90
It is worth mentioning that compounds Iꢀ2, Iꢀ4, IIꢀ4, Iꢀ5, IIꢀ7, Iꢀ8 and IIꢀ8 gave
good activities against both spider mite eggs and larvae.
Insecticidal Activities against Lepidopteran Pests and Mosquito Larvae.
Table 4 shows the insecticidal activities of the target compounds Iꢀ1–Iꢀ13, IIꢀ1–IIꢀ9
and etoxazole against lepidopteran pests larvae (oriental armyworm, cotton bollworm
and corn borer) and mosquito larvae,. It could be seen that most of the target
compound exhibited certain insecticidal activities but were much lower than etoxazole,
Nevertheless, there are still some compounds with good activities that could be found.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 12 of 27
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
Compound IIꢀ7 exhibited excellent activity against cotton bollworm and corn borer,
higher than etoxazole. This compound also gave excellent activity against spider mite
eggs and larvae. Compounds Iꢀ5, Iꢀ7 and Iꢀ11 showed higher activities against
mosquito than etoxazole, although they only had moderate activities against the other
three insects.
In summary, a series of 2,4ꢀdiphenylꢀ1,3ꢀoxazolines containing sulfone/sulfoxide
groups were designed and synthesized, on the basis of sulfonylurea receptor protein
binding site for CSI. The results of the bioassay showed that whatever sulfones or
sulfoxides they all exhibited considerable acaricidal activities against the eggs and
larvae of spider mite. Especially Iꢀ4 (containing a 4ꢀfluorophenyl sulfonyl group at
the para position of 4ꢀphenyl) gave very high activity against spider mite eggs; the
ꢀ1
mortality was 82% at 1 mg L . IIꢀ3 and IIꢀ4 (containing a 4ꢀchlorophenyl and a
4ꢀfluorophenyl sulfinyl group, respectively) showed excellent activity against spider
ꢀ1
mite larvae; the mortality was 87%, 83% at 1 mg L , respectively, all better than
etoxazole. We speculate sulfone/sulfoxide groups enhance the binding between the
compound and target site, and fluorine atom can change charge distribution of the
molecules, strengthen the lipotropy, which all are beneficial to the improvement of the
activity. It indicated that based on the target site to design pesticide molecules is
reasonable.
ACS Paragon Plus Environment

Page 13 of 27
Journal of Agricultural and Food Chemistry
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
ASSOCIATED CONTENT
Supporting Information. The physical data of target compounds Iꢀ1–Iꢀ13, IIꢀ1–IIꢀ9
can be found in Supporting Information. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: +86ꢀ(0)22ꢀ23499842. Fax: +86ꢀ(0)22ꢀ23499842. Eꢀmail: wang98h@263.net
or wangqm@nankai.edu.cn.
Funding Sources
This work was supported by the National Natural Science Foundation of China
(21132003, 21421062, 21372131), the Specialized Research Fund for the Doctoral
Program of Higher Education (20130031110017).
Notes
The authors declare no competing financial interest.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 14 of 27
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
REFERENCES
(1) Leeuwen, T. V.; Pottelberge, S. V.; Tirry, L. Comparative acaricide susceptibility
and detoxifying enzyme activities in fieldꢀcollected resistant and susceptible strains of
Tetranychus urticae. Pest Manag. Sci. 2005, 61, 499–507.
(2) Dekeyser, M. A. Acaricide mode of action. Pest Manag. Sci. 2005, 61, 103–110.
(3) Leeuwen, T. V.; Vontas, J.; Tsagkarakou, A.; Dermauwa, W.; Tirry, L. Acaricide
resistance mechanisms in the twoꢀspotted spidermite Tetranychus urticae and other
important acari: a review. Insect Biochem. Mol. Biol. 2010, 40, 563–572.
(4) Burke, M. V.; Mutharasan, R. K.; Ardehali, H. The sulfonylurea receptor, an
atypical ATPꢀbinding cassette protein, and its Regulation of the KATP channel. Circ.
Res. 2008, 102, 164–176.
(5) Bryan, J.; Crane, A.; VilaꢀCarriles, W. H.; Babenko, A. P.; AguilarꢀBryan, L.
Insulin secretagogues, sulfonylurea receptors and KATP channels. Curr. Pharm. Des.
2005, 11, 2699–2716.
(6) AboꢀElghar, G. E; Fujiyoshi, P.; Matsumura, F. Significance of the sulfonylurea
receptor (SUR) as the target of diflubenzuron in chitin synthesis inhibition in
Drosophila melanogaster and Blattella germanica. Insect Biochem. Mol. Biol. 2004,
34, 743–752.
(7) Matsumura, F. Studies on the action mechanism of benzoylurea insecticides to
inhibit the process of chitin synthesis in insects: A review on the status of research
activities in the past, the present and the future prospects. Pestic. Biochem. Physiol.
2010, 97, 133–139.
ACS Paragon Plus Environment

Page 15 of 27
Journal of Agricultural and Food Chemistry
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
87
88
89
90
91
92
93
94
95
96
97
98
99
00
01
02
03
04
05
06
07
08
(8) Leeuwen, T. V.; Demaeght, P.; Osborne, E. J.; Dermauw, W.; Gohlke, S.; Nauen,
R.; Grbic, M.; Tirry, L.; Merzendorfer, H.; Clark, R. M. Population bulk segregant
mapping uncovers resistance mutations and the mode of action of a chitin synthesis
inhibitor in arthropods. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 4407–4412.
(9) Liu, Y. X.; Wei, X. C.; Li, Y. Q.; Yang, N.; Wang, Q. M. Design, synthesis and
acaricidal/insecticidal activities of etoxazole analogues. New J. Chem. 2013, 37,
1803–1810.
(10) Lee, C. W.; Chung, J. D. Characteristics and ringꢀopening isomerization
polymerization
of
2ꢀ(1,3,3ꢀtrimethylꢀ6ꢀazabicyclo[3,2,1]ꢀoctꢀ6ꢀyl)ꢀ4,5ꢀdihydroꢀ1,3ꢀoxazoline
Polymer (Korea) 2012, 36, 262–267.
(TAO).
(11) Li, Y. Q.; Li, C. J.; Zheng, Y. L.; Wei, X. C.; Ma, Q. Q.; Wei, P.; Liu, Y. X.; Qin,
Y. G.; Yang, N.; Sun, R. F.; Ling, Y.; Yang, X. L.; Wang, Q. M. Design, Synthesis,
Acaricidal Activity, and Mechanism of Oxazoline Derivatives Containing an Oxime
Ether Moiety. J. Agric. Food Chem. 2014, 62, 3064–3072.
(12) Fitzjohn, S.; Robinson, M. P. Benzoxazole and benzothiazole derivatives. W.O.
Patent 9406783, 1994.
(13) Hiromichi, I.; Masakazu, T.; Ten, U.; Seiichi, K. Preparation of
disulfonylthiadiazoles and their use as agrochemical microbicides. J.P. Patent
94116252, 1994.
(14) Fry, F. H.; Okarter, N.; Smith, C. B.; Kershaw, M. J.; Talbot, N. J.; Jacob, C. Use
of a substrate/alliinase combination to generate antifungal activity in situ. J. Agric.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 16 of 27
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Food Chem. 2005, 53, 574–580.
(15) Wang, T.; Xue, S. J. The synthesis and biological activity of derivates of
benzisothiazole oxide. Chemical Reagents 2000, 22, 339–340.
(16) Andrew, P.; Jutta, E. B.; Janice, B.; Timothy, D. S. Isoxazoline derivatives and
their preparation, herbicidal composition, and use as herbicides to control weeds or
plant growth inhibition. W.O. Patent 2006024820, 2006.
(17) Tai, X. S.; Yin, X. H.; Tan, M. Y. Crystal structure and antitumor activity of
tri[2ꢀ[Nꢀ(4’ꢀmethylꢀbenzylsulfonyl)amino]ethyl]ꢀamine. Chin. J. Struc. Chem. 2003,
22, 411–414.
(18) Vedula, M. S.; Pulippaka, A. B.; Venna, C.; Chintakunta, V. K.; Jinnapally, S.;
Kattuboina, V. A.; Vallakati, R. K.; Basetti, V.; Akella, V.; Rajgopai,S.; Reka, A. K.;
Teepireddy, S. K.; Mamnoor, P. K.; Rajagopalan, R.; Bulusu, G.; Khandelwal, A.;
Upreti, V. V.; Mamidi, S. R. New styryl sulfones as anticancer agents. Eur. J. Med.
Chem. 2003, 38, 811–824.
(19) Silvestri, R.; Artico, M.; Regina, G. L.; Martino, G. D.; Colla, M. L.; Loddo, R.;
Colla, P. L. AntiꢀHIVꢀ1 activity of pyrryl aryl sulfone (PAS) derivatives: synthesis and
SAR studies of novel esters and amides at the position 2 of the pyrrole nucleus. II
Farmaco 2004, 59, 201–210.
(20) Foroumadi, A.; Mirzaei, M.; Shafiee, A. Antituberculosis agents II. Evaluation of
in
vitro
antituberculosis
activity
and
cytotoxicity
of
some
2ꢀ(1ꢀmethylꢀ5ꢀnitroꢀ2ꢀimidazolyl)ꢀ1,3,4ꢀthiadiazole derivatives. II Farmaco 2001, 56,
621–623.
ACS Paragon Plus Environment

Page 17 of 27
Journal of Agricultural and Food Chemistry
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
(21) Foroumadi, A.; Asadipour, A.; Mirzaei, M.; Karimi, J.; Emami, S.
Antituberculosis agents V. Synthesis, evaluation of in vitro antituberculosis activity
and cytotoxicity of some 2ꢀ(5ꢀnitroꢀ2ꢀfuryl)ꢀ1,3,4ꢀthiadiazole derivatives. II Farmaco
2002, 57, 765–769.
(22) Yu, X. L.; Liu, Y. X.; Li, Y. Q.; Wang, Q. M. Design, Synthesis, and
Acaricidal/Insecticidal Activities of Oxazoline Derivatives Containing a Sulfur Ether
Moiety. J. Agric. Food Chem. 2015, 63, 9690–9095.
(23) Tang, R.Y.; Zhong, P.; Lin, Q. L. A convenient conversion of pyrazolyl disulfide
to sulfides by sodium dithionite and synthesis of sulfoxides. J. Fluorine Chem. 2006,
127, 948–953.
(24) Li, Y. X.; Wang, Y. M.; Liu, B.; Wang, S. H.; Li, Z. M. Synthesis and herbicidal
activity of 2ꢀalkyl(aryl)ꢀ3ꢀmethylsulfonyl(sulfinyl)pyrano[4,3ꢀc]pyrazolꢀ4 (2H)ꢀones.
Heteroatom Chem. 2005, 16, 255–258.
(25) Sun, R. F.; Liu, Y. X.; Zhang, Y. L.; Xiong, L. X.; Wang, Q. M. Design and
Synthesis of Benzoylphenylureas with Fluorinated Substituents on the Aniline Ring as
Insect Growth Regulators. J. Agric. Food Chem. 2011, 59, 2471–2477.
(26) Sun, R. F.; Li, Y. Q.; Xiong, L. X.; Liu, Y. X.; Wang, Q. M. Design, Synthesis,
and Insecticidal Evaluation of New Benzoylureas Containing Isoxazolines and
Isoxazole Group. J. Agric. Food Chem. 2011, 59, 4851–4859.
(27) Kuhn, D. G.; Kameswaran, V. Insecticidal, acaricidal and molluscicidal
1ꢀ(substituented)thioalkylpyrroles. U.S. Patent 5302383, 1993.
(28) Wang, Y. J.; Ou, X. M.; Pei, H.; Lin, X. M.; Yu, K. Toxicities of novel insecticide
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 18 of 27
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
chlorfenpyr against several insects in lab. Agrochem. Res. Appl. 2006, 10, 20–23.
(29) Liu, Z. H.; Lei, Q.; Li, Y. Q.; Xiong, L. X.; Song, H. B.; Wang, Q. M. Design,
Synthesis, Structure, and Acaricidal/Insecticidal Activity of Novel Spriocyclic
Tetronic Acid Derivatives Containing an Oxalyl Moiety. J. Agric. Food Chem. 2011,
59, 12543–12549.
(30) Song, H. J.; Liu, Y. X.; Xiong, L. X.; Li, Y. Q.; Yang, N.; Wang, Q. M. Design,
Synthesis, and Insecticidal Activity of Novel Pyrazole Derivatives Containing
aꢀHydroxymethylꢀNꢀbenzyl Carboxamide, αꢀChloromethylꢀNꢀbenzyl Carboxamide,
and 4,5ꢀDihydrooxazole Moieties. J. Agric. Food Chem. 2012, 60, 1470–1479.
(31) Zhao, Q. Q.; Shang, J.; Liu, Y. X.; Wang, K. Y.; Bi, F. C.; Huang, R. Q.; Wang, Q.
M.
Synthesis
and
insecticidal
activities
of
novel
NꢀsulfenylꢀN’ꢀtertꢀbutylꢀN,N’ꢀdiacylhydrazines. 1. NꢀAlkoxysulfenate derivatives. J.
Agric. Food Chem. 2007, 55, 9614–9619.
(32) Huang, Z. Q.; Cui, Q. M.; Xiong, L. X.; Wang, Z. W.; Wang, K. Y.; Zhao, Q. Q.;
Bi, F. C.; Wang, Q. M. Synthesis and insecticidal activities and SAR studies of novel
benzoheterocyclic diacylhydrazine derivatives. J. Agric. Food Chem. 2009, 57,
2447–2456.
(33) Hsu, A. C.; Murphy, R. A.; Aller, H. E.; Hamp, D. W.; Weinstein, B. Insecticidal
N’ꢀsubstituentedꢀN,N’ꢀdisubstituentedhydrazines. U.S. Patent 5117057, 1992.
(34) Chen, L.; Huang, Z. Q.; Wang, Q. M.; Shang, J.; Huang, R. Q.; Bi, F. C.
Insecticidal benzoylphenylureaꢀSꢀcarbamate: a new propesticide with two effects of
both benzoylphenylureas and carbamates. J. Agric. Food Chem. 2007, 55, 2659–2663.
ACS Paragon Plus Environment

Page 19 of 27
Journal of Agricultural and Food Chemistry
Figure Captions
Figure 1 The Design of the Target Compounds.
Figure 2 General Synthetic Procedure for the Target Compounds Iꢀ1−Iꢀ13 and
IIꢀ1−IIꢀ9 and Chemical Structures of the Target Compounds.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 20 of 27
Figure 1
O
O
S
O
NH
O
HN
O
NH
Cl
Glidenclamide
double acting
sites
F
O
O
C
H
H
C
N
N
Cl
O
N
O
F
S
NH
Diflubenzuron
N
HN
O
NH
O
S
O
O
F
Benzoylureas Insecticide
Insect Biochem. Mol. Biol.
Glipizide
N
O
R
2
004, 34, 743-752
F
SUR inhibitors
Curr. Pharm. Des. 2005, 11, 2699-2716
O
S
F
OCH2CH3
N
O
R
F
F
N
O
S
O
S
O
F
O
F3C
CN
I
HN
O
Etoxazole
N
active groups
O
H
H2N
Cl
N
Oxazolines Acaricide
J. Agric. Food. Chem.
014, 62, 3064-3072
Proc. Natl. Acad. Sci. U.S.A.
012, 109 (12), 4407-4412
N
Cl
CF3
2
F
CF3
CF3
Fipronil
2
Flubendiamide
ACS Paragon Plus Environment

Page 21 of 27
Journal of Agricultural and Food Chemistry
Figure 2
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 22 of 27
Table 1 Acaricidal Activities of the Target Compounds against Spider
Mite
Mortality (%) against larvae
Mortality (%) against eggs
Conc.
100 50
25
2.5
1
100
50
25
2.5
1
ꢀ
1
(
mg L )
Iꢀ1
100 87
100 89
75
80
66
73
53
49
79
68
78
87
80
83
86
76
—
48
—
88
78
79
—
100
100
100
94
100 100 95
100 100 93
100 100 93
67
63
73
49
51
66
IIꢀ1
Iꢀ2
100 100 100 88
100 89 80 71
IIꢀ2
Iꢀ3
86
73
61
78
75
100 100 100 89
100 100 100 96
100 100 100 91
100 100 100 96
100 100 100 95
100 100 100 87
100
100
100
100
100
100
100
100
100
100
100
100
100
100 84
100 89
IIꢀ3
Iꢀ4
100 100 100 82
IIꢀ4
Iꢀ5
100 100 89
100 100 91
67
64
66
40
50
30
63
67
65
43
IIꢀ5
Iꢀ6
89
77
75
51
85
89
73
76
60
61
44
57
36
100 88
IIꢀ6
Iꢀ7
100 100 84
100 84 72
100 100 86
IIꢀ7
Iꢀ8
100 100 100 93
100 100 100 89
100 100 100 91
100 100 94
100 100 89
100 100 92
IIꢀ8
Iꢀ9
100 78
69
54
83
74
62
ACS Paragon Plus Environment

Page 23 of 27
Journal of Agricultural and Food Chemistry
IIꢀ9
Iꢀ10
Iꢀ11
Iꢀ12
Iꢀ13
93
84
79
64
83
68
79
64
50
79
57
76
23
—
77
36
72
77
100
100
100
100
100
100
100 100 90
100 89 75
100 100 93
67
71
63
45
—
63
100 85
100 92
90
94
76
89
92
89
82
77
73
41
Etoxazole 100 100 100 88
100 100 90
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 24 of 27
Table 2 LC , LC Values of IIꢀ3, IIꢀ4, and Etoxazole against Larvae of
5
0
90
Spider Mite
ꢀ
ꢀ
compd
y=ax + b
LC (mg L ) LC (mg L ) correlation
5
0
90
coefficient
0.9697
IIꢀ3
IIꢀ4
y=2.24x + 5.85 0.42
y=2.93x + 5.69 0.58
1.55
1.58
2.53
0.9770
Etoxazole y=2.49x + 5.27 0.78
0.9841
Table 3 LC , LC Values of Iꢀ4 and Etoxazole against Eggs of Spider
5
0
90
Mite
ꢀ
ꢀ
compd
y=ax + b
LC (mg L ) LC (mg L ) correlation
5
0
90
coefficient
0.9956
Iꢀ4
y=6.20x + 6.15 0.65
1.05
2.48
Etoxazole y=2.43x + 5.32 0.74
1.0000
ACS Paragon Plus Environment

Page 25 of 27
Journal of Agricultural and Food Chemistry
Table 4 Insecticidal Activities of the Target Compounds (Mortality,
Percent)
compd
cotton
corn borer
oriental
mosquito
bollworm
armyworm
ꢀ1
ꢀ1
ꢀ1
ꢀ1
(
600 mg L ) (600 mg L ) (600 mg L ) (10 mg L )
Iꢀ1
80
65
40
45
55
45
80
15
55
75
35
50
55
65
65
40
35
40
35
75
5
50
70
75
70
40
65
40
35
25
70
70
80
10
10
5
IIꢀ1
Iꢀ2
70
10
5
IIꢀ2
Iꢀ3
IIꢀ3
Iꢀ4
25
15
5
IIꢀ4
Iꢀ5
c
45
65
25
45
50
100/40
IIꢀ5
Iꢀ6
10
5
IIꢀ6
Iꢀ7
25
c
d
100/100 /20
a
b
a
b
IIꢀ7
Iꢀ8
100/100 /60 100/100 /80 30
70
25
5
45
65
35
40
55
30
15
80
75
IIꢀ8
Iꢀ9
50
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
Page 26 of 27
IIꢀ9
25
40
65
75
65
10
30
65
70
60
45
50
50
15
65
20
Iꢀ10
10
c
Iꢀ11
100/60
25
Iꢀ12
Iꢀ13
10
a
b
a
b
a
b
c
Etoxazole
100/100 /40 100/100 /30 100/100 /0
100/0
a
ꢀ1.
b
ꢀ1
c
ꢀ1
Activities at 200 mg L
Activities at 2 mg L .
Activities at 100 mg L . Activities at 5 mg L .
d
ꢀ1
ACS Paragon Plus Environment

Page 27 of 27
Journal of Agricultural and Food Chemistry
TOC graphic
Agrochemical Bioregulators
ACS Paragon Plus Environment