Synthesis and Insecticidal Activity Evaluation of Virtually Screened Phenylsulfonamides

Article abstract of DOI:10.1021/acs.jafc.0c02153

The fastest and most effective way to control pests is to use pesticides. However, with the accumulation of pesticide resistance and the difficulties of rapidly producing new pesticides, it is of great significance to create new pesticides through new synthetic methods. In this study, we report a computer-aided drug design (CADD)-assisted method to obtain two lead sulfonamides by homology modeling and virtual screening. On this basis, the lead compounds were synthesized from p-chlorocresol by four steps of esterification, sulfonation, sulfonamidation, and amidation. Further, 71 derivatives were synthesized by optimizing the lead compounds, and their insecticidal activities against Mythimna separata were evaluated by the leaf-dipping method. Notably, seven sulfonamides (5a, 5g, 5h, 5m, 6b, 6g, and 6m) with excellent insecticidal activity were obtained, and the possible binding modes between receptors and active groups in sulfonamides were verified by structure-activity relationship and docking simulation, which provided theoretical support for the subsequent development of these novel candidate insecticides.

Full text of DOI:10.1021/acs.jafc.0c02153

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Agricultural and Environmental Chemistry
Synthesis and Insecticidal Activity Evaluation
of Virtually Screened Phenylsulfonamides
Fangli Gang, Xiaoting Li, Chaofu Yang, Lijuan Han, Hao
Qian, Shaopeng Wei, Wenjun Wu, and Jiwen Zhang
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.0c02153 • Publication Date (Web): 25 Sep 2020
Downloaded from pubs.acs.org on September 27, 2020
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Synthesis and Insecticidal Activity Evaluation of Virtually
Screened Phenylsulfonamides
Fangli Ganga, †, Xiaoting Lia,d, †, Chaofu Yanga, Lijuan Hana, Hao Qiana, Shaopeng Weic,
Wenjun Wuc, Jiwen Zhang a,b,c 
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a College of Chemistry & Pharmacy, Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University,
Yangling, Shaanxi, 712100, P. R. China
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b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China
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c Key Laboratory of Botanical Pesticide R&D in Shaanxi Province, Yangling, Shaanxi, 712100, P. R. China
d Shanxi Normal University, Linfen, Shanxi, 041004, P. R. China
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 Corresponding author. Tel.: +86-029-87092191; E-mail: nwzjw@nwafu.edu.cn (Jiwen Zhang)
† These two authors contribute equally to this work.
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ABSTRACT
The fastest and most effective way to control pests is to use pesticides. However, with the
accumulation of pesticide resistance and the difficulties of rapidly producing new pesticides, it is of great
significance to create new pesticides through new synthetic methods. In this study, we report a computer-
aided drug design (CADD)-assisted method to obtain two lead sulfonamides by homology modeling and
virtual screening. On this basis, the lead compounds were synthesized from p-chlorocresol by four steps
of esterification, sulfonation, sulfonamidation and amidation. Further, 71 derivatives were synthesized
by optimizing the lead compounds, and their insecticidal activities against Mythimna separate were
evaluated by the leaf-dipping method. Notably, seven sulfonamides (5a, 5g, 5h, 5m, 6b, 6g, 6m) with
excellent insecticidal activity were obtained, and the possible binding modes between receptors and
active groups in sulfonamides were verified by structure-activity relationship and docking simulation,
which provided theoretical support for the subsequent development of these novel candidate insecticides.
KEYWORDS：sulfonamides, virtual screening, insecticidal activity, docking simulation
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INTRODUCTION
A stable and high-yield crop production is necessary for the ever-growing world population in the
21st century. At present, the application of pesticides is still the most rapid and effective means to control
the problem of grain yield reduction caused by agricultural pests. In view of the increasing pesticides
resistance and the difficulties of rapidly producing new pesticides,1-5 it is imperative to create new
pesticides through new synthetic approaches.
Generally, the creation of new pesticides are mainly as follows: (1) direct synthesis of compound
or substitute;6-12 (2) random screening;13-17 (3) derivative methods.18-21 Direct synthesis centers on
obtaining natural products with good compatibility as a template to obtain biomimetic new pesticides
through chemical modification. Random screening takes advantage of existing knowledge and
experience to discover novel structures and targets. Derivative methods track the latest pesticide literature
for opportunities to modify biologically active molecular structures to develop new active derivatives. In
summary, the traditional methods used to create new pesticides are comprised of random screening or
modification based on existing active compounds, which also have many drawbacks, such as long
development cycle, large investment, difficulties in finding novel chemical structures and low success
rate. Therefore, in recent years, many new methods have emerged for the creation of pesticides, 22-24 the
most representative being computer-aided drug design (CADD). 25-28
Based on the known structure of pesticide receptors or ligands, CADD can generate theoretically
active molecules through biological design, thus determining a number of candidate lead compounds
(Scheme 1). This method can facilitate the discovery of drug candidates by reducing the number of
screened compounds while increasing the efficiency of lead compound discovery.
In our previous work, celangulin V is a representative β-dihydroagarofuran derivative with excellent
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insecticidal activity against Mythimna separata Walker. We have shown that its effective target is the
subunit H of V-ATPase.29-30 Based on the above experimental results, information from the Specs
database for research compounds was screened using homology modeling and molecular docking of
subunit H of V-ATPase of Mythimna separata Walker, and two high-score compounds (3h and 3i) were
found as lead compounds. Furthermore, 71 derivatives were synthesized by optimizing lead compounds,
and their insecticidal activities were further tested.
MATERIALS AND METHODS
General
All reagents are commercially available in analytical grade and used without any further purification.
Melting points were determined using a WRS-1B melting point apparatus (Shanghai YiCe Apparatus
and Equipment Co., Ltd, Shanghai, China) and left uncorrected. 1H NMR and 13C NMR were recorded
utilizing a Bruker AMX-500 spectrometer at 500 and 125 MHz in CDCl3, MeOD and DMSO-d6 with
tetramethylsilane (TMS) as internal standard. High-resolution mass spectrometry (HRMS) was carried
out on an LTQ Orbitrap XL instrument (Thermo Scientific, Waltham, MA, USA). The course of the
reactions was monitored by thin-layer (TLC) analysis on silica gel GF254, and all compounds were
purified by silica gel (200–300 mesh). M. separate and fresh wheat leaves were provided by the Key
Laboratory of Botanical Pesticide R&D in Shaanxi Province, Northwest A&F University (Yangling,
China).
Computer-aided drug design
Homology modeling of V-ATPase H subunit and identification of active sites in Mythimna
separate. Taking the known structure of the Saccharomyces cerevisiae V-ATPase H subunit as a template,
the 3D structural modeling of the Mythimna separate V-ATPase H subunit was carried out by the
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Acrylrys Discovery Studio (DS) software “Homology Modeling” module. Then, the rationality and
credibility of the 3D structure of V-ATPase H subunit of M. separate were evaluated by using Procheck
software of the NIH MBI Laboratory. According to the possible active sites defined by the protein cavity,
the DS-software was used to molecularly dock the celangulin to the active site to determine the possible
binding sites of the celangulin V.
Virtual screening of V-ATPase H subunit inhibitors. Virtual screening of V-ATPase H subunit
inhibitors was carried out by using “LibDock” module of Discovery Studio software. The protein was
prepared by using the "Prepare Protein" module, and the “LibDock” module was used to dock with the
ligand optimized in the Specs database. The top 2 docking compounds were purchased from the Specs
database and used as lead compounds for insecticidal activity evaluation.
Chemical synthesis
General procedure for compound A and C. A 100 mL oven-dried round-bottomed flask was
charged with substituted phenol (23 mmol), solvent, halogenated hydrocarbon (48.6 mmol) and
carbonate (47 mmol). The resulting solution was stirred under reflux for 4 h until no change was observed
by TLC. After evaporating the filtrate under reduced pressure, the crude product can be put into the next
reaction without further purification.
General procedure for compound B. To a solution of compound A (4 mmol, 1.0 g) in anhydrous
CH2Cl2 (30 mL) was added chlorosulfonic acid (12 mmol, 1.53 g) slowly under ice-cooling. The mixture
was then stirred at reflux for 2 hours. After the completion of the reaction, the mixture was poured into
ice water, extracted twice with water, combined with the organic phase, and dried over anhydrous
Na2SO4. The crude mixture was purified by flash column chromatography to provide 80% yield of
compound B.
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General procedure for compounds D. A round bottom flask was added with compound C (4.3
mmol), 10 drops of DMF and excess of SOCl2, then refluxed for 4 h. After the reaction was completed,
the SOCl2 was distilled off and re-dissolved in DCM.
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General procedure for compounds 1a-g, 5a-h and 6a-h. Mixed compound B/D (4 mmol) was
dissolved in anhydrous CH2Cl2 (20 mL) with fatty amine (24 mmol), DMAP (0.4 mmol), TEA (10 mL)
under ice-cooling. The reaction mixture was stirred at room temperature overnight. Then the crude
mixture was washed with H2O for three times, dried over Na2SO4, and purified by flash column
chromatography to afford the pure products (1a-h).
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General procedure for compounds 1h-k. Mixed compound B (2 mmol) was dissolved in
anhydrous CH2Cl2 (20 mL) with aniline (2 mmol), TEA (2 mmol) in anhydrous CH2Cl2 (20 mL) under
ice-cooling at room temperature for 6 h. The reaction mixture was quenched with 5% Na2CO3, washed
with H2O, dried over Na2SO4, and purified by flash column chromatography on silica to provide
compounds 1h-k.
General procedure for compounds 1l, 5i-m and 6i-m. The reaction was conducted with
compound B/D (4 mmol), piperazine (24 mmol) DMAP (0.4 mmol), and anhydrous CH2Cl2 (20 mL)
under ice-cooling at room temperature for 6 h. After completion of the reaction by TLC, the reaction was
quenched with NaHCO3, washed with H2O, dried over Na2SO4, and purified by flash column
chromatography to afford the target products.
General procedure for compounds 2a-k. Substrate 1a (1 mmol) and NaOH (1 N, 3 mL) were
combined in acetonitrile (5 mL) in a 50 mL oven-dried round-bottomed flask. The reaction was stirred
at room temperature for 1 h. Then, 10% HCl (3 mL) was added, and the reaction mixture was washed
with brine for three times, dried over Na2SO4, and concentrated onto silica gel for purification by column
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chromatography to afford the corresponding compounds 2a-k.
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General procedure for compounds 3a-l/4a-l. Compound 1a (1 mmol) was stirred in NH3 [aq] /
N2H4 [aq] (10 mL) at room temperature until no change was observed by TLC. Then the mixture was
extracted with ethyl acetate, combined with the organic phase, dried with anhydrous Na2SO4, and purified
by flash column chromatography on silica to provide pure products 3a-l/4a-l.
General procedure for compounds 5a-h and 6a-h. Amine (18 mol), TEA (6 mmol), DMAP (0.6
mmol) and DCM (50 mL) were placed in a 200 mL flask, which was cooled to 0 °C in an ice bath.
Compound D (6 mmol) was dissolved in DCM and added dropwise to the mixture at 0 °C, and stirred at
room temperature overnight. After the TLC tracking reaction was completed, the reaction was quenched
with 5% Na2CO3 aqueous solution, washed with saturated salt for three times. The product was isolated
by silica gel column chromatography to give a yellow solid.
Insecticidal activity assay
The insecticidal activities of synthetic compounds against the third instar M. separata starved for
24 h were evaluated using the leaf-dipping method. In the primary bioassay, fresh wheat leaves (5 mm ×
5 mm) were immersed in an acetone solution containing the test compound (20 mg / mL). After
volatilization of acetone, the drug-loaded leaves were placed in a 12-well cell plate for feeding healthy
and starved third-instar larvae. Each compound was treated with 36 test larvae and repeated three times.
Leaf disks treated with celangulin V and acetone served as positive and blank controls, respectively.
Then the cell plate was wrapped with a wet cloth and placed in a controlled environment with 25 °C
temperature and 70% relative humidity. Mortality rates were recorded within 24 h, and the toxicity of
the corresponding compound with a mortality of more than 50% was determined by further determination
of the median lethal dose (LC50).
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In the second bioassay, the active compound and the positive control celangulin V were formulated
into six gradient concentrations chosen such that the concentration limits correspond to a range of 10%
to 90% of mortality rate. If the selected concentration was too large or too small, the concentration
gradient was set in an equal or equal proportional sequence within a certain concentration range until the
mortality rate appeared between 10% and 90%. Finally, the LC50 was calculated using the SPSS 22.0
software.
Docking simulation
The structures of the ligands were constructed using Discovery Studio. The ligands minimized in
this way were docked in the model of the Mythimna separate V-ATPase H subunit. The docking results
were analyzed by Discovery Studio 2019 Client.
Statistical analysis
All data are expressed as means; the standard deviation (SD) values are also given, and for each
dataset, at least three independent experiments are conducted. One-way analysis of variance (ANOVA)
followed by post hoc tests using SPSS 22.0 software were used to determine the statistical significance
of difference between two groups. Values of ** (p＜0.01) were considered statistically significant.
RESULTS AND DISCUSSION
Computer-aided drug design (CADD)
By comparing the predicted amino acid sequence of Mythimna separate with the primary structure
of Saccharomyces cerevisiae V-ATPase H subunit (Figure S1), it can be seen that the amino acid
homology of the two subunits is 27%, which is slightly higher than that of the ambiguous region (25%).
Therefore, it is feasible to construct the 3D structure of Mythimna separate V-ATPase H subunit based
on Saccharomyces cerevisiae V-ATPase H subunit as template.
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Next, the 3D structural model of the V-ATPase subunit H of Mythimna separate was constructed
as shown in Figure 1a, using the 3D structure of Saccharomyces cerevisiae V-ATPase H subunit as
template. Then, 17 active sites were defined from receptor cavities, and a possible active site (site 18)
was defined according to the reported active sites of cerevisiae V-ATPase H subunit. The molecular
docking of celangulin V with 18 defined active sites was carried out using the DS software (Table S1).
According to the dissociation constant (KD value) (253.0 μM) of the tested compounds with the V-
ATPase H subunit of Mythimna separate, the correlation analysis with the predicted active sites showed
that site 17 (located in the C-terminal cavity of the H subunit) was a likely candidate binding site (Figure
S2). Moreover, the celangulin V forms various hydrogen bonds with the residues of different amino acids
at this site (Figure 1b), and the hydrogen bonding force is approximately the same as the KD value of H
subunit.
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Finally, virtually screening of V-ATPase H subunit inhibitors was carried out, and the top 2 docking
scores compounds (3h and 3i) were selected as lead compounds through docking of receptor protein-
ligand molecules (Figure 1c). Obviously, the chemical structures of the lead compounds are different
from that of Celangulin V, which may be due to these two kinds compounds acting on different sites of
the same enzyme.
Chemistry
Two virtual screened lead compounds (3h and 3i) were synthesized from p-chlorocresol in four
steps as illustrated in Scheme 2. Then, according to the structure of lead compounds, a series of novel
benzene sulfonamide derivatives were synthesized with satisfactory yields. Initially, precursor A was
obtained from 4-chloro-2-methylphenol using simple esterification. Next, compound A was sulfonated
with chlorosulfonic acid to give the corresponding compound B with good yields. Notably, excess
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chlorosulfonic acid should be added in this step because the process was divided into two stages: fast
reaction and slow reaction. Excess chlorsulfonic acid can ensure that the reaction proceeds to completion
to obtain target intermediate B with a yield of 77%. The mechanism is shown in Figure S2. Subsequent
treatment of B with different amines using DMAP and TEA as catalyst in CH2Cl2 give the corresponding
benzene sulfonamides (1a-l), which were used in a further reaction with NaOH/NH3•H2O/N2H4•H2O to
give benzene sulfonamide derivatives (2a-k/3a-l/4a-l) in good yields.
According to previous literature,31 propargyl sulfonamides demonstrate increased insecticidal
activity compared to other sulfonamides. The activity of propargyl sulfonamides are investigated. First,
taking sodium hydroxybenzenesulfonate or sodium 2-chloro-5-hydroxybenzenesulfonate as the starting
materials, introducing propargyl at their phenolic hydroxyl groups to obtain the corresponding
intermediate C. Then, the corresponding sulfonyl chloride compounds D were prepared by SOCl2
treatment and reacted with different amines under a catalytic amount of DMAP to obtain the target
compounds 5a-m and 6a-m.
The structures of intermediates and target compounds (1a-l, 2a-k, 3a-l, 4a-l, 5a-m and 6a-m) were
1
characterized using H NMR and 13C NMR. All newly synthesized compounds were purified by flash
1
column chromatography on silica and their physical characteristics, H NMR and 13C NMR data are
reported in the Supporting Information.
Insecticidal activity
The insecticidal activity of target compounds against the 3rd-instar larvae of M. separata was
evaluated by the leaf-dipping method. Celangulin V and acetone were used as positive and blank control,
respectively. As shown in Table 1, most of the compounds had no insecticidal activity against the 3rd
instar larvae of M. separate at a concentration of 20 mg/mL within 24 h, except compounds 5a, 5b, 5d,
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5h, 5m, 5j, 5g, 6a, 6b, 6d, 6e, 6m, 6k, 6j and 6g. These compounds showed good activity against test
larvae; in particular, 5a, 5h, 5m, 5g, 6b, 6m and 6g led to mortality greater than 85%. The insecticidal
activities of these seven compounds were further evaluated by the determination of their LC50 values.
As showed in Figure 2b, the LC50 values of these seven compounds were much lower than the
positive control (23.901 mg/mL), indicating that their insecticidal activities were stronger than celangulin
V. Compound 5h demonstrated the best insecticidal activity with an LC50 value of 0.293 mg/mL.
During the biological activity assay, a series of specific symptoms were observed in the tested larva
(Figure 2a). Compared with the blank control (I), the larva fed with compounds 5a-m were anaesthetized
within 10 minutes after feeding 3%-5% wheat leaves (II). The bodies of poisoned larva were rapidly
observed to become immobile and unresponsive. The test larva fed with high concentrations of
compounds 5a-m showed no signs of awakening after 24 hours. The anesthesia time would be
increasingly delayed with a decrease in concentration; in some cases, the test larva would wake up within
24 hours. Comparatively speaking, the poisoning symptoms of larva fed with compounds 6a-m were
delayed compared to those of compounds 5a-m. Symptoms of excitation and twisting convulsions
occurred within 2 h to 4 h after 20-30% feeding (IV); vomiting and tail dehydration appeared around 8
h (V); and death occurred after 24 h (VI). In addition, the symptoms of M. separata poisoning following
treatment by propargyl sulfonamides were similar to that of celangulin V, so we can infer that the
synthetic derivatives have a similar toxicological mechanism and common targets as celangulin V.
Structure−activity relationship
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The bioassay results demonstrated that the lead compounds (3h and 3i) and most of the derivatives
had no obvious poisoning effect on the 3rd-instar larvae of M. separata. Notably, the compounds 5a-m
and 6a-m obtained by further reasonable optimization have different insecticidal activities against M.
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separata. Furthermore, the presence of a chlorine atom on the benzene ring has no effect on the
insecticidal activity, while the introduction of propargyl on phenolic hydroxyl group plays a key role in
the activity. Moreover, the insecticidal activity of different amino substituents R4 was as follows: chain
group > aryl group > saturated heterocyclic substituents. The LC50 of compounds 5h (0.904 mg/mL), 5m
(0.293 mg/mL), 5g (0.471 mg/mL) and 6g (0.985 mg/mL) were significantly lower than the positive
control (29.3 mg/mL).
Docking simulation
In support of the structure-activity relationship (SAR), the representative compounds 5g, 5h and 5m
were docked with V-ATPase H subunit of M. separate. Figure 3 suggests that the compounds were
capable of forming hydrogen bonds or having Pi-Alkyl or van der Waals interactions with the H subunit.
It is possible that the H bonds formed between SO2NH and CYS282 and O and LYS283. For 5g, 5h and
5m, the propyne fragments formed Pi-Alkyl interactions with ALA278, HIS275, LYS232, and the
benzene rings formed Pi-Alkyl bonds of with ALA235, ILE236, etc. These interactions could had
provided stability for the compound to interact well with the receptor. Interestingly, the angle of
propargyl was 178.53o, which supports the induced fit theory.
In general, based on our previous studies on the insecticidal activity of extracts from celastrus, we
established two sulfonamide lead compounds by homology modeling and virtual screening with the help
of computer-aided drug design. Then the target lead compounds were obtained by four steps of
esterification, sulfonation, sulfonamidation and amidation, using p-chlorocresol as initial material.
Further, 71 novel derivatives were synthesized, and all compounds’ insecticidal activities were evaluated.
The bioassay results showed that LC50 values of the compounds 5a, 5g, 5h, 5m, 6b, 6g and 6m were
about one or two orders of magnitude lower than that of the positive control celangulin V (23.9 mg/mL),
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indicating that their insecticidal activities were stronger than that of celangulin V. These compounds are
promising new candidate insecticides. Notably, the active groups of the sulfonamides and the possible
binding mode with the receptor were verified through characterization of their structure-activity
relationship and docking simulations, which provided theoretical support for the subsequent development
of pesticides.
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NOTE
The authors declare no conflict of interest.
ACKNOWLEDGMENTS
This work was supported by grants from the National Natural Science Foundation of China
(21977083), and from the Open Fund of State Key Laboratory of Bioorganic and Natural Products
Chemistry (SKLBNPC19248), Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for Jiwen Zhang: nwzjw@nwafu.edu.cn; Tel.: +86-029-87092191
ORCID
Fangli Gang: 0000-0002-1507-2539
Jiwen Zhang: 0000-0001-6613-4077
SUPPORTING INFORMATION
Figure S1 Sequence alignment of subunit H of Saccharomyces cerevisiae and Mythimna separate. (a)
BLAST result of subunit H of Mythimna separate; (b) Sequence alignment of subunit H of
Saccharomyces cerevisiae and Mythimna separata, 1HO8 represents subunit H of Saccharomyces
cerevisiae; V-ATP represents subunit H of Mythimna separate.
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Figure S2 the correlation of docking score and KD values.
Table S1 Docking score of celangulin V and active sites
Figure S3 Mechanism of synthesis of compound B.
Characterization Data of Products
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Table 1. Insecticidal activity of the target compounds against the 3rd instar larvae of M. separata at a
concentration of 20 mg/mL within 24 h.
Mortality ±SD
(%)
Mortality ±SD
(%)
Mortality ±SD
(%)
Mortality
±SD (%)
Comp.
Comp.
Comp.
Comp.
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
2a
2b
2c
2d
2e
2f
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
2h
2i
2l
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
4d
4e
4f
4g
4h
4i
4j
4k
4l
5a
5b
5c
5d
5e
5f
5g
5h
5i
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
100 ± 1.4
41.7 ± 0.8
0.0 ± 0.0
32.4 ± 0.5
0.0 ± 0.0
0.0 ± 0.0
100 ± 0.0
100 ± 0.0
0.0 ± 0.0
7.4 ± 0.5
5k
5l
5m
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
0.0 ± 0.0
0.0 ± 0.0
100 ± 0.0
30.6 ± 0.8
100 ± 0.0
0.0 ± 0.0
9.3 ± 0.5
14.8 ± 0.5
0.0 ± 0.0
100 ± 0.0
0.0 ± 0.0
0.0 ± 0.0
46.3 ± 1.2
43.5 ± 0.9
46.3 ± 1.2
86.1 ± 0.8
0.0 ± 0.0
51.3 ± 2.1
2k
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
4a
4b
4c
6m
acetone
celangulin-V
2g
5j
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FIGURE CAPTIONS
Scheme 1. The process of creating new pesticides by computer aided drug design (CADD).
Figure 1. (a) 3D structure model of V-ATPase subunit H of Mythimna separata based on homology
modeling. (b) The interaction of celangulin V and active site 17. (c) Leading compounds (3h and 3i) in
the top 2 docking scores.
Scheme 2. Synthesis of benzene sulfonamide derivatives 1a–l, 2a-k, 3a-l, 4a-l.
Scheme 3. Synthesis of benzene sulfonamide derivatives 5a–n (R3=H, Sulfonyl group is in the para
position of ether group), 6a-n (R3=H, Sulfonyl group is in the meta position of ether group).
Figure 2. (a) Larva at various stages of poisoning: (I) blank control; (II, III) poisoned larva with
narcotized and immobile body; (IV) poisoned larva with twisted and convulsed body; (V) poisoned larva
with body dehydration; (VI) dead atrophic larvae.
Figure 3. 2D interaction diagram of 5g(a, d), 5h(b) and 5m(c) with V-ATPase H subunit of M. separate.
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Scheme 1
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Figure 1
(b)
(a)
(c)
H
N
Cl
O
O
S
O
O
NH2
3h
H
Cl
O
O
S
N
O
O
O
NH2
3i
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Scheme 2
O
S
Cl
R1
Cl
O
O
S
Cl
Cl
Cl
Cl
O
R1
O
S
O
NaOH, H2O, MeCN
or N2H4
ClSO3H
DCM
BrCOOC2H5
K2CO3, KI, Me2CO
R1-H
R2
O
O
B
O
O
O
H2O,EtOH
TEA, DCM
OH/NH2/NHNH2
OH
O
O
O
O
O
or NH3
O
H2O
2
2a-k
3a-l
4a-l
, R =H
2
A
, R =CH3
1a-l
2
, R =CH3
H
N
H
N
H
N
H
N
H
N
R1
=
N
N
g
f
a
c
b
d
e
H
N
H
N
H
N
H
N
N
O
N
j
h
i
l
k
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Scheme 3
R3
R3
O
R3
SO3Na
O
S
R4
R3
SO3Na
Cl
S
R3-H
Br
O
O
DMF
SOCl2
TEA, DMAP
Na2CO3, CH3OH
O
O
O
OH
3
5a-m
6a-m
, R =H
C
D
3
, R =Cl
H
N
H
N
H
N
H
N
H
N
R3 =
N
O
F
F
a
f
c
d
b
e
N
NH
O
NH
N
N
HN
HN
N
N
j
m
k
g
h
i
l
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Figure 2
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Figure 3
(b)
(a)
(c)
(d)
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TOC graphic
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