Bioorganic
&
Medicinal
Chemistry
Letters
Synthesis and insecticidal activity in vitro and vivo of novel benzenesulfonyl
derivatives based on potent target subunit H of V-ATPase
Chaofu Yang a, #, Xiaoting Li a, #, Jielu Wei a, Feng Zhu a, Fangli Gang a, Shaopeng Wei b, Yunlong Zhao a,
Jiwen Zhang a, b*, Wenjun Wu b*
a College of Chemistry & Pharmacy, Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling 712100, Shaanxi,
People’s Republic of China
b Key Laboratory of Botanical Pesticide R&D in Shaanxi Province, Northwest A&F University, Yangling 712100, Shaanxi, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Two lead compounds with benzenesulfonamide were found through virtual screening based on
the 3D structure of the subunit H of V-ATPase in previous study. 74 benzenesulfonyl derivatives
were synthesized and their insecticidal activities were evaluated. The derivatives with propargyl
substituents exhibit excellent insecticidal activities against Mythimna separata Walker. The
LD50 values of compounds A5.7 (28.0μg.g-1) and B5.7 (36.4 μg.g-1) were significantly less than
that of Celangulin V (344.0 μg.g-1). Furthermore, Isothermal Titration Calorimetry (ITC) data
indicate there is a strong binding affinity between A5.7 and V-ATPase Subunit H. These results
demonstrate that it is a practical way to develop pesticides targeting at H subunit of V-ATPase.
Revised
Accepted
Available online
Keywords:
Subunit H of V-ATPase
Benzenesulfonyl derivatives
Insecticidal activities
Isothermal titration calorimetry
© 2018 Elsevier Ltd. All rights reserved.
Currently, 10-16% of global crop production is consumed by
pests, such as insects, fungi, bacteria.1 The more resistant the
pests are, the more urgent the need to find new pesticides.
Natural products are one of the most important sources to
generate pesticides with high-level insecticidal activity. They are
lead compounds and probes to find new targets. Based on the
target structures of lead compounds, many pesticides were
synthesized, including nicotine and scytalone dehydratase
inhibitors.2 Our laboratory has an ongoing research program
focused on Celastrus angulatus Maxim against insects. The β-
dihydroagarofuran derivatives with excellent insecticidal activity
have been isolated, determined, synthesized and biologically
evaluated.3-6 In particular, Celangulin V (1, Figure 1) is the
representative β-dihydroagarofurananalog and demonstrates
outstanding insecticidal activity. It is considered to act on the
vacuolar H+ -ATPase (V-ATPase) of the M. separata midgut
after oral administration.7 V-ATPase is a proton pump associated
with ATP transporters and provides energy for organelles and
membranes and present in almost all eukaryotic cells. 1 The V-
ATPase is made up of two complexes, the V0 and V1 complexe.8
The subunit H of V-ATPase is seated at V1 complex near the
interface between the V1 and V0 complex and has been proved to
silence ATP hydrolysis by free V1 through linking the stator and
rotary domains.9 In the previous work of our group, the subunit H
of V-ATPase of M. separate was purified and determined as
1807 bp full length which was similar to subunit H of yeast’s V-
ATPase.10
Applications of specific interactions between biological
macromolecules and their ligands are especially important in
drug discovery and development. Based on these interactions,
virtual screening techniques can facilitate the discovery of drug
candidates by discerning promising lead compounds and
reducing the number of experiments.11 Now application of
receptor-based rational drug design in agriculture has become an
important research field. 12-16 The subunit H model of V-ATPase
of M. separata (2, Figure 1) was set up based on known structure
of H subunit of yeast’s V-ATPase(1HO8).17With Diseovery
Studio software, active sites were defined and identified. Specs
data are virtually screened using homology model and molecular
docking of the subunit H of V-ATPase of M. separata.
Compounds 1 and 2 (3 and 4, Figure 1) with high scores
exhibited significant stomach poisoning activity against M.
separata with a series of symptoms, such as excitement,
convulsions and body fluids loss, which is similar to Celangulin
V (Detail in supplementary data). To investigate the effects of
substituents of benzene ring and amino groups of sulfonamide of
these two lead compounds on the insecticidal activity, we
synthesized 74 benzene sulfonamide derivatives, and
systematically evaluated their insecticidal activity against M.
separata.
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* Corresponding author. fax: +86-029-87093987; e-mail:
nwzjw@nwsuaf.edu.cn; wuwenjun@nwsuaf.edu.cn
# These two authors contribute equally to this work.
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