Thioether-bridged arylalkyl-linked N-phenylpyrazole derivatives: Design, synthesis, insecticidal activities, structure-activity relationship and molecular-modeling studies

Article abstract of DOI:10.1016/j.bmcl.2018.04.022

Owing to thioether diverse physicochemical properties by non-covalent interactions with bio-macromolecules, thioether derivatives containing heterocyclic moiety are known for their interesting insecticidal bioactivities and attracting considerable attenti

Full text of DOI:10.1016/j.bmcl.2018.04.022

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Thioether-bridged arylalkyl-linked N-phenylpyrazole derivatives:
Design, synthesis, insecticidal activities, structure-activity relationship
and molecular-modeling studies
a
a
⇑
Chengcheng Fei , Yanfei Chen , Zhiyan Jiang, Dingxin Jiang
Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou 510642, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Owing to thioether diverse physicochemical properties by non-covalent interactions with bio-macro-
molecules, thioether derivatives containing heterocyclic moiety are known for their interesting insectici-
dal bioactivities and attracting considerable attention as neuroactive insecticides. Here we synthesis a
series of novel thioether bridged N-phenylpyrazole derivatives incorporating various (hetero)aromatic
substituents into 4-position of the pyrazole ring. Structure-activity relationship (SAR) studies resulted
in compounds 6d and 7d with the most potent insecticidal activity among the series containing various
substituted benzene substituents (LC50 = 13.70–25.47 lg/g). Further optimization to increase the
lipophilicity and charge density of aromatic substituents of compounds 6d and 7d resulted in compounds
12d, 14d and 16d with sulfur-containing heterocycle substituents possessing good insecticidal activity
against Musca domestica L. among the series (LC50 = 0.67–1.30 lg/g). The thioether bridge N-phenylpyra-
zole derivatives, which exhibit different length of the spacer arm introduced between N-phenylpyrazole
moiety and the (hetero)aromatic substituents, were also prepared and evaluated. By contrast, the insec-
ticidal activities of compounds containing the short thioether bridge, 1,2-bis((hetero)aromatic thio)
ethane, are higher than that containing the long thioether bridge, 1,3-bis((hetero)aromatic thio) propane.
The results of molecular docking and pharmacophore analyses indicated A299, T303, and L306 of a sub-
unit were essential to form non-covalent interactions contacts with the ligands. Specially, the sulfur-con-
taining heterocycle substituent derivatives 12d and 14d as the sterically favored areas could form the
important hydrophobic interactions with the deeper residue P295.
Received 9 December 2017
Revised 4 April 2018
Accepted 11 April 2018
Available online xxxx
Keywords:
N-Phenylpyrazole derivatives
Thioether bridge
Insecticidal activities
Structure-activity relationship
Molecular-modeling studies
Ó 2018 Elsevier Ltd. All rights reserved.
N-Phenylpyrazole moiety has been shown to bestow biological
activity, including insecticidal, miticidal, and herbicidal activity.1
More specifically, N-phenylpyrazoles with a cyano or acetyl groups
on 3-position, a sulfenyl, sulfinyl, thioalkyl, alkyl, acyl, alkynyl or
cyano groups on 4-position, and an amino (or substituted amino)
on 5-position of the pyrazole ring exhibit potent insecticidal activ-
ity.2–6 Fipronil, an N-phenylpyrazole insecticide with a trifluo-
romethylsulfinyl substituent at 4-position, has attracted
particular attention of researchers due to their more favorable
selective toxicity in invertebrates relative to mammals.7 The selec-
tive toxicity of fipronil is due in part to differ in binding between
insect and mammalian GABA receptors8, but is also dependent
on the relative rates of conversion to the less selective sulfone
fipronil metabolite at 4-positon of the pyrazole ring.9 The change
in single substituent, i.e., thioalkyl vs sulfinyl (Fig. 1), alters the
lipophilicity and electronic properties and potentially also the pho-
tochemical and metabolic fate, effectiveness, and toxicology.10 For
example, high insecticidal activity and selective toxicity, low mam-
malian toxicity of N-phenylpyrazole insecticides was observed
such as vaniliprole (Fig. 1A), pyrafluprole (Fig. 1B) and pyriprole
(Fig. 1C) with 4-SCF3, 4-SCH2F and 4-SCF2H instead of 4-SOCF3 at
4-position of the pyrazole ring. However, fipronil with a trifluo-
romethylsulfinyl moiety probably exists in the cyclic hydrogen-
bonded form allowing interaction of the sulfinyl and amino moi-
eties, and may be the first step in extrusion of SO from fipronil to
give higher toxic and persistent desulfinylfipronil, then lead to
more toxic and persistent detrifluoromethylsulfinyl product than
parent fipronil by photolysis reactions.9 But the sulfide analogs of
fipronil at 4-position of the pyrazole ring are much more stable
and do not undergo an analogous photoextrusion reaction.11 In
addition, the sulfur-aromatic interaction is often described as
improving the stability for modulation of protein interactions12,13
⇑
Corresponding author.
E-mail address: dxj2005@scau.edu.cn (D. Jiang).
a
The authors contributed equally to the work.
https://doi.org/10.1016/j.bmcl.2018.04.022
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fei C., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.04.022

2
C. Fei et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
ꢀ ꢀ
ꢀ ꢀ
ꢀ ꢀ
ꢀ
fipronil
Vaniliprole (A)
pyrafluprole (B)
pyriprole (C)
Fig. 1. Structure of thioalkyl fipronil derivatives.
and one-third of all known protein structures contain an energet-
ically stabilizing methionine-aromatic motif.14 Considering fipronil
(trifluoromethylsulfinyl phenylpyrazole) have higher insecticidal
activity than sulfone fipronil (trifluoromethylsulfonyl phenylpyra-
zole)15 and intramolecular thioether-bridge formation is an effec-
tive way to protect compound against mixed function oxidases
degradation in vivo, we speculated that thioalkyl fipronil deriva-
tives may be increasing frequency near aromatic side-chains of
add a spacer linker between the N-phenylpyrazole moiety and
thiophenol/aromatic thiol. The structure notably included
phenylpyrazole ring connected to the aromatic moiety via two
thioether bond. Using the cleavage of S–S bond chemical reaction
by intermediates 1a–29a, the target fipronil derivatives were syn-
thesized easily and quickly in good yields.
The structures of the synthetic compounds were confirmed by
melting points, 1H NMR, 13C NMR and the structures of the title
compounds 1d–29d were confirmed by HRMS spectroscopic data
additionally.
a
c-aminobutyric acid receptor proteins and altering bioavailability
of drugs due to ligand(drug)-proteins interaction, and then
improved insecticidal activity.
The preliminary insecticidal activities of compounds 1d–29d
were assessed against Musca domestica L. by the artificial diet dip-
ping methods as the final mortality rates at 20 lg/g and fipronil as
Meanwhile, after decades of intensive use, many target pests
have developed higher resistance to fipronil, and owing in part to
its high toxicity to beneficial organisms16,17, fipronil was greatly
limited to be used as a pesticide in China since 2009 and the Euro-
pean Union followed suit in 2013.18 To reduce resistance and tox-
icological risk, we developed several fipronil derivatives by
modifying the amino group at 3-position of the pyrazole ring with
salicylide, substituted phenoxyacetyl, amino acid and inner salt
groups.19–24
Inspired by these reports, herein we report a series of fipronil
derivatives containing an arylalkyl thioether moiety at 4-position
of the pyrazole ring (Scheme 1). In addition, the binding site of
meta-diamides was demonstrated to be distinct from that of con-
ventional noncompetitive antagonists such as fipronil. Thus, it is
expected to become a prominent insecticide against pests with
resistance to cyclodienes and fipronil.25,26 So, different modes of
actions of novel fipronil derivatives containing an arylalkyl
thioether moiety at 4-position of the pyrazole ring may have
appeared and it is expected to be effective against resistant pest
insects.
positive controls. The mortalities of Musca domestica L. were shown
in Tables 1 and 2. Among all the tested compounds, compounds
12d, 13d, 14d, 16d and fipronil showed potent insecticidal activity
(96.67%–100%); compounds c, 2d, 3d, 6d, 7d and 29d showed mod-
erate insecticidal activity (40.00%–53.33%). Insecticidal activities of
other compounds were very low (<36.67%).
To gain further insight into potent toxicity of these compounds,
fipronil and the ten compounds 2d, 3d, 6d, 7d, 12d, 13d, 14d, 16d,
29d and c were investigated further at serial concentration gradi-
ent to determine their LC50s (Table 3). The bioactivities of com-
pounds 12d, 14d and 16d being equipotent to fipronil against
Musca domestica L. The LC50 values of fipronil and compounds
12d, 14d and 16d were 0.68, 0.67, 0.90 and 1.30
Comparable to fipronil, compound 13d dramatically reduced the
insecticidal activity (LC50 = 6.00 g/g). Compounds 2d, 3d, 6d, 7d,
29d and c displayed inferior activity as well, their LC50s were
22.79, 22.47, 13.70, 25.47, 22.00 and 19.07 g/g, respectively.
lg/g, respectively.
l
l
Initially, in order to find the optimal aromatic substitution, a
series of thioether N-phenylpyrazole derivatives substituted with
naphthalene, 2-methoxybenzene, 4-methoxybenzene, 2-fluo-
robenzene, 4-fluorobenzene, 2-chlorobenzene, 4-chlorobenzene,
2-bromobenzene, 4-bromobenzene were prepared and evaluated.
Insecticidal activity data showed that derivatives containing the
short thioether bridge, 1,2-bis((hetero)aromatic thio) ethane, far
better than that of the long thioether bridge, 1,3-bis((hetero)aro-
matic thio) propane (4d–11d vs 19d–26d). In particular, fluoro
substituted benzene derivatives 6d and 7d possessed the most
The bioactivities of the target compounds were evaluated, the
structure-activity relationships and molecular docking studies of
these compounds are shown in this paper.
The target thioalkyl fipronil derivatives were prepared from 5-
amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole
(b) as shown in Scheme 1. The thiophenol or aromatic thiol was
reacted with dibromoalkane in the presence of potassium carbon-
ate and potassium iodide to afford the intermediates 1a–29a. In
addition, 1H-benzo[d]imidazole-2-thiol, 2-methoxybenzenethiol,
1H-1,2,4-triazole-3-thiol, thiazole-2-thiol and 1,3-dibromo-
propane; 4-methoxybenzenethiol and 1,2-dibromoethane were
also tried but failed to give target products under similar condi-
tions. We have tried to react with a more laborious reaction path-
way, unfortunately the reaction was unsuccessful due to the
complex formation between substrate and the catalyst. Compound
b was converted to the key intermediate, bis(5-amino-3-cyano-1-
(2,6-dichloro-4-trifluoromethylphenyl)pyrazol-4-yl) disulfide (c),
according to the reported method.3 The cleavage of disulfide c by
intermediates 1a–29a assisted with an alkali and a reducing
reagent afforded the target thioalkyl fipronil derivatives 1d–29d.15
According to experimental result, the aromatic halides such as
phenyl bromide could not react with pyrazolyl disulfide.15 We
potent bioactivities, with the LC50s of 13.70 lg/g and 25.47 lg/g,
respectively. Inspired by the potent activity possessed by the fluoro
substituted benzene derivatives, further research on heteroaro-
matic motif with strong lipophilicity and charge density were car-
ried out.
Based on a rationally conceived pharmacophore model to
increase the lipophilicity and charge density of aromatic sub-
stituents, nitrogen, oxygen, sulfur-containing heterocycle sub-
stituents were introduced to explore the SAR (Tables 2 and 3).
The target compounds of nitrogen, oxygen-containing heterocycle
substituents (except compound 13d) showed much less potency
compared to fipronil against Musca domestica L. The target com-
pounds of sulfur-containing heterocycle substituents displayed
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C. Fei et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
R=
Scheme 1. Synthesis of derivatives 1d–29d. Reagents and conditions: (i) Br(CH2)nBr, K2CO3, KI, acetone, rt, 5 h; (ii) S2Cl2, CH2Cl2, 0 °C-rt, 2 h; (iii) Na2HPO4, Na2S2O4, DMF,
H2O, rt, 3 h.
enhanced insecticidal activity. Compounds 12d, 14d and 16d were
the most active compounds in this series, being equipotent to
fipronil. However, compound 2d containing sulfur-heterocycle
substituent was much less active, but compound 13d containing
Table 1
24-h effect of N-phenylpyrazole derivatives containing
various substituted benzene substituents against Musca
domestica L.
Table 2
Compound
Mortality (%)*
24-h effect of N-phenylpyrazole derivatives containing
heteroaromatic substituents against Musca domestica L.
4d
5d
6d
7d
8d
9d
10d
11d
19d
20d
21d
22d
23d
24d
25d
26d
c
36.67 1.20 d**
33.33 0.33 d
43.33 0.88 c
43.33 0.67 c
6.67 0.33 f
33.33 0.67 d
26.67 1.20 e
36.67 0.33 d
3.33 0.33 g
0.00 0.00 e
3.33 0.33
3.33 0.33 g
6.67 0.67 f
6.67 0.67 f
0.00 0.00 e
0.00 0.00 e
53.33 0.88 b
100.00 0.00 a
0.00 0.00 e
Compound
Mortality (%)*
1d
2d
3d
4d
36.67 0.33 d**
40.00 1.00 c
46.67 0.88 b
36.67 1.20 d
100.00 0.00 a
100.00 0.00 a
96.67 0.33 a
33.33 0.67 e
100.00 0.00 a
3.33 0.33 h
10.00 0.00 g
30.00 2.08 e
20.00 0.58 f
46.67 0.67 b
100.00 0.00 a
0.00 0.00 i
12d
13d
14d
15d
16d
17d
18d
27d
28d
29d
Fipronil
ck
Fipronil
ck
*
*
Test concentration is 20 lg/g.
Data followed by the same letter in a column are
Test concentration is 20 lg/g.
Data followed by the same letter in a column are
**
**
not significantly different at 5% level by DMRT.
not significantly different at 5% level by DMRT.
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C. Fei et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Table 3
The LC50 of thioether bridged N-phenylpyrazole derivatives against Musca domestica L. after 24-h.
*
Compound
Linear regression equation (y = a + bx)
Correlation coefficient (r)
LC50
(l
g/g)
95% CI**
(lg/g)
2d
3d
6d
7d
12d
13d
14d
16d
29d
c
y = 1.2431 + 2.7672x
y = 2.3534 + 1.9581x
y = 3.5069 + 1.3135x
y = 1.3087 + 2.6253 x
y = 5.3067 + 1.7778 x
y = 2.3026 + 3.4669 x
y = 5.0747 + 1.7078 x
y = 4.7396 + 2.2676 x
y = 1.2850 + 2.7672 x
y = 1.1000 + 3.0461 x
y = 5.2932 + 1.7501 x
0.9997
0.9913
0.9930
0.9988
0.9880
0.9994
0.9990
0.9941
0.9940
0.9930
0.9945
22.79
22.47
13.70
25.47
0.67
6.00
0.90
1.30
18.32–25.17
15.48–32.63
8.03–23.37
14.62–44.39
0.24–1.88
4.51–7.98
0.40–2.06
0.83–2.05
22.00
19.07
0.68
13.89–34.97
13.23–27.48
0.48–0.97
Fipronil
*
LC50: concentration required to kill 50%.
CI: confidence interval.
**
nitrogen-heterocycle substituent showed good insecticidal
activity.
Similar trends were observed with the thioether N-phenylpyra-
zole derivatives of aromatic substituents (Tables 2 and 3). In gen-
eral, the N-phenylpyrazole derivatives of sulfur-containing
heterocycle substituents containing the short thioether bridge dis-
played excellently insecticidal activity (Tables 2 and 3). In particu-
lar, compounds 12d, 14d and 16d bearing a thiophene, 5-methyl-
1,3,4-thiadiazole, thiazole substituent respectively, were equiva-
lent to or better than that of fipronil against Musca domestica L.
Compound 12d and 14d containing the short thioether bridge,
bearing a thiophene and 5-methyl-1,3,4-thiadiazole substituent
respectively, showed a 2- to 3-fold higher activity compared to
its long thioether bridge derivatives (12d vs 27d; 14d vs 29d). As
a similar result, compound 13d containing the short thioether
bridge showed a 5-fold higher activity compared to compound
28d containing long thioether bridge derivative.
To understand the interaction between compound 12d, 14d and
the amino acid residues in the acting sites of M. domestica GABA
receptor, ligand-docking studies were performed using an M.
domestica GABA receptor homology model. The model was built
using the X-ray crystal structure of pentameric ligand-gated ion
channel of Gloeobacter violaceus as a template. The M. domestica
sequence similarity in M1-4 regions aligned with Gloeobacter vio-
laceus was 44.1%. Compound 12d, 14d and fipronil were docked
into the pore formed by M2s with the predicted closed conforma-
tion model (Fig. 2). Compounds docked with the inter-subunit cav-
ity of M. domestica GABA receptor homology model in the closed
conformation with the best scores (Fig. 3), indicating compounds
potentially fit to the inter-subunit cavity.27 Thus, these are possible
to hypothesize that it would bind and stabilize a closed state of the
receptor.
Fig. 2. Top view of the homology model of Musca domestica GABA receptor subunit
homomer in closed state without the N-terminal and C-terminal extracellular
domains.
The results showed that compound 12d, 14d and fipronil are
well embedded in the binding site. Compound 12d, 14d and fipro-
nil are capable of non-covalent interactions with residues A299,
T303, and L306, which are equivalent to A302, T306 and L309 in
Drosophila GABA receptor subunit repectively25, to stabilize the
complexes (Fig. 4A–C). The newly introduced thioether moiety
and sulfur-containing heterocycles of compound 12d and 14d
would be extend and form hydrophobic interactions with the dee-
per residue P295 (Fig. 4B and C).
When the length of the spacer arm introduced between N-
phenylpyrazole moiety and the (hetero)aromatic substituents
equal to two carbons could form a new hydrophobic interaction
between sulfur-containing heterocycles and the residue P295.
However, the length of the spacer arm more than two carbons,
the hydrophobic interaction would disappear. At this point, it
could be convinced by the docking results of fipronil, compounds
12d and 14d (Fig. 4A–C). The docking mode of compound 12d
Fig. 3. Three superimposed best scoring docking poses for compound 12d, 14d and
the control fipronil in the internal pocket as a green, yellow and red carbon stick
model, respectively.
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C. Fei et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
Fig. 4. Binding modes of Musca domestica M2 regions in complex with fipronil (A), 12d (B) and 14d (C) as a red, green, and yellow carbon stick model respectively. The closed
conformation are rendered as red ribbon models. The amino acid residues interacted with compound are shown as ball and stick models, and the non-covalent interactions
are presented as the dashed line.
exhibited the lowest CDOCKER energy of 1.95435 kcal molÀ1
Meanwhile, compare with fipronil (3.10111 kcal molÀ1), com-
pound 14d displayed the CDOCKER energy of 10.7804 kcal molÀ1
.
(2016A020210082), the Science and Technology Planning Project
of Guangzhou (201607010181), and the Science and Technology
Program of Zhongshan, China (2016F2FC0016).
.
According to Fig. 3, compound 12d and 14d were still located in
the vicinity of the residue P295. The hydrophobic interaction with
P295 might be the main reason for the high activity of compound
12d and 14d (Fig. 4B and C).
A. Supplementary data
Supplementary data (synthetic procedure, 1H and 13C NMR,
HRMS spectra and biological assay method and molecular docking
scheme) associated with this article can be found, in the online ver-
sion, at https://doi.org/10.1016/j.bmcl.2018.04.022.
In summary, a series of novel thioether N-phenylpyrazole
derivatives incorporating various (hetero)aromatic substituents
into 4-position of the pyrazole ring have been reported. SAR stud-
ies have shown that the insecticidal activity of thioether N-
phenylpyrazole derivatives substituted with heteroaromatic sub-
stituents into 4-position of the pyrazole ring was higher than that
of various substituted benzene substituents, and containing the
short thioether bridge, 1,2-bis((hetero)aromatic thio) ethane, far
better than that of the long thioether bridge, 1,3-bis((hetero)aro-
matic thio) propane against Musca domestica L. Molecular docking
analyses allowed us to speculate the binding mechanism of
thioether-bridged arylalkyl-linked N-phenylpyrazole derivatives
and the sulfur-containing heterocycle substituents of the ligands
were the sterically favored areas, which mainly formed hydropho-
bic interactions with the residue P295. Among the derivatives pre-
pared, thioether N-phenylpyrazole derivatives substituted with
sulfur-containing heterocycle substituents into 4-position of the
pyrazole ring leads to excellent insecticidal activity. This indicates
that further investigation is need to improve the lipophilicity and
charge density of the heteroaromatic substituents into 4-position
of the pyrazole ring. The discovery of compound 12d and the
SAR and the insecticidal activity studies reported here will provide
insight into further optimization of thioether N-phenylpyrazole
derivatives for the prevention and treatment of hygienic and agri-
cultural pest insect.
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