Synthesis, insecticidal activities, and SAR studies of novel piperazine-containing heterocyclic mono-/di-/tri-amide derivatives

Article abstract of DOI:10.1016/j.cclet.2021.02.002

Diamide compounds such as chlorantraniliprole, a famous anthranilic diamide insecticide targeting the insect ryanodine receptor (RyR), have received continuous attention in pesticide research during the past 15 years owing to their excellent insecticidal potentials. With the aim of discovering new heterocyclic pesticides used for crop protection, based on the structural information of compound M from the reported pharmacophore-based virtual screening for RyR insecticides and diamide compound, a series of new heterocyclic mono-, di-, and tri-amide derivatives containing piperazine moiety have been synthesized in this paper. The new compounds were identified and confirmed by melting point, ¹H NMR, ¹³C NMR and HRMS. Compound M was firstly validated for insecticidal activities, and the new synthesized compounds were all made comprehensive insecticidal evaluations against diamondback moth and oriental armyworm. The bioassay results showed that some of the compounds exhibit favorable insecticidal potentials, particularly some novel piperazine-containing heterocyclic mono-/di-/tri-amide derivatives such as 8g, 14a, 15a, 15g, 15i, 15j, 15k, 15l, and 15m could be used as new insecticidal leading structures for further study (e.g., towards diamondback moth, 15i-15m LC₅₀: 0.0022?0.0081 mg/L). The structure-activity relationships of the compounds discussed in detail provide useful guidance for further design and development of new insecticides.

Full text of DOI:10.1016/j.cclet.2021.02.002

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CCLET-6131; No. of Pages 6
Chinese Chemical Letters xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Synthesis, insecticidal activities, and SAR studies of novel
piperazine-containing heterocyclic mono-/di-/tri-amide derivatives
*
Huan Li, Hang Liu, Yan Zhang, Na Yang, Lixia Xiong, Zhengming Li, Baolei Wang
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Diamide compounds such as chlorantraniliprole, a famous anthranilic diamide insecticide targeting the
insect ryanodine receptor (RyR), have received continuous attention in pesticide research during the
past 15 years owing to their excellent insecticidal potentials. With the aim of discovering new
heterocyclic pesticides used for crop protection, based on the structural information of compound M
from the reported pharmacophore-based virtual screening for RyR insecticides and diamide compound,
a series of new heterocyclic mono-, di-, and tri-amide derivatives containing piperazine moiety have
been synthesized in this paper. The new compounds were identified and confirmed by melting point, 1H
NMR, 13C NMR and HRMS. Compound M was firstly validated for insecticidal activities, and the new
synthesized compounds were all made comprehensive insecticidal evaluations against diamondback
moth and oriental armyworm. The bioassay results showed that some of the compounds exhibit
favorable insecticidal potentials, particularly some novel piperazine-containing heterocyclic mono-/di-/
tri-amide derivatives such as 8g, 14a, 15a, 15g, 15i, 15j, 15k, 15l, and 15m could be used as new
Received 18 November 2020
Received in revised form 21 December 2020
Accepted 1 February 2021
Available online xxx
Keywords:
Heterocyclic amide derivatives
Piperazine-containing compounds
Synthesis
Insecticidal activity
Structure-activity relationship
insecticidal leading structures for further study (e.g., towards diamondback moth, 15i-15m LC50
:
0.0022ꢀ0.0081 mg/L). The structure-activity relationships of the compounds discussed in detail provide
useful guidance for further design and development of new insecticides.
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Pesticides, particularly organosynthetic pesticides play a very
important role in crop protection and ultimately bring numerous
benefits to our life. Among the commercial organosynthetic
pesticides produced in the last twenty years, there are about
70% structures of them containing the heterocyclic characteristics,
which may be owing to the versatile physicochemical and
biological properties of heterocyclic compounds [1– 3]. Therefore,
all kinds of new synthesized structures with different heterocycles
are rich potential resources for the discovery and development of
novel pesticides.
It is well known in pesticide chemistry area that the ryanodine
receptor (RyR) has become one of the most attractive targets for
the discovery of novel insecticides since the natural ryanodine was
found have high insecticidal activity [4]. In the past 15 years, some
new insecticides targeting at RyR have been successfully devel-
oped and marketed. As representatives of these insecticides,
flubendiamide (discovered by Nippon Kayaku Co., Ltd., Fig. 1),
chlorantraniliprole and cyantraniliprole (discovered by DuPont,
Fig. 1) show potent and selective activating effect towards insect
RyR, and possess exceptional activities upon a broad range of
Lepidoptera, Diptera, Isoptera, and Coleoptera insects [5– 7].
However, due to the overuse or misuse of these insecticides,
resistance issue has been developed in some pests, such as Tuta
absoluta, Plutellidae Plutella, and Spodoptera exigua [8– 10].
Therefore, there is an urgent need to develop new insecticides
to address the resistance and safety issues associated with this
kind of insecticides. From the viewpoint of molecular structures of
them, there are two amide bonds being composed of two carbonyl
groups and two active NH groups that may have essential H-bond
receptor and/or donor functions, especially there are pyridine and
pyrazole heterocyclic motifs both in chlorantraniliprole and
cyantraniliprole. Furthermore, cyclaniliprole, another recently
developed insecticide by Ishihara Sangyo Kaisha (Fig. 1) [11], also
has such two amide bonds and heterocyclic features.
Since the discovery of RyR insecticides, structural modifications
related to them have received considerable attention. Although a
variety of new compounds have been designed and synthesized
based on their structures during the past 15 years, most of the
synthesized compounds with favorable insecticidal activities still
have such main diamide structural features [12]. Recently, Sindhu
et al. carried out the pharmacophore-based virtual screening
study to identify potential insect RyR modulators; as a result, five
*
Corresponding author.
E-mail address: nkwbl@nankai.edu.cn (B. Wang).
https://doi.org/10.1016/j.cclet.2021.02.002
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: H. Li, H. Liu, Y. Zhang et al., Synthesis, insecticidal activities, and SAR studies of novel piperazine-containing
heterocyclic mono-/di-/tri-amide derivatives, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2021.02.002

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Fig. 1. Commercial diamide insecticides.
top-ranked compounds, code-named as ChemBridge_9217967,
ChemBridge_7904959, ChemBridge_5913730, ChemBridge_7903714,
and ChemBridge_6652261 (chemical structures shown in Supporting
information), were obtained from a virtual screening of ChemBridge
chemical database which contains 5,20,000 compounds using the
pharmacophore model they developed [13]. Although Sindhu et al. did
not report the further insecticidal bioassay for those “hit”
compounds, that is, the experimental validation of their computa-
tional model and results [13], those hit structure information have
alreadyprovidedpotentialresourceforthedesignanddevelopment
of new insecticides. Inspired by this, one heterocyclic compound
among the fives – (4-(4-chloro-2-nitrophenyl)piperazin-1-yl)(5-
methyl-2-phenylfuran-3-yl)methanone (ChemBridge_7903714)
(compound M in Fig. 2) raised our interest in viewing of its special
skeletonoffuranoylpiperazineandrelativelyconvenientprocedure
for synthesis, and was selected to carry out the synthesis and
bioactivity investigations of itself and some derivative new
compounds based on its structural motifs in this paper. In addition,
there are also other two reasons that compound M was considered
as a structural precursor in this research. For one thing this
compound is quite different in structure from the diamide RyR
insecticides available, which would lead to new findings for RyR
modulator research; for another, piperazine-containing com-
pounds deserve being studied and developed for insecticidal agents
since they are relatively rarely reported in the field of pesticides
(especially insecticides), in spite of their wide applications in
pharmaceutical area such as antifungal [14], anticancer [15],
antituberculous [16], and antimicrobial [17] agents.
other groups including alkyl, substitutedphenyl, and pyrimidyl
groups. Furthermore, in view of the heterocyclic amide structure
of the anthranilic diamide insecticide, e.g. chlorantraniliprole,
some new piperazine-containing compounds (series of 14 and 15)
were designed by means of introducing various substitutedpiper-
azine moiety into the skeleton of pyridylpyrazole amide and
synthesized for insecticidal activity evaluation. In addition, the
anthranilamide moiety of chlorantraniliprole structure was also
taken into account for the structure-activity relationship (SAR)
exploration; a combination of it with the phenylfuran acyl motif (a
partial group of compound M) could lead to new compound 16
(Fig. 2). Based on these strategies, in this study a series of new
heterocyclic mono-, or di-, or tri- amide derivatives containing
piperazine moiety mentioned above have been obtained under
different reaction conditions, by taking into account of the
structures of compound M along with that of RyR insecticide
chlorantraniliprole. The insecticidal activities of the synthesized
compounds were evaluated on diamondback moth and oriental
armyworm and the SAR were also analyzed in detail.
Due to space constraints, the specific synthetic procedures of
the intermediates and title compounds were included in the
Supporting information. As shown in Scheme 1, compound 1-(4-
chloro-2-nitrophenyl)piperazine (intermediate 2) was successfully
prepared in 41.2% yield from a nucleophilic substitution reaction of
1,4-dichloro-2-nitrobenzene and piperazine in DMF at 100 ꢁC.
Using ethyl 3-oxo-3-phenylpropanoate 3 as starting material, the
key intermediate 5-methyl-2-phenylfuran-3-carboxylic acid 6 was
prepared via multi-step reactions of carbon anion nuleophilic
substitution, Paal-Knorr furan synthesis [18], and ester hydrolysis,
successively. Treating phenylfuran acid 6 with oxalyl chloride gave
the acyl chloride 7, which was further reacted with piperazine 2 led
to the compound M in 68.2% yield; using the similar procedure
Based on the apparent insecticidal activity of the compound
M from the preliminary evaluation, some new analogues 8a-8i
were thus designed for an extension with 2-nitro-4-chlorophenyl
group in piperazine ring of precursor M being replaced by some
Fig. 2. Design of the title compounds.
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Scheme 1. Synthesis of compound M.
mono- and di-acylated products (15f and 15h) were obtained;
when using arylamine intermediates 11g-11l which all contain Cl
group for R1 group to carry out this reaction, unexceptionally, the
di-acylated products 15i-15o were achieved in moderate yield.
These results indicated that after the first acylation of compounds
13 and 11g-11l, the activity of H atom in the generated ꢀꢀCONHꢀꢀ
group (mono-acylated product) may be increased by its neigh-
Scheme 2. Synthesis of the title compounds 8.
bouring Cl (R1) and carbonyl (ꢀꢀ(C
¼O)ꢀꢀ) groups due to the
electron-withdrawing conjugative/inductive effect, the second
acylation therefore would be easier to occur to give the di-acylated
products. Whereas, in the case of arylamine 11e, besides mono-
acylated product 15f, a certain amount of di-acylated product 15h
was also formed, which may be derived from the electronic effect
influence of both carbonyl group (ꢀꢀ(C¼O)ꢀꢀ) generated in mono-
acylation step and the o-NO2Ph group of piperazine part (amide
NꢀꢀH activated). In addition, using a similar procedure, phenyl-
furan acyl chloride 7 and 2-amino-5-chloro-N,3-dimethylbenza-
mide reacted in pyridine at 0 ꢁC to reflux, new compound 16 was
obtained in 52.6% yield.
Scheme 3. Synthesis of the intermediates 11.
The novel structures of the related intermediates and title
compounds were confirmed by 1H NMR, and 13C NMR. The
measured high-resolution mass spectroscopy (HRMS) data were
also consistent with the corresponding calculated values (pre-
sented in Suppoting information). In the 1H NMR of the new
piperazine-containing arylamines 11a-11L, the active proton (NH2)
signal was observed at highfield with the chemical shift of 4.25–
4.77 ppm. However, the active proton (NH) signals of the di-amide
compounds 15a-15g showed up one group of peak at very
downfield with the chemical shift of 10.06–10.41 ppm, due to the
deshielding effects of its neighbouring carbonyl and phenyl groups.
In the cases of the piperazine-containing intermediates and title
compounds (i.e., 11, 8, 14 and 15), the proton signals in the
piperazine ring (CH2) mostly appeared at chemical shift of 2.04–
4.11 ppm as some groups of “brs” peaks with partial overlaps.
Especially, in the 1H NMR of tri-amide compounds 15h-15m, there
were eight groups of “brs” peaks for the corresponding piper-
azineꢀꢀCH2 protons being observed. This result indicated that each
of protons in four piperzineꢀꢀCH2 groups of these compounds may
be probably in different chemical surroundings, owing to a chair
conformation of the existing six-membered piperazine ring
[21,22]. Moreover, in the 13C NMR of these piperazine compounds,
the carbon signals of the piperazine ring were observed as four
groups of peaks at different chemical shift from 41 ppm to 55 ppm,
further indicating the “difference” of four piperzineꢀꢀCH2 groups.
Initially, compound M was successfully synthesized in our lab,
and was then investigated on its insecticidal effect for the first
time. It was found that M exhibited obvious larvicidal activity at a
test concentration of 200 mg/L, with modest lethality rate of 35.0%
with various 1-substitutedpiperazine as material, the title new
compounds 8a-8i were successfully synthesized (Scheme 2).
Adopting a similar procedure [19,20] – a reaction of substituted
2-aminobenzoic acid 9 with bis(trichloromethyl)carbonate (BTC),
followed by the treatment of the generated substituted-benzo[d]
[1,3]oxazine dione 10 with excess 1-substitutedpiperazine (1.5
equiv.) in boiling THF, afforded new intermediates 11 in moderate
to high yield (48%– 88%) (Scheme 3).
As shown in Scheme 4, the nucleophilic addition-condensation
reaction of N-pyridylpyrazole acyl chloride 13 and various 1-
substitutedpiperazine also smoothly gave rise to the new title
compounds 14a-14g.
For the synthesis of the title compounds 15 by means of the
mono-acylation reaction between N-pyridylpyrazole acyl chloride
13 and the piperazine-containing arylamine 11, when initially
using triethylamine as acid binding agent it was found that the
reaction mainly led to the di-acylated product (for R1 = Cl in most of
cases); the desired mono-acylated product was also included, but
the amount was little, and the work-up process to get pure product
was difficult. The relatively weaker base pyridine was further tried
for such reaction. The experiments showed that the reaction is
comparatively clean under conditions of pyridine (both as acid
binding agent and solvent) and room temperature to reflux,
leading to an easier purification process. As a result, when using
arylamine intermediates 11 with R1 group as Me to conduct the
reaction by the pyridine-protocol, the new mono-acylated
products 15a-15g can be successfully obtained in good yield;
when using 11e (R1 = Me, R = 2-NO2Ph) as arylamine reactant, both
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Scheme 4. Synthesis of the title compounds 14, 15, and 16.
and 30.0% (100% means total kill) against oriental armyworm
(Mythimna separata Walker) and diamondback moth (Plutella
xylostella L.), respectively (Table 1). This result could not only
provide a good validation for Sindhu’s pharmacophore model to a
certain extent, but also give us an useful clue for further structural
modifications based on this interesting structure that contains
piperazine and furan heterocycles, and mono-amide (non-
NH type) motif. Subsequently, new derivatives 8a-8i, 14a-14g,
15a-15o and 16 were further synthesized for insecticidal activity
evaluation.
As a result, these novel compounds synthesized with mono-, or
di-, or tri- amide structural characteristics showed good, even
remarkable insecticidal activities towards diamondback moth and
oriental armyworm on the whole. It should be noted that the
compound may not be determined further at lower concentrations
in most of the cases when the tested compound does not exhibit
better insecticidal potentials at higher concentration of 200 mg/L
or 100 mg/L (generally lower than 80%), since this is based on an
unified bioassay pattern for a preliminary activity evaluation
(Tables 1, 2 and 4). While partial compounds with a promising
activity trend may be carried out further determination for LC50
values (Table 3). The detailed bioactivity and SAR analysis are
discussed as follows.
As shown in Table 1, the mono-amide derivatives 8a-8i, as the
new analogues of compound M, were found to have better
insecticidal activity against diamondback moth than that of
compound M, e.g., compound 8c possessed lethality rate of 80.0%
and 40.0% at the concentration of 100 mg/L and 10 mg/L,
respectively; compound 8g that bears a 4-Cl-2-CF3Ph group in
thepiperazineringparticularlyshowedthebestinsecticidalactivity
in this series of compounds – 50.0% lethality rate at 1 mg/L. The R
substituent corresponding tothe insecticidal activityof compounds
8a-8i generally displayed a trend of substituted phenyl ꢂ methyl >
substituted pyrimidyl > 4-chlorobenzyl. For the substituted phenyl
groups, the activity trend was 4-Cl-2-CF3Ph > 2-MePh > 2-NO2Ph >
2-ClPh > 4-ClPh. Interestingly, a structural modification from 4-Cl-
2-NO2Ph (M) to 4-Cl-2-CF3Ph (8g) led to a great improvement of
insecticidal activity against diamondback moth, indicating that the
substituents at phenyl ortho- and para- positions of piperazine
group would result in great influence on the insecticidal activity of
the corresponding compounds, possibly via their electronic/steric
effect. Compared with the conventional structures of anthranilic
diamide insecticides, these piperazine- and phenylfuran- contain-
ing mono-amide compounds have novel and simple structures, and
favorable insecticidal potentials, especially 8g could be taken as a
new lead compound for further study.
Table 1
Larvicidal activities of compounds M, 8a-8i and chlorantraniliprole against oriental armyworm (Mythimna separata Walker) and diamondback moth (Plutella xylostella L.).
Compd.
Activity against oriental armyworm (%) at 200 mg/L
Activity against diamondback moth (%) at a concentration of (mg/L)
200
100
10
1
M
8a
8b
8c
8d
8e
8f
8 g
35.0
0
0
30.0
100
n.t.*
70.0
n.t.
80.0
50.0
n.t.
65.0
100
n.t.
n.t.
n.t.
n.t.
40.0
n.t.
n.t.
n.t.
83.0
n.t.
n.t.
100
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
50.0
n.t.
n.t.
100
70.0
97.0
80.0
60.0
90.0
100
80.0
80.0
100
25.0
70.0
30.0
40.0
70.0
10.0
25.0
100
8h
8i
n.t.
100
Chlorantraniliprole
*
n.t. – not test.
4

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Chinese Chemical Letters xxx (xxxx) xxx–xxx
substituents (R1 = Me, R2 = Br, R = 2-NO2Ph), tri-amide compound
15h had much higher insecticidal activity than that of di-amide
compound 15f (70.0% at 0.1 mg/L (15h) vs. 45.0% at 10 mg/L (15f)).
For the di-amide compounds 15a-15g, when R2 was fixed as Br, the
R group in the piperazine of the corresponding compounds
exhibited an activity trend: 2-ClPh > 2-MePh > Me > 4-Cl-2-NO2Ph
> 2-NO2Ph > 2,4-Cl2Bn (15e > 15d > 15b > 15 g > 15f > 15c); when
R = Me, the activity trend for R2 group is CF3CH2O > Br (15a > 15b).
For the tri-amide compounds 15h-15o, when R1 = Cl and R2 = Br,
the R group indicated an activity sequence: Me > 2-ClPh > 2,4-
Cl2Bn > 2-MePh > 4-CF3Pyrimidyl > 2-NO2Ph (15j > 15m > 15k >
15l > 15o > 15n); when R1 and R were fixed as Cl and Me,
respectively, the R2 group in corresponding compounds showed an
activity trend of Br > Cl (15j > 15i); when R2 and R were fixed as Br
and 2-NO2Ph, respectively, the R1 group displayed an activity
sequence of Me > Cl (15h > 15n). The results indicated that the
piperazine moiety containing various groups have significant
influence on the insecticidal activity of such novel di- and tri-
amide compounds; a possible synergistic effect of substituted
piperazine moiety with other groups such as pyridylpyrazole, two
amide bonds (one “NH” and one “non-NH”) and three amide bonds
(three “non-NH”) may contribute to the favorable insecticidal
activity of this type of compounds.
From the same Table 2, it was found that compound 16 also
show high insecticidal activity and can even possess 61.0% lethality
rate at a lower test concentration of 0.1 mg/L towards diamond-
back moth. As mentioned above, compound 16 is derived from
both compound M (from pharmacophore-based virtual screening
[13]) and chlorantraniliprole. Based on the common anthranilic
diamide skeleton, the structural difference of compound 16 and
chlorantraniliprole is that the former has a phenylfuran group and
the latter has a pyridylpyrazole group. Although less effective than
chlorantraniliprole, compound 16 might provide an useful refer-
ence for further design and development of new insecticidal
agents, owing to its novel heterocyclic structure of phenylfuran.
In addition, some compounds with high insecticidal activity
against diamondback moth were made further investigation on
LC50 values. As shown in Table 3, compounds 15a,15e, and 15i-15m
displayed favourable larvicidal activity against diamondback moth
with LC50 value of 0.0022ꢀ0.0237 mg/L. Among which, 15i-15 m
whose LC50 values were 0.0022ꢀ0.0081 mg/L, were comparable
with that of chlorantraniliprole (0.0031 mg/L). Particularly, 15i,
15m, and 15l held LC50 values of 0.0042 mg/L, 0.0035 mg/L, and
0.0022 mg/L, respectively, close to even superior to chlorantrani-
liprole (0.0031 mg/L) under the same bioassay conditions.
As shown in Tables 1 and 4, most of the title compounds 8,14,15
and 16 mainly exhibited apparent insecticidal activity against
oriental armyworm at 200 mg/L. Partial compounds were found to
retain good activity at lower dosages, better than that of compound
M. For examples, 14a, 14c, 15f, 15g, 15k, and 15l possessed lethality
rate of 40.0%–100% at 100 mg/L; 14a, 15g, and 15l at 50 mg/L
showed larvicidal activity of 60.0%, 70.0%, and 40.0%, respectively.
The substituent (R) in the piperazine ring also had an impact on the
insecticidal activity of the corresponding compounds in some
extent. Take the situation in compounds 15 as an example, the
structure-activity relationship indicated that the R substituent
showed an activity sequence of 4-Cl-2-NO2Ph > 2-NO2Ph > 2-ClPh
> 2-MePh, 2,4-Cl2Bn > Me for the di-amide compounds 15b-15g
(R1 = Me, R2 = Br), and 2-MePh > 2,4-Cl2Bn > 2-NO2Ph > 2-ClPh, 4-
CF3Pyrimidyl > Me for the tri-amide compounds 15j-15o (R1 = Cl,
R2 = Br), respectively.
Table 2
Larvicidal activities of the title compounds 14a-14 g, 15a-15o, 16 and chloran-
traniliprole against diamondback moth (Plutella xylostella L.).
Compd.
Activity (%) at a concentration of (mg/L)
200
100
10
1
0.1
0.01
14a
14b
14c
14d
14e
14f
14 g
15a
15b
15c
15d
15e
15f
15 g
15 h
15i
15 j
15k
15l
100
75.0
0
100
n.t.
n.t.
n.t.
n.t.
n.t.
70.0 n.t.
100
100
67.0
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.*
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
70.0
40.0
80.0
100
100
100
75.0
100
100
90.0
100
100
100
100
100
100
100
100
100
100
100
100
90.0 75.0 40.0
80.0 50.0 n.t.
n.t.
88.0 65.0 27.0
93.0 78.0 45.0
60.0 n.t.
n.t.
n.t.
100
100
77.0
100
100
100
100
100
100
100
100
100
100
100
100
100
45.0 n.t.
85.0 n.t.
n.t.
n.t.
n.t.
n.t.
100
100
100
100
100
100
100
100
100
100
90.0 70.0 30.0
100
100
100
100
100
85.0 60.0
100 83.0
90.0 70.0
87.0
100
60.0
75.0
n.t.
15 m
15n
15o
16
70.0 37.0
75.0 44.0 n.t.
90.0 61.0
100 100
n.t.
Chlorantraniliprole 100
80.0 (0.001 mg/L)
*
n.t. – not test.
Table 3
LC50 values of compounds 15a, 15e, 15i, 15j, 15k, 15l, 15m and chlorantraniliprole
against diamondback moth (Plutella xylostella L.).
Compd.
y = a + bx
LC50 (mg/L)
R
15a
15e
15i
15 j
15k
15l
y = 6.43 + 0.88x
y = 6.78 + 0.93x
y = 10.14 + 2.17x
y = 9.91 + 2.21x
y = 10.20 + 2.48x
y = 10.25 + 1.97x
y = 10.05 + 2.06x
y = 10.64 + 2.25x
0.0237
0.0122
0.0042
0.0059
0.0081
0.0022
0.0035
0.0031
0.9609
0.9643
0.9920
0.9916
0.9952
0.9846
0.9859
0.9812
15 m
chlorantraniliprole
As shown in Table 2, mono-amide derivatives 14a-14g which
were derived from a structural modification of compounds 8 by a
substitution of phenylfuran group with N-pyridylpyrazole group
mostly exhibited good larvicidal activity against diamondback
moth at 200 mg/L (70.0%– 100%). At lower test concentrations,
most of compounds 14 generally exhibited lower insecticidal
potential than that of compounds 8 except that 14a had a lethality
rate of 67.0% towards diamondback moth at 10 mg/L.
From the data listed in Table 2, we can see that almost all the
compounds 15 showed excellent insecticidal activity against
diamondback moth at 200 mg/L and 100 mg/L. At lower concen-
trations, compounds 15a, 15b, 15d, 15e, and 15h-15o held 70.0%–
100% lethality rate at 1 mg/L; especially, compounds 15i-15m still
possessed 60.0%–83.0% activity at 0.1 mg/L, close to that of
chlorantraniliprole.
An overall structure-activity relationship based on the dia-
mondback moth bioassay data of compounds 15 could be
concluded as follows. For one thing, a combination of pipera-
zine-containing arylamine and pyridylpyrazole groups would
generate very high insecticidal effect. For another, the tri-amide-
like derivatives (di-acylated compounds) were more effective
than the di-amide derivatives (mono-acylated compounds) in
general. For example, under situation of bearing the same
According to the bioassay results of these synthesized com-
pounds towards diamondback moth and oriental armyworm, some
novel piperazine-containing mono-/di-/tri-amide compounds
such as 8 g, 14a, 15a, 15g, 15i, 15j, 15k, 15l, and 15m could be
used as new insecticidal leading compounds for further
5

G Model
CCLET-6131; No. of Pages 6
H. Li, H. Liu, Y. Zhang et al.
Chinese Chemical Letters xxx (xxxx) xxx–xxx
Table 4
some novel piperazine-containing heterocyclic mono-/di-/tri-
amide derivatives such as 8g, 14a, 15a, 15g, 15i, 15j, 15k, 15l, and
15m could be used as new insecticidal leading structures for
Larvicidal activities of the title compounds 14a-14g, 15a-15o, 16 and chloran-
traniliprole against oriental armyworm (Mythimna separata Walker).
Compd.
Activity (%) at a concentration of (mg/L)
further study (e.g., towards diamondback moth, 15i-15m LC50
:
0.0022ꢀ0.0081 mg/L). The structure-activity relationships of these
compounds discussed in detail provide useful guidance for further
design and development of new insecticides.
200
100
50
14a
14b
14c
14d
14e
14f
14 g
15a
15b
15c
15d
15e
15f
15 g
15 h
15i
15 j
15k
15 l
15 m
15n
15o
16
100
15.0
100
100
n.t.*
65.0
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
40.0
100
n.t.
n.t.
n.t.
40.0
100
n.t.
n.t.
n.t.
n.t.
100
60.0
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
70.0
n.t.
n.t.
n.t.
n.t.
40.0
n.t.
n.t.
n.t.
n.t.
100
25.0
80.0
15.0
20.0
80.0
30.0
50.0
50.0
70.0
100
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
100
30.0
30.0
40.0
100
Thiswork was financiallysupportedby theNationalKey Research
and Development Program of China (No. 2017YFD0200505), and the
National Natural Science Foundation of China (No. 21772103). This
article is dedicated to the 100th anniversary of Chemistry at Nankai
University.
100
50.0
60.0
50.0
55.0
100
Appendix A. Supplementary data
Chlorantraniliprole
Supplementary material related to this article can be found,
in the online version, at doi:https://doi.org/10.1016/j.
cclet.2021.02.002.
*
n.t. – not test.
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