Design, synthesis, and insecticidal activities of novel diamide derivatives with alpha-amino acid subunits

Article abstract of DOI:10.1002/jhet.4268

A series of diamide derivatives containing α-amino acids were designed and synthesized. These compounds were evaluated for their insecticidal activities against Plutella xylostella, Mythimna separate, Myzus persicae, and Tetranychus cinnabarinus. Most of the title compounds containing an l-phenylglycine skeleton were endowed with good activities at the concentration of 500 mg·L^?1. Compounds (R)-A6 showed a potential value for further optimization as an insecticidal lead with the LC₅₀ value of 86.8 mg·L^?1.

Full text of DOI:10.1002/jhet.4268

Received: 30 November 2020
DOI: 10.1002/jhet.4268
Revised: 16 February 2021
Accepted: 26 March 2021
A R T I C L E
Design, synthesis, and insecticidal activities of novel
diamide derivatives with alpha-amino acid subunits
Rui-Jia Chen1
| Jun-Jie Wang1 | Li Han1 | Yu-Cheng Gu2
|
Zhi-Ping Xu1 | Jia-Gao Cheng1 | Xu-Sheng Shao1 | Xiao-Yong Xu1 | Zhong Li1,3
1Shanghai Key Laboratory of Chemical
Abstract
Biology, School of Pharmacy, East China
University of Science and Technology,
Shanghai, China
2Syngenta, Jealott's Hill International
Research Centre, Bracknell,
Berkshire, UK
A series of diamide derivatives containing α-amino acids were designed and
synthesized. These compounds were evaluated for their insecticidal activities
against Plutella xylostella, Mythimna separate, Myzus persicae, and Tetranychus
cinnabarinus. Most of the title compounds containing an L-phenylglycine skel-
eton were endowed with good activities at the concentration of 500 mgÁLÀ1
.
3Shanghai Collaborative Innovation
Center for Biomanufacturing Technology,
East China University of Science and
Technology, Shanghai, China
Compounds (R)-A6 showed a potential value for further optimization as an
insecticidal lead with the LC50 value of 86.8 mgÁLÀ1
.
Correspondence
Zhong Li, Shanghai Key Laboratory of
Chemical Biology, School of Pharmacy,
East China University of Science and
Technology, 200237 Shanghai, China.
Email: lizhong@ecust.edu.cn
Funding information
Innovation Program of Shanghai
Municipal Education Commission, Grant/
Award Number: 2017-01-07-00-02-E00037;
National Key Research and Development
Program of China, Grant/Award Number:
2017YFD0200500; Syngenta PhD
Fellowship Award
1 | INTRODUCTION
They can cause an uncontrolled release of calcium ions
and the ultimate death of pests [2–5]. Since diamide
insecticides exhibit good activities against lepidopteran
pests, less toxicity to mammals, and no cross-resistance
with other existing insecticides, they are wildly applied in
integrated pest management programs [6,7]. However, a
series of problems arose in the field such as high persis-
tence in soil, chronic risk to aquatic invertebrates [8,9],
and increased resistance [10–12] of pests. Structural mod-
ifications of diamide insecticides have attracted the con-
tinuous attention of researchers.
Diamide insecticides (Figure 1), represented by
flubendiamide (phthalic) and chlorantraniliprole (anthra-
nilic), are classified as the group 28 insecticides with
unique mechanism of action in Insecticide Resistance
Action Committee Mode of Action Classification Scheme
due to their particular structures and action mechanisms.
Diamide insecticides act selectively on insect ryanodine
receptors (RyRs) which control the calcium channel [1].
The chemical structures of anthranilic insecticides
can be generally divided into two amide linkers and three
components: terminal aliphatic moiety (Part A), central
This paper is dedicated to Professor Youyou Tu, the 2015 Nobel Prize
Laureate of Physiology or Medicine on the occasion of her 90th
birthday.
J Heterocyclic Chem. 2021;1–8.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
CHEN ET AL.
FIGURE 1 Commercialized diamide insecticides
Exemplified by insulin and bacitracin, amino acids have
their lion's share in the early discoveries of the modern
drug. Due to the ease of synthesizing amino acids with dif-
ferent side chains, the convenience of further structural
modification, the desire of “escape from flatland” and the
diversity of steric structure and pharmacologic properties,
amino acids are valuable as diverse elements for potential
central components, peptidomimetic drugs, and structure–
activity relationship (SAR) investigations in drug discover-
ies [21–25]. For decades, α-amino acid fragments have
appeared in more drugs, such as Nateglinide [26],
Telaprevir [27], Pasireotide [28], and Pramiracetam [29],
while they are found only in a small number of agrochemi-
cals [30,31] (Figure 3).
The distance between pharmacophoric groups can
affect the activity of compounds. The two amide bonds of
flubendiamide and chlorantraniliprole are both situated
at ortho-positions. Broflanilide, a commercialized insecti-
cide, has similar terminal groups to the phthalic and
anthranilic insecticide [32]. The diamide structure of bro-
flanilide is not ortho-position but meta-position while
broflanilide acts on the insect γ-aminobutyric acid recep-
tors instead of RyRs [33,34]. In the studies of structural
modifications on diamide insecticides, some compounds
with different distances between the two amide bonds
also exhibited insecticidal activities against lepidopteran
pests [35–37].
In our previous research, we have modified the
phthalic or anthranilic central subunits (Part B) of exis-
ting diamide insecticides. And several series of novel
diamide compounds with different distances between
two amide bonds and different biological activities
were reported [38–40]. Encouraged by those discover-
ies, we tried to expand our scope of the investigation to
other acceptable central components of diamide
insecticides.
FIGURE 2 General structure of diamide insecticides
aromatic moiety (Part B), and terminal heterocyclic moi-
ety (Part C) (Figure 2). In recent years, quantities of
researches have been reported for modification on
anthranilic insecticides. But most of them were devoted
in Part A [13,14], Part C [15–17], or amide linkers [18].
The coexistence of amino ( NH2) groups, carboxyl
( COOH) groups, and various side chains contributes to
the attractive properties of amino acids and their
corresponding derivatives. And α-amino acids, whose
amino and carboxyl groups attached to the same (α-) car-
bon atom, have particular importance in biology, pharma-
cology, and chemistry [19,20]. Twenty-two α-amino acids,
as the building blocks of proteins, perform extensive func-
tions including forming the scaffolding system of cells, cat-
alyzing biochemical reactions, and transporting various
molecules. Some α-amino acids, represented by glutamate,
glycine, and cysteine, provide the neurotransmitters for ver-
tebrates. And α-amino acids are the precursors of vast bio-
molecules such as porphyrins, purines, and pyrimidines.

CHEN ET AL.
3
FIGURE 3 Commercialized drugs and agrochemicals with amino acid skeletons
FIGURE 4 Molecular design of novel α-diamides
In this study, α-amino acids were introduced to replace
the original central component of chlorantraniliprole.
A series of novel diamides with two amide bonds linked to
the same carbon atom were designed, synthesized, and
evaluated for their insecticidal activities. Figure 4 shows
the molecular design strategy for the target compounds.

4
CHEN ET AL.
SCHEME 1 General synthetic procedure for target compounds A1–A10 and B1–B11
2 | MATERIAL AND METHODS
2.1 | Instrumentation and chemicals
3 | RESULT AND DISCUSSION
3.1 | Synthesis
Unless otherwise noted, all reagents and solvents were
obtained from commercial sources and used without
further purification. Melting points (m.p.) were recorded
on Büchi Melting Point B-540 (Büchi Labortechnik AG,
As illustrated in Scheme 1, the target compounds A1–
A10 and B1–B11 were obtained through a four-step reac-
tion from the key intermediate 3-bromo-1-(3-chloro-
pyridin-2-yl)-1H-pyrazole-5-carboxylic acid
6
and
1
Flawil, Switzerland) are uncorrected. H NMR and 13C
corresponding tert-butoxycarbonyl amino acids 8. Based
on the similar method reported in the related literature
[41], 6 was synthesized from commercially available
2,3-dichloropyridine 1 with minor modifications. Com-
pound 1 and hydrazine hydrate (50% in water) were
directly refluxed without other solvents to obtain
3-chloro-2-hydrazinylpyridine 2 in 83% yield. Compound
3 was prepared by the condensation of 2 and diethyl
maleate in the presence of sodium ethoxide (NaOEt).
Treat 3 with phosphorus oxybromide (POBr3) in acetoni-
trile (MeCN) to get the bromine-substituted pyrazoline
4 in 95% yield. Subsequent oxidation of 4 by potassium
persulfate afforded the N-pyridylpyrazole 5. And the
intermediate acid 6 was obtained from the hydrolysis of
ester 5 in quantitative yield.
NMR spectra were recorded on Bruker AM-400 spec-
trometer with dimethyl sulfoxide (DMSO)-d6 or CDCl3
as solvent and TMS as internal standard. Chemical
shifts are reported in δ (parts per million). High-
resolution electron mass spectra were performed on a
micromass liquid chromatography time-of-flight spec-
trometer. Specific rotations were recorded on Polarime-
ter (Rudolph Research Analytical Autopol Ш).
Analytical thin-layer chromatography was performed on
precoated plates (silica gel 60 F254), and spots were visu-
alized with ultraviolet light.
2.2 | Insecticidal assay
In
the
present
of
benzotriazol-1-yl-
According to statistical requirements, the bioassay
was repeated three times at 25 1ꢀC. All compounds
were dissolved in DMSO and diluted with water con-
taining Triton X-100 (0.1 mgÁLÀ1) to obtain series con-
centrations of 500.0, 100.0 mgÁLÀ1, and others for
bioassays.
oxytripyrrolidinophosphonium
hexafluorophosphate
(PyBop) and N,N-diisopropylethylamine (DIPEA), amides
9 could be conveniently prepared in 67%–92% yield by the
reaction of commercially available Boc-protected amino
acids 8 and various amines including aliphatic amines and
substituted anilines. Deprotected by trifluoroacetic acid,

CHEN ET AL.
5
TABLE 1 Insecticidal activities of compounds A1–A10 and B1–B11
Compound
R1
R2
Conc.
(mgÁLÀ1
Mortality (%)
)
Plutella
xylostella
72 h
Mythimna
separate
72 h
Myzus
persicae
48 h
Tetranychus
cinnabarinus
72 h
(S)-A1
(R)-A1
Ph
Ph
500
500
0
0
0
0
50.0
31.0
0
0
(S)-A2
(R)-A2
(S)-A3
–CH(CH3)2
–CH(CH3)2
Ph
Ph
Ph
500
500
500
0
0
75.7
17.0
88.0
0
0
0
0
0
0
60.0
(R)-A3
Ph
500
46.7
73.3
0
0
(S)-A4
(R)-A4
(S)-A5
Ph
Ph
Ph
500
500
500
50.0
0
13.0
11.0
70.0
0
0
0
0
0
0
76.7
(R)-A5
Ph
500
80
56.7
0
0
(S)-A6
(R)-A6
Ph
Ph
Ph
Ph
500
500
100
500
500
500
500
500
500
500
500
500
500
500
500
500
100
500
100
500
100
96.7
100
80.0
100
60
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
(S)-A7
(R)-A7
(S)-A8
(R)-A8
(S)-A9
(R)-A9
(S)-A10
(R)-A10
(R)-B1
(R)-B2
(R)-B3
(R)-B4
(R)-B5
Benzyl
Benzyl
Ph
11.2
0
23.6
0
Ph
Ph
90
63.3
13.3
14.3
16.6
33.3
51.6
0
Ph
83.3
0
Isobutyl
Isobutyl
Methyl
Methyl
Ph
Ph
Ph
0
Ph
21.6
33.3
Ph
Cyclopropyl
Cyclopentyl
Isopropyl
Propyl
Isobutyl
Ph
0
Ph
0
Ph
0
Ph
100
58.3
100
34.1
11.6
0
(R)-B6
(R)-B7
Ph
Ph
4- Cl-phenyl
4-CN-
phenyl
(Continues)

6
CHEN ET AL.
TABLE 1 (Continued)
(R)-B8
(R)-B9
(R)-B10
(R)-B11
Ph
Ph
Ph
Ph
2-CH3-
phenyl
500
100
500
100
500
100
500
100
100
0
3-CH3-
phenyl
100
37.2
100
18.7
4-CH3-
phenyl
4-OCH3-
phenyl
0
0
CK
0
0
0
0
Chlorantraniliprole
Imidacloprid
Avermectin
10
10
10
100
100
100
100
9 was converted to the corresponding amines 10. Mean-
while, 6 was prepared into acid chloride 7 with oxalyl
chloride [(COCl)2] and then coupled with 10 using DIPEA
as acid capture to obtain target compounds A1–A10 and
B1–B10 in 72%–85% yield. The structures of those com-
pounds were confirmed by analyzing their NMR and ESI
spectral data.
concentration of 500 mgÁLÀ1, (S)-A1 containing (S)-
tryptophan had no insecticidal activities on
P. xylostella, and (R)-A1 containing (R)-tryptophan
showed moderate activities. At the same concentration,
there was a 60% difference in the lethality rate against
M. separate between the enantiomers (S)-A2 and (R)-
A2 while the difference between (S)-A3 and (R)-A3
was about 15%. (S)-A4 and (R)-A4 contained methio-
nines with a different configuration. These two com-
pounds showed similar insecticidal activities against
M. separate but their insecticidal activities on
P. xylostella were different. As the insecticidal activities
of (S)-A3, (S)-A6, and (R)-A6 against M. separate and
the activities of (R)-A5, (S)-A6, (R)-A6, (S)-A8, and
(R)-A8 against P. xylostella are all over 80% at the con-
centration of 500 mgÁLÀ1, β-methyl (S)-aspartate, (R)-
proline, phenylglycines, and O-methyl-serines were
proved to be acceptable α-amino acid central compo-
nents for diamide insecticides. Among all title com-
pounds, the activities of (R)-A6 were relatively higher
than that of others with the LC50 value of 86.8 mgÁLÀ1
against M. separate. The larvae treated by (R)-A6
ceased feeding, sequentially contracted, and ultimately
died. The abnormal symptoms were similar to those
caused by chlorantraniliprole. It indicated that (R)-A6
might exhibit its activity by activating insect RyRs.
3.2 | Insecticidal activity
The insecticidal activities of α-diamide derivatives against
Plutella xylostella, Mythimna separate, Myzus persicae,
and Tetranychus cinnabarinus were evaluated, using
chlorantraniliprole as the control compound. The results
are listed in Table 1.
At the outset of the study, we use aniline as the fixed
substituent of Part A and prepared 20 derivatives A1–
A10 with differing side chains to investigate the effects
on biological activities of replacing the central compo-
nents with α-amino acids. The results indicated that most
of the compounds exhibited moderate larvicidal activities
against P. xylostella and M. separate at the concentration
of 500 mgÁLÀ1 (Table 1).
The side chains and configurations of central amino
acids are what the insecticidal activities of title com-
pounds depended on, as the two factors often determine
the difference in the biological activities of drugs con-
taining amino acid subunits [42,43]. At the
We took compound (R)-A6 as the potent lead for fur-
ther optimization on Part A. Various amino groups,
including aliphatic amines and substituted anilines, were

CHEN ET AL.
7
investigated and 11 compounds B1–B11 were prepared.
Majority of the compounds in this subseries exhibited
good larvicidal activities against M. separate, but they did
not lead to significant improvement over the lead.
Aliphatic amine groups except isobutyl [compound
(R)-B5] eliminated the insecticidal activity. It indicated
that the introduction of a big steric amino group in Part
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How to cite this article: Chen R-J, Wang J-J,
Han L, et al. Design, synthesis, and insecticidal
activities of novel diamide derivatives with alpha-
amino acid subunits. J Heterocyclic Chem. 2021;
1–8. https://doi.org/10.1002/jhet.4268