Design, synthesis and nematicidal activitives of trifluorobutene amide derivatives against Meloidogyne incognita

Article abstract of DOI:10.1016/j.bmcl.2021.127917

Plant parasitic nematodes have always been a pressing problem in the field of plant protection. Well-established chemical nematicides, especially organophosphorus and carbamates are the most used products for nematode control worldwide. Due to long-term overuse, they have developed serious resistance and new innovative solutions are urgently required. In this study, thirty-one novel trifluorobutene amide derivatives were designed and synthesized, and their nematicidal activities were determined. Three different synthetic methods have been developed for the final amidation reaction enabling the successfully syntheses of the target compounds independently from the nucleophilicities of the substrate amino group. Most target compounds showed good nematicidal activity in our in vitro test. Among all the compounds, compounds A8 and A23 exhibited excellent nematicidal activity against Meloidogyne incognita, their LC₅₀ values are 2.02 mg L^?1 and 0.76 mg L^?1, respectively. In particular, compound A23 has found to be almost as active as the commercial nematicide fluensulfone. Furthermore, most compounds gave full control (100% inhibition) of M. incognita at 40 mg L^?1 in the in vivo tests in sandy soil, the best compounds were further investigated for in vivo activity in matrix soil. Among the compound tested, compound A8 showed excellent in vivo nematicidal activity. At a concentration of 5 mg L^?1 still 56% inhibition was observed. The results of our study indicate that compound A8 possesses excellent in vitro and in vivo nematicidal activity, and can be considered as promising lead molecule for further modification.

Full text of DOI:10.1016/j.bmcl.2021.127917

Bioorg. Med. Chem. Lett. 40 (2021) 127917
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and nematicidal activitives of trifluorobutene amide
derivatives against Meloidogyne incognita
,
,
,
b
,
,*
Haiping Yanga †, Ruifeng Zhanga †, Zhong Lia, Peter Maienfischa *, Xiaoyong Xua
a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b CreInSol MCB, CH-4118 Rodersdorf, Switzerland
A R T I C L E I N F O
A B S T R A C T
Keywords:
Plant parasitic nematodes have always been a pressing problem in the field of plant protection. Well-established
chemical nematicides, especially organophosphorus and carbamates are the most used products for nematode
control worldwide. Due to long-term overuse, they have developed serious resistance and new innovative so-
lutions are urgently required. In this study, thirty-one novel trifluorobutene amide derivatives were designed and
synthesized, and their nematicidal activities were determined. Three different synthetic methods have been
developed for the final amidation reaction enabling the successfully syntheses of the target compounds inde-
pendently from the nucleophilicities of the substrate amino group. Most target compounds showed good
nematicidal activity in our in vitro test. Among all the compounds, compounds A8 and A23 exhibited excellent
nematicidal activity against Meloidogyne incognita, their LC50 values are 2.02 mg Lꢀ 1 and 0.76 mg Lꢀ 1, respec-
tively. In particular, compound A23 has found to be almost as active as the commercial nematicide fluensulfone.
Furthermore, most compounds gave full control (100% inhibition) of M. incognita at 40 mg Lꢀ 1 in the in vivo tests
in sandy soil, the best compounds were further investigated for in vivo activity in matrix soil. Among the com-
pound tested, compound A8 showed excellent in vivo nematicidal activity. At a concentration of 5 mg Lꢀ 1 still
56% inhibition was observed. The results of our study indicate that compound A8 possesses excellent in vitro and
in vivo nematicidal activity, and can be considered as promising lead molecule for further modification.
Trifluorobutene
Amide
In vitro
In vivo
Nematicidal activity
Root-knot nematodes (Meloidogyne spp.) are considered to be the
most destructive nematodes in the world,1 they can infect more than
3000 plants, including peppers, tomatoes, onions and watermelons.2
According to recent reports, the annual global damage caused by plant
parasitic nematodes exceed ten billion dollars.3 In the past few decades,
chemical nematicides have been regarded as the most effective control
method.4,5 Common nematicides include carbamate and organophos-
phorus, such as fenamiphos, carbofuran and aldicarb. However, with the
enhanced awareness for environmental and health protection, organo-
phosphorus and carbamate, that are highly toxic and result in higher
levels of residues, do not any longer meet the requirements of modern
agricultural sustainable development.6,7 Therefore, there is an urgent
need to discover and develop nematicides with novel mode of actions
and favorable safety profiles such as being eco-friendly and of low
mammalian toxicity.
have been made in the quest for modern nematode control.8 Among
them, trifluorobutene compounds have attracted the utmost attention of
major pesticide companies in the world since 1980s due to their high
nematicidal activity and good environmental compatibility, and have
become a hotspot in the field of nematicide research. Fluoroalkenyl
compounds (Fig. 1, a-d) resulting from such research have demonstrated
to exhibit high nematicidal activity.9–12 As the first compound from the
trifluorobutene chemical class fluensulfone (Fig. 1) has been brought to
the market and is currently sold under the product name Nimitz. This
new nematicide was originally discovered by Bayer CropScienc,13 and
later developed and launched in market by Adama. Fluensulfone rep-
resents a new generation of green and efficient nematicides possessing a
clearly more favourable toxicity than organophosphorus and carbamate
nematicides.14 Furthermore this innovative nematicide has a unique
mechanism of action and controls a broad variety of plant parasitic
nematodes including Meloidogyne incognita (M. incognita).15,16
In recent years a series of new innovations and important discoveries
* Corresponding authors at: Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai
200237, China (P. Maienfisch).
E-mail addresses: peter.maienfisch@syngenta.com (P. Maienfisch), xyxu@ecust.edu.cn (X. Xu).
†
These two authors are co-first author.
https://doi.org/10.1016/j.bmcl.2021.127917
Received 12 November 2020; Received in revised form 22 February 2021; Accepted 24 February 2021
Available online 9 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

H. Yang et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127917
the trifluorobutene pharmacophore was retained, the amide was intro-
duced as a linker resulting in the design of compound A, which has
demonstrated good biological activity against M. incognita. Based on this
structure, the chlorothiazole ring in compound A was replaced with
different heterocycles to obtain the target compounds A1-A18. The
nematicidal activities of compound A1-A18 were evaluated against
M. incognita, and it was found that compounds with a pyrazine group as
heterocyclic moiety possess the best activity against southern root-knot
nematodes. In a next step, we investigated the influence of different
substituents at the pyrazine moiety and synthesized compounds A19-
A30 (Fig. 3) and evaluated their nematicidal activities.
Figure 1. The structures of the previously reported nematicides containing
Three different synthetic methods have been used to synthesize
amide target compounds, addressing the different nucleophilicities of
the substrate amino group as shown in Scheme 1. Method A: The target
compounds A-A6 are obtained from the intermediate amine and
4,5,5-trifluoropentenoic acid, benzotriazol-1-yl-oxytripyrrolidinopho
sphonium hexafluoro-phosphate (Pybop) as coupling agent and trime-
thylamine as base; Method B: 4,5,5-trifluoropentenoic acid was con-
verted to its acid chloride with oxalyl chloride, and the resulting 4,5,5-
trifluoropentenoyl chloride then reacted with an amine to obtain the
target compounds A7-A12; Method C: The intermediates amine reacted
with 4,5,5-trifluoropentenoic acid and phosphorus oxychloride to
generate the corresponding target compound A13-A30. Details on the
synthetic methods, yields and characteristics of the target compounds
are described in the Supporting Information (Table S1). Target com-
pounds A-A30 were characterized by melting points, 1H NMR, 13C NMR,
19F NMR and HRMS. The NMR spectral data, HRMS and melting point
data of all compounds can also be found in Supporting Information.
Intermediates have been obtained through a few simple reactions, the
specific synthetic procedure were depicted in Supporting Information.
trifluorobuene.
Pesticides with amide functionalities are well known and widely
used in crop protection. Most recent examples of such “amide in-
secticides” include chlorantraniliprole and cyantraniliprole,17,18 which
are diamides insecticides discovered by DuPont. These compounds act
on ryanodine receptors and possess excellent activity and favorable
safety profiles.19 In the field of fungicides, the succinate dehydrogenase
inhibitors (SDHI) fungicides containing amide structures have become,
with compounds like fluxapyroxad, furametpyr, fluopyram, one of the
most successful new class of fungicides worldwide.20 Throughout the
history of non-fumigant nematicides, amide nematicides (Fig. 2) also
have been used widely, for example, the traditional organophosphorus
nematicide phosphamidon,21 carbamate nematicides carbofuran and
oxamyl.22–24 Recently, some nematicidal compounds containing amide
group with new mechanism of action have been developed. Fluopyram
(Fig. 2) was originally discovered and registered as a fungicide by Bayer,
later studies found that it exhibited excellent nematicidal activity and
recently was registered as a nematicide.25 This compound interacts with
succinate dehydrogenase succinate (SDH) in nematodes as a new mode
of action in nematode control.26 Fluazaindolizine (Fig. 2) is a new
amide-containing nematicide discovered by DuPont. Fluazaindolizine
has strong control effect against various plant parasitic nematodes. It is
harmless to operators and non-target organisms and is safe for the
environment.27 The product is expected to be registered in 2020.28
Phenylpyrazole amide compounds (Fig. 2, E), reported by Bayer, have
shown excellent activity against M. incognita.29 Liu et al synthesized a
series of pyrazole carboxamide compounds (Fig. 2, F) that showed good
activity against southern root-knot nematodes.30
Nematicidal activity in vitro
According to the bioassay data from in vitro test in Table 1, the
mortality of compound A against M. incognita at 40 mg Lꢀ 1 after 72 h of
exposure was found to be 92%, which is valuable for further research.
The substituent Cl group on the thiazole ring of compound A was
removed to give compound A1, which showed 94% mortality. Then, we
replaced the chlorothiazole ring of compound A with different hetero-
cycles to obtain seventeen novel compounds. Among the synthesized
compounds, the mortality of A, A1, A2, A3, A4, A5, A7, A8 and A9 at the
concentration of 40 mg Lꢀ 1 against M. incognita were more than 85%. In
order to further explore the nematicidal activity of these nine com-
pounds, the LC50/72h values against M. incognita were investigated.
Among nine compounds A-A9, compound A8 containing pyrazine het-
erocycle had the best nematicidal activity with an LC50/72h value of 2.02
mg Lꢀ 1 (Table 1).
In this article, we describe our recent results on amide nematicides.
Considering the structural features of the trifluorobutene nematicides,
In a next step we wanted to explore the influence of the different
substituents at the different positions on the pyrazine ring of compound
A8, twelve compounds A19-A30 were synthesized. The results were
shown in Table 2. Only compound A29 exhibited about 90% mortality at
24 h. The mortality of A26 and A22 reached 68.96% and 64.50%,
respectively, which suggested that compound A29 is faster acting than
Figure 2. Nematicidal chemicals containing amide group.
Figure 3. Design of target compounds A-A30.
2

H. Yang et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127917
Scheme 1. Synthetic procedure for target compounds A-A30.
other compounds. After 48 h of treatment, other compounds reached the
same high level of control as demonstrated by the mortality of com-
pounds A1, A20, A22, A23, A29, which all exceed 90% activity. 72 h
after treatment, the nematicidal activities of these compounds increased
further. Compounds A2, A4, A20, A22, A23, A26 and A29 reached 98%
mortality. Overall, there were 17 novel compounds synthesized
exhibited good nematicidal activities in the in vitro test.
The LC50/72h values revealed that, for the same substituent, when the
substituent is located at the position 5 of the pyrazine ring (A20 (5-Cl),
A23 (5- CH3), A26 (5-OCH3), A29 (5-CN)), the activities were superior
to the compounds substituted at position 6 (A19 (6-Cl), A22 (6-CH3),
A25 (6-OCH3), A28 (6-CN)). For the different substituents at the same
position 5, compound A23 with weak electron-donating substituent
methyl (CH3) has the best activity with an LC50/72h value of 0.76 mg Lꢀ 1
.
Analyzing the relationship between the structure and the activity, it
was found that when the substituent position is position 3 of the pyr-
azine ring, the nematicidal activities of four compounds A21, A24, A27
and A30 were less than 40% mortality after 72 h. While the substituent
located at position 5 or 6 of the pyrazine ring, compounds A19, A20,
A22, A23, A25, A26, A28, and A29 exhibited more than 80% mortality.
In order to further investigate the nematicidal activity, the LC50/72h
values of eight compounds against M. incognita were also evaluated.
Compound A23 possesses comparable activity to fluensulfone and
shows clearly improved potency compared to compound A9. Our results
also indicate that a methyl group located at the position 5 of the pyrazine
ring is more favorable than other substituents at this position such as
hydrogen, chloro, cyano and methoxy. The strong electric-donating
group or electric-withdrawing group was not contributed to the bioac-
tivity. Moreover, it is also found that when the substituents located in
the para or meta-position of key pharmacophore trifluorobutene amide
3

H. Yang et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127917
The activities of compounds A, A1, A2, A3, A4, A5, A7, A8, A9, A10 and
A11 against M. incognita were greater than 85% (Table 3). Compounds
A19-A20, A22-A23, A25-A26 and A28-A29 were derived from com-
pound A8, they also showed excellent nematicidal activity with inhibi-
tory rate of 100% (Table 3), this was consistent with the results of in vitro
test. Next, the compounds with good activity in sand were investigated
for the in vivo activity in the matrix soil.
Table 1
Nematicidal activity of the target compounds A-A18 against M. incognita in vitro
(40 mg Lꢀ 1).
Mortality (%)
Compd.
24 h
48 h
72 h
92.00
LC50/72h
95% confidence
interval
(mg Lꢀ 1
)
A
7.75
19.75
3.03
2.12 ~ 4.56
A1
35.15
3.16
2.11
0.00
3.00
1.45
0.70
13.43
4.02
0.70
0.00
0.00
0.00
0.70
0.00
0.00
0.00
0.00
49.97
0.00
92.50
16.32
8.95
94.45
97.37
92.63
98.42
97.64
5.80
9.54
6.03 ~ 14.23
A2
14.33
11.12 ~ 19.07
Nematicidal activity in vivo (matrix soil)
A3
29.08
23.33 ~ 36.87
A4
13.16
27.70
2.20
28.70
23.44 ~ 38.77
The in vivo test in matrix soil can stimulate the real field environment
of nematodes, which is important for the evaluation of the bioactivity
and the estimation of the commercial value of a nematicide and to
decide further progression. Surprisingly, we found that compound A10
had 100% inhibition rate against nematodes in sand and matrix soil
(Table 3), despite its low in vitro nematicidal activity of only 28.80% at
40 mg Lꢀ 1 after 72 h. This phenomenon may be because the in vitro trial
time is short (only 72 h), and compound A10 only acts slowly and needs
a longer time to exhibit its full effect. Among compounds A1-A18,
compound A8 had the most significant effect on nematodes in matrix
soil and displayed 56.25% inhibitory activity at 5 mg Lꢀ 1 (Table 4). In
the further derivatization of the pyrazine ring, it was found that when
compound A8 was substituted at the position 5 and 6 of the pyrazine
ring, the activities of the compounds in the matrix soil against
M. incognita were generally lower than that of compound A8. At 5 mg
Lꢀ 1, the activities of seven compounds were completely lost. At 10 mg
A5
9.03
6.79 ~ 11.14
A6
–
–
A7
56.10
81.27
29.10
15.15
2.80
95.80
85.03
87.70
28.80
6.70
3.22
1.45 ~ 4.99
A8
2.02
1.13 ~ 2.88
A9
16.15
11.33 ~ 21.78
A10
A11
A12
A13
A14
A15
A16
A17
A18
Fluensulfonea
CKb
–
–
–
–
0.90
7.00
–
–
7.50
49.00
2.60
–
–
0.00
–
–
0.00
0.96
–
–
0.00
0.00
–
–
0.00
0.00
–
–
0.00
0.00
–
–
100.00
100.00
0.22
0.02 ~ 0.41
1.13
2.36
–
–
a
Fluensulfone at the concentration of 5 mg Lꢀ 1
.
b
CK: negative control.
L
ꢀ 1, the activity of compound A20 had the highest with the inhibitory
rate, which reached 93.75%. It is higher than the activity of compound
A8 at 10 mg Lꢀ 1 (87.50%), but when the concentration was reduced to 5
mg Lꢀ 1, compound A20 was completely inactive. Our findings suggest
that this compound might degrade faster in the matrix soil, the specific
reason needs to be further analyzed and verified.
Table 2
Nematicidal activity of the target compounds A19-A30 against M. incognita in
vitro (40 mg Lꢀ 1).
Table 3
Nematicidal activity of the target compounds against M. incognita in vivo (40 mg
Mortality (%)
Lꢀ 1).
Compd.
R
24 h
48 h
72 h
LC50/72h
(mg
95%
Inhibition rate (%)
confidence
interval
Lꢀ 1
)
Compd.
Sand
Matrix soil
A19
A20
A21
A22
A23
6-Cl
5-Cl
3-Cl
6-CH3
5-
19.00
43.20
2.26
69.20
99.40
6.02
86.00
98.70
24.10
98.70
98.70
2.07
1.52
–
1.91 ~ 2.89
1.21 ~ 1.79
–
A
100.00
100.00
100.00
100.00
100.00
100.00
0.00
100.00
100.00
100.00
95.00
88.10
100.00
–
A1
A2
64.50
38.89
90.45
90.85
2.73
0.76
2.41 ~ 3.11
0.66 ~ 0.89
A3
A4
CH3
3-
A5
A24
A25
A26
A27
0.95
5.48
3.45
54.11
88.64
7.45
35.50
81.51
98.70
34.20
–
–
A6
CH3
6-
A7
100.00
100.00
100.00
100.00
94.20
0.00
100.00
100.00
100.00
100.00
14.20
–
18.96
1.14
–
14.20 ~ 27.76
0.82 ~ 1.39
–
A8
OCH3
5-
A9
68.96
1.52
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
A29
A30
Fluensulfonea
OCH3
3-
OCH3
6- CN
5- CN
3- CN
40.19
0.00
–
A28
13.10
88.15
1.00
30.09
99.40
1.55
91.40
98.70
6.85
11.35
1.41
–
0.22
–
8.09 ~ 11.32
–
A29
1.13 ~ 1.64
0.00
–
A30
–
0.00
–
Fluensulfonea
50.13
99.40
98.70
0.02 ~ 0.41
0.00
–
CKb
1.30
0.60
1.30
–
0.00
–
100.00
100.00
–
100.00
100.00
–
a
Fluensulfone at the concentration of 5 mg Lꢀ 1
CK: negative control.
.
b
100.00
100.00
–
100.00
100.00
–
56.25
100.00
–
68.75
100.00
–
group, the compounds exhibited higher bioactivities than ortho posi-
tion. It indicated that steric hindrance was not benefit for the increase of
nematicidal activity.
100.00
100.00
–
75.00
81.25
–
Nematicidal activity in vivo (sand)
The compounds in series A were initially tested for their inhibitory
100.00
100.00
activity against M. incognita in sand at the concentration of 40 mg Lꢀ 1
.
a
Fluensulfone at the concentration of 5 mg Lꢀ 1
.
4

H. Yang et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127917
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As part of our research on trifluorobutene nematicides, we designed
and synthesized a series of novel trifluorobutene amide derivatives and
the in vitro and in vivo nematicidal activities were evaluated. We hy-
pothesized that the -SOCH2- moiety of fluensulfone can be replaced by
an amide group and thiazole group by bioisosteric replacement while
maintaining the excellent nematicidal activity. The bioassay results
showed that most of the target compounds exhibited good activity
against M. incognita both in vitro and in vivo. Among the compounds A-
A18 containing different heterocycles in the in vitro test, compound A8,
bearing a pyrazine ring, possessed the best activity against M. incognita
with an LC50 value of 2.02 mg Lꢀ 1. During further optimization, intro-
ducing a methyl group at the 5-position on the pyrazine ring of com-
pound A8 to give the most active compound A23 with LC50 value of
0.76 mg Lꢀ 1 and was comparable with the positive control fluensulfone.
In the in vivo test of matrix soil, compound A8 kept good performance
and the inhibition rate was 56.25% at 5 mg Lꢀ 1. From the over-all
performance of in the in vitro and in vivo test we concluded that tri-
fluorobutene amide A8 is a very promising new nematicidal compound
as well as an interesting new lead for further research.
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Declaration of Competing Interest
22 Lalita SR. Nematicidal activity of the leaf extract of Vinca rosea, carbofuran and their
combinations against Meloidogyne incognita infesting papaya. Pestic Res J. 2015;27:
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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.
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Acknowledgments
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This work was financial supported by the National Natural Science
Foundation of China (21672061). National Key Research Program of
China (2018YFD0200105). This work was also supported by Innovation
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We are very thankful to Dr. Bingli Gao and his co-workers in Huzhou
Modern Agricultural Biotechnology Innovation Center, Chinese Acad-
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Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127917.
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