Design, Synthesis, and Fungicidal Activities of Novel Piperidyl Thiazole Derivatives Containing Oxime Ether or Oxime Ester Moieties

Article abstract of DOI:10.1021/acs.jafc.0c07581

To explore the influence of the positions of the two nitrogen atoms on the thiazole ring and the isoxazoline ring on the activity, a series of novel piperidyl thiazole derivatives containing oxime ether and oxime ester moieties with two nitrogen atoms on the same or opposite sides have been designed, synthesized, and first evaluated for their fungicidal activities against Phytophthora capsici in vitro. The bioassay results showed that the target compounds possessed moderate to good fungicidal activities against P. capsici, among which oxime ether compound 11b shows the highest fungicidal activity in vitro (EC50 = 0.0104 μg/mL) which is higher than dimethomorph (EC50 = 0.1148 μg/mL) and diacetylenyl amide (EC50 = 0.040 μg/mL). Compared with oxime ether compounds (the two nitrogen atoms are on the opposite sides), the activities of oxime ester compounds were significantly reduced. It is different from the commercial fungicide fluoxapiprolin, and the activities of the compounds with the two nitrogen atoms on the same side were significantly reduced compared to the compounds with the two nitrogen atoms on the opposite sides. Moreover, compounds 11b, 11d, 11e, and 11g showed moderate to good antifungal activities in vivo against Phytophthora capsici, Pseudoperonospora cubensis, and Phytophthora infestans. Scanning electron microscopy of compound 11b on the hyphae morphology showed that compound 11b might cause mycelial abnormalities of P. capsici.

Full text of DOI:10.1021/acs.jafc.0c07581

pubs.acs.org/JAFC
Article
Design, Synthesis, and Fungicidal Activities of Novel Piperidyl
Thiazole Derivatives Containing Oxime Ether or Oxime Ester
Moieties
Qiang Bian,* Rui-Qi Zhao, Xing-Jie Peng, Li-Jie Gao, Guo-Na Zhou, Shu-Jing Yu,
and Wei-Guang Zhao*
Cite This: J. Agric. Food Chem. 2021, 69, 3848−3858
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: To explore the influence of the positions of the two nitrogen atoms on the thiazole ring and the isoxazoline ring on
the activity, a series of novel piperidyl thiazole derivatives containing oxime ether and oxime ester moieties with two nitrogen atoms
on the same or opposite sides have been designed, synthesized, and first evaluated for their fungicidal activities against Phytophthora
capsici in vitro. The bioassay results showed that the target compounds possessed moderate to good fungicidal activities against P.
capsici, among which oxime ether compound 11b shows the highest fungicidal activity in vitro (EC50 = 0.0104 μg/mL) which is
higher than dimethomorph (EC50 = 0.1148 μg/mL) and diacetylenyl amide (EC50 = 0.040 μg/mL). Compared with oxime ether
compounds (the two nitrogen atoms are on the opposite sides), the activities of oxime ester compounds were significantly reduced.
It is different from the commercial fungicide fluoxapiprolin, and the activities of the compounds with the two nitrogen atoms on the
same side were significantly reduced compared to the compounds with the two nitrogen atoms on the opposite sides. Moreover,
compounds 11b, 11d, 11e, and 11g showed moderate to good antifungal activities in vivo against Phytophthora capsici,
Pseudoperonospora cubensis, and Phytophthora infestans. Scanning electron microscopy of compound 11b on the hyphae morphology
showed that compound 11b might cause mycelial abnormalities of P. capsici.
KEYWORDS: piperidyl thiazole derivatives, oxime ether, oxime ester, positions of the two nitrogen atoms, fungicidal activity
pathogenic oomycetes other than saprophytes, it has attracted
extensive attention of pesticide enterprises.9−12 In 2011, Bayer
developed another piperidyl thiazoline-isoxazoline fungicide
fluoxapiprolin.13
INTRODUCTION
■
Oomycetes differ from fungi in many respects.1 The cell wall of
most fungi is composed of chitin, while the cell wall of
oomycetes is cellulose. The nutritive bodies of oomycetes were
diploid, and most of the nutritive bodies of fungi were haploid.
Zoospores of oomycetes are with double flagella, while the
spores produced by fungi are generally free of flagella and cannot
swim. The important component of the fungal cell membrane
contains ergosterol, which the oomycete does not have.2
Because of the special properties of oomycetes, it is necessary
to study oomycetes separately.
From the current structure−activity relationship, we can see
that piperidine-thiazole-isoxazoline is the core skeleton
structure, by calculating the lowest energy conformation; it
can be shown that the thiazole ring and the isoxazoline ring are
close to the coplanar position, the nitrogen atoms on thiazole
and isoxazoline are on the same side, and the bond between the
two rings is free to rotate (Figure 2). When the two rings are at
different angles, the interaction of nitrogen atoms in the two
rings with the target protein will be affected, which may have
important influence on the fungicidal activity. In this work, we
connected the thiazole ring and the isoxazoline ring with two
carbon atoms and opened the isoxazoline ring, designed, and
synthesized oxime ether and oxime ester analogues with two
nitrogen atoms on the same or opposite sides, explored the
influence of the positions of the two nitrogen atoms on the
activity, and studied the fungicidal activities against Phytoph-
As an important plant pathogen, oomycetes can parasitize
plant body and cause plant lesions.3 The host range of
oomycetes is also very wide, including: fruit trees, vegetables,
flowers, hemp, and other important cash crops. The reason why
oomycetes are extremely destructive and cause devastating
damage to the host is that oomycetes are highly infectious and
can infect plants for many times during the whole stage of plant
growth and development, causing epidemic diseases. Oomy-
cetes caused great economic losses to crops such as potatoes,
tomatoes, peppers, and soybeans.
However, there are only two kinds of special pesticides for
controlling oomycetes diseases, namely, carboxyamides4 and
piperidyl thiazole (Figure 1). In 2007, the first piperidyl
thiazoline-isoxazoline fungicide oxathiapiprolin was developed
by DuPont.5−8 Because oxathiapiprolin shows extremely high
activity and unique mechanism of action against plant
Received: December 1, 2020
Revised: March 10, 2021
Accepted: March 18, 2021
Published: March 29, 2021
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858
© 2021 American Chemical Society
3848

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Figure 1. Commercial fungicides used to kill oomycetes.
Figure 2. Design of target compounds.
and purified, according to standard techniques just before use. The
synthetic routes are given in Schemes 1−3.14−22
thora capsici in vitro and its structure−activity relationship
(Figure 2). Moreover, the selected compounds were studied for
antifungal activities in vivo against Phytophthora capsici,
Pseudoperonospora cubensis, and Phytophthora infestans. Fur-
thermore, scanning electron microscopy (SEM) observations
were performed to explore the preliminary antifungal mecha-
nism of these compounds.
In order to study the effect of positions of nitrogen of oxime ether
and thiazolidine on activity, we first synthesized compounds with the
nitrogen of oxime ether and thiazolidine on the opposite sides. Then,
we synthesized compounds with the nitrogen of oxime ether (ester) and
thiazolidine on the same side. The operating steps and physical data in
detail of intermediates and target compounds 11a−11s, 13a−13n,
20a−20j, and 21 can be found in the Supporting Information.
MATERIALS AND METHODS
Biological Assay. Each bioassay was repeated three times at 25
1
■
°C. Activity results were estimated, according to a percentage scale of
0−100 (0, no activity; 100, total kill). The results are presented as
means standard errors.
Instruments. 1H, 13C nuclear magnetic resonance (NMR) spectra
were recorded on Bruker Avance 400 Ultrashield NMR spectrometers.
Chemical shifts (δ) were given in parts per million (ppm) and were
measured downfield from internal tetramethylsilane. High-resolution
mass spectrometry (HRMS) data were obtained on an FTICR-MS
instrument with a q-TOF mass analyzer (Ionspec 7.0 T). The melting
points were determined on an X-4 microscope melting point apparatus
and are uncorrected. Conversion was monitored by thin layer
chromatography. Flash column chromatography was performed over
silica gel (200−300 mesh). The microscopic morphology of fungal
hyphae was observed by SEM (Hitachi, S-3400N, Japan).
Fungicidal Activity against Phytophthora capsici (in Vitro). The in
vitro fungicidal activities of the synthesized compounds against P. capsici
were determined, as previously described.23 The detailed biological
assay methods are given in the Supporting Information.
In Vivo Fungicidal Activities. The detailed biological assay methods
of the in vivo fungicidal activities of the synthesized compounds against
P. capsici, P. cubensis, and P. infestans are given in the Supporting
Information.
Scanning Electron Microscopy Observations. SEM observa-
tions on the hyphae of P. capsici were conducted, according to the
method of a previous work.24 The detailed methods are given in the
Supporting Information.
General Synthesis. Dimethomorph (BASF SE), mandipropamid
(Syngenta), oxathiapiprolin (synthesized, according to the related
literature), and other reagents were purchased from commercial
sources and were used as received. All anhydrous solvents were dried
3849
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Scheme 1. Synthesis of Compounds 11
Scheme 2. Synthesis of Compounds 13
low yield. When the mixture of pyridine and 1,4-dioxane was
used as the reaction solvent, the reaction proceeded slowly at
room temperature, and there would be a new byproduct under
reflux. Finally, the amount of the byproduct exceeded that of the
target product, leading to a low yield. When toluene was used as
the reaction solvent and reacted at room temperature, the post-
treatment was simple, and the yield was significantly improved
(82.2%).
RESULTS AND DISCUSSION
■
Synthesis. Optimization of Reaction Conditions for the
Synthesis of Compound 3. This reaction belongs to the
preparation of thioamide. Lawson’s reagent, a common
thionating reagent, was used for the reaction. Three different
reaction solvents were selected for comparison during the
experiment (Table 1).
When THF was used as the reaction solvent, it did not react at
room temperature and required heating to reflux with extremely
3850
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Scheme 3. Synthesis of Compounds 20 and 21
is better than that of fluorine-substituted compound (11d);
however, for these compounds containing meta-substituents,
the activity of methyl-substituted compound (11f) is lower than
that of fluorine-substituted compound (11h). The influence of
substituent positions on activity shows the following trend: the
ortho-substituted compounds > meta-substituted compounds >
para-substituted compounds (e.g., 11d vs 11h vs 11l); for most
of the compounds, monosubstituted compounds exhibited
higher antifungal activities than that of non-substituted and
disubstituted compounds (e.g., 11a vs 11b vs 11r). We further
screened the antifungal activities against Phytophthora capsici by
lowering the screening concentration; compound 11b showed
an 89.7% inhibitory activity at 0.05 μg/mL, which is higher than
that of dimethomorph (26.3% at 0.05 μg/mL). This compound
can be used as an active lead for further study.
Table 1. Yields of Compound 3 under Different Reaction
Conditions
pyridine:
solvent
tetrahydrofuran 1,4-dioxane (1:1)
toluene
reaction temperature
condition
reflux
reflux
room
temperature
yield
15.3%
27.9%
82.2%
Optimization of Reaction Conditions for the Synthesis of
Compound 16. The synthesis of compound 16 first refers to the
synthesis process of intermediate 6, and the reaction system of
tert-butanol and triethylamine was used. In the experimental
process, it was found that the target product 16 can be
generated, but the yield was low (only 36.7%). We then
optimized the solvent for the reaction, and when methanol and
pyridine were used as the solvent, the reaction can be completed
within 4 h. No obvious decomposition of the product was found
when prolonging the reaction time, and the yield could reach
46.5%.
The oxime ester compounds showed fungicidal activities
against P. capsici, and 13a, 13c, 13i, and 13j showed 100%
fungicidal activities at 50 μg/mL. However, compared with
oxime ether compounds, the activities of these compounds were
significantly reduced (Table 3).
We then tested their EC50 values of selected compounds with
highly active compounds, among which compounds 11b, 11d,
11e, 11g, and 11h showed good fungicidal activities against P.
capsici (EC50 < 1 μg/mL) (Table 4). In particular, compound
11b (EC50 = 0.0104 μg/mL) showed much higher activity than
the control drug dimethomorph (EC50 = 0.1148 μg/mL) and
diacetylenyl amide (EC50 = 0.040 μg/mL) (Figure 3).
It is not like the commercial fungicide fluoxapiprolin, a new
structure−activity relationship was exhibited. For these
compounds with the nitrogen of oxime ether and thiazolidine
on the same side, all of them have certain fungicidal activity.
Compounds 20b, 20f, and 21 showed 100% fungicidal activity at
In Vitro Activity. When the nitrogen of oxime ether and
thiazolidine are on the opposite sides: for the oxime ether
compounds, monosubstituted compounds showed a good
inhibitory effect against P. capsici at the concentration of 50
μg/mL, in particular, compounds 11b, 11d, 11e, 11g, 11h, and
11j showed 100% antifungal activity (Table 2). The electrical
properties, positions, and number of substituents on the
benzene ring have an effect on the antifungal activity. The
electrical properties of substituents have an important effect on
the activity of compounds containing ortho-substituents and
meta-substituents, and for these compounds containing ortho-
substituents, the activity of methyl-substituted compound (11b)
3851
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Table 2. In Vitro Antifungal Activities of Oxime Ether Compounds 11a−11s against P. capsici
50 μg/mL (Table 5). However, their activities were significantly
decreased compared to these compounds with the nitrogen
atom on the opposite sides. This indicates that the position of
nitrogen atoms on the oxime ether (ester) and thiazole plays a
decisive role in determining the fungicidal activity of these
compounds.
We also tested the EC50 for these compounds (Table 6); the
most active compound was 20b (EC50 = 1.1283 μg/mL), with
an ortho-F substituent on the benzene ring. However, its activity
was significantly lower than diacetylmorph (EC50 = 0.1148 μg/
mL) and mandipropamid (EC50 = 0.04 μg/mL) and even lower
than 11b (EC50 = 0.0108 μg/mL). The structure−activity
relationship further indicated that the positions of nitrogen of
oxime ether and thiazolidine had a great influence on the
activity.
In Vivo Activity. We then tested the antifungal activities of
highly active compounds 11b, 11d, 11e, and 11g against P.
capsici, P. cubensis, and P. infestans in vivo, and the bioassay results
showed that these four compounds showed moderate to good
activities against these oomycetes. It showed the following
activity trend 11b > 11d > 11e > 11g, which was consistent with
the in vitro activity regularity. The activity of 11b against the
three oomycetes was better than that of mandipropamid (Table
7 and Figure 4).
SEM of Compound 11b on the Hyphae Morphology.
The mycelial morphology of P. capsici treated with EC50 of
3852
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Table 3. In Vitro Antifungal Activities of Oxime Ester Compounds 13a−13n against P. capsici
compound 11b was observed by SEM (Figure 5). The mycelium
morphology of the blank control was smooth and plump, with
good extension, uniform thickness, and smooth hyphal lines. It
was seen that compound 11b and oxathiapiprolin could
effectively destroy the mycelial structure and reduce its
virulence, some mycelia collapsed and folded obviously.
Presumably, compound 11b destroyed the cell membrane and
wall of P. capsici, culminating in the death of hyphae.
In summary, a series of novel piperidyl thiazole derivatives
containing oxime ether and oxime ester moieties with two
3853
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Table 4. EC50 of Compounds 11 and 13 against P. capsici
compound
11b
11d
11e
11f
11g
11h
11i
11j
11l
11m
13a
13b
13c
13d
13e
13h
y = ax + b
r2
EC50 μg/mL
95% confidence interval
y = 1.7840x + 8.5058
y = 2.1362x + 6.8961
y = 1.8279x + 6.0826
y = 1.9803x + 2.3833
y = 1.8014x + 5.7409
y = 1.4468x + 5.0785
y = 2.5494x + 2.0111
y = 1.3592x + 3.9884
y = 2.3849x + 1.8795
y = 2.4896x + 2.1622
y = 1.8285x + 4.1494
y = 2.0604x + 2.5349
y = 2.2346x + 3.3841
y = 1.9619x + 2.5723
y = 2.1827x + 2.1744
y = 2.2143x + 2.1794
y = 2.6280x + 2.3298
y = 2.6920x + 2.2535
y = 2.1981x + 2.2907
y = 1.6678x + 3.6272
y = 2.1001x + 2.2649
y = 2.2311x + 8.4774
y = 1.6550x + 6.5558
y = 0.8459x +6.9643
0.9815
0.9879
0.9978
0.9910
0.9785
0.9820
0.9927
0.9973
0.9925
0.9886
0.9922
0.9970
0.9894
0.9910
0.9967
0.9856
0.9737
0.9799
0.9985
0.9855
0.9979
0.9885
0.9930
0.9790
0.0108
0.1295
0.2557
20.9584
0.3879
0.8825
14.8731
5.5501
20.3430
13.7987
2.9187
15.7190
5.2859
17.2758
19.7035
18.7846
10.3765
10.4768
17.0836
6.6551
20.0602
0.0400
0.1148
0.0048
0.0085−0.0139
0.1079−0.1555
0.2371−0.2758
17.6930−24.8264
0.3069−0.4902
0.6858−1.1357
12.9661−17.0607
5.1164−6.0205
14.4705−23.6877
11.6431−16.3534
2.5036−3.4026
14.3911−17.1695
4.4576−6.2681
14.7551−20.2271
17.8381−21.7639
15.2875−23.0817
7.9668−13.5152
8.3302−13.1766
16.0105−18.2286
5.3031−8.3520
18.5349−21.7111
0.0305−0.0516
0.1005−0.1311
0.0031−0.0072
13i
13j
13l
13m
13n
mandipropamid
dimethomorph
oxathiapiprolin
Figure 3. In vitro antifungal activities of 11b and oxathiapiprolin.
nitrogen atoms on the same or opposite sides have been
designed and synthesized to explore the influence of the
positions of the two nitrogen atoms of the thiazole ring and the
isoxazoline ring on the activity. Then, we systematically studied
their fungicidal activities against P. capsici. The bioassay results
showed that the target compounds possessed moderate to good
fungicidal activities against P. capsici. For these compounds with
the nitrogen of oxime ether and thiazolidine on the opposite
sides, compound 11b shows the highest fungicidal activity in
vitro (EC50 = 0.0108 μg/mL) which is higher than the control
drug dimethomorph (EC50 = 0.1148 μg/mL) and mandipropa-
mid (EC50 = 0.040 μg/mL), and the activities of oxime ester
compounds were significantly reduced compared with oxime
ether compounds. It is not like the commercial fungicide
fluoxapiprolin, a new structure−activity relationship was
exhibited. The activities of these compounds with the nitrogens
of oxime ether and thiazolidine on the same side (20) were
significantly reduced, as compared to these compounds with the
nitrogen atoms on the opposite sides (11). This indicates that
the position of nitrogen atoms on the oxime ether (ester) and
thiazole plays a decisive role in determining the fungicidal
activity of these compounds, which provides important
information for the study of mechanism of action. The in vivo
antifungal test results showed that compounds 11b, 11d, 11e,
and 11g showed moderate to good activities against P. capsici, P.
cubensis, and P. infestans. SEM of compound 11b on the hyphae
morphology showed that compound 11b might cause mycelial
abnormalities of P. capsici cell membrane permeability changes.
Further investigations on structural optimization and mode of
action are in progress in our laboratory.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jafc.0c07581.
3854
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Table 5. In Vitro Antifungal Activities of Oxime Ether and Ester Compounds 20a−20j and 21 against P. capsici
Wei-Guang Zhao − National Pesticide Engineering Research
Center (Tianjin), State Key Laboratory of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China; Email: zwg@nankai.edu.cn
Synthetic procedures and spectroscopic data; fungicidal
activity against P. capsici (in vitro and in vivo), P. cubensis
(in vivo), and P. infestans (in vivo); SEM observations; and
1H NMR, 13C NMR, and HRMS spectra (PDF)
Authors
AUTHOR INFORMATION
■
Rui-Qi Zhao − National Pesticide Engineering Research Center
(Tianjin), State Key Laboratory of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Xing-Jie Peng − National Pesticide Engineering Research Center
(Tianjin), State Key Laboratory of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Corresponding Authors
Qiang Bian − National Pesticide Engineering Research Center
(Tianjin), State Key Laboratory of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China; orcid.org/0000-0001-8796-4264;
Phone: +86-(0)22-23503703; Email: bianqiang@
nankai.edu.cn; Fax: 86-(0)22-23503703
3855
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Table 6. EC50 of Compounds 20 and 21 against P. capsici
compound
20a
20b
20c
20d
20f
20g
20i
20j
y = ax + b
r2
EC50 μg/mL
95% confidence interval
y = 1.1298x + 4.4879
y = 1.3260x + 4.9305
y = 1.3507x + 3.4676
y = 1.1242x + 3.8087
y = 1.6617x + 3.7167
y = 1.6647x + 3.5229
y = 2.0703x + 3.2124
y = 1.2660x + 3.6307
y = 1.7835x + 3.7169
y = 2.2311x + 8.4774
y = 1.6550x + 6.5558
y = 0.8459x + 6.9643
0.9862
0.9864
0.9750
0.9855
0.9977
0.9949
0.9936
0.9859
0.9870
0.9885
0.9930
0.9790
2.8398
1.1283
13.6318
11.4743
5.9189
7.7154
7.3018
12.0666
5.2409
0.0400
0.1148
0.0048
2.2465−3.5899
0.8782−1.4495
10.3001−18.0412
9.4720−13.8997
5.4887−6.3827
6.8076−8.7442
6.3234−8.4316
9.9912−14.5730
4.3656−6.2917
0.0305−0.0516
0.1005−0.1311
0.0031−0.0072
21
mandipropamid
dimethomorph
oxathiapiprolin
Table 7. Fungicidal Activities against P. capsici, P. cubensis, and P. infestans in Vivo
control (%)
compound
11b
concentration μg/mL
P. capsici
P. cubensis
P. infestans
50
25
12.5
6.25
3.125
50
81.6 2.3
65.3 3.1
51.2 3.6
37.6 2.4
20.6 1.2
58.4 2.6
44.6 1.6
32.3 3.1
25.3 1.4
14.3 1.6
45.6 3.4
38.6 2.2
25.6 1.5
17.6 2.4
8.9 0.6
43.3 4.2
35.6 1.3
24.8 2.3
15.6 1.3
0.0 0.0
73.2 2.3
62.3 3.1
48.6 2.4
35.6 2.7
24.3 1.6
100.0 0.0
89.2 2.3
70.0 1.5
62.5 2.6
52.0 1.3
85.5 2.1
72.3 1.3
56.5 2.6
45.6 3.1
32.3 2.4
65.6 1.5
43.2 2.6
31.5 1.4
19.5 2.7
0.0 0.0
52.3 1.5
38.6 2.6
24.6 1.8
12.5 0.7
0.0 0.0
88.6 2.3
75.7 3.1
62.3 1.6
54.4 1.7
35.7 2.2
71.8 3.1
61.4 2.4
48.9 1.6
35.7 2.1
24.6 0.6
55.6 1.6
48.7 2.6
34.5 3.4
23.6 1.2
14.3 0.9
51.4 1.8
48.7 3.3
37.6 1.2
24.5 2.4
12.6 0.9
80.5 2.4
69.6 3.2
61.3 1.7
55.6 3.3
38.3 1.7
85.3 3.4
72.3 2.4
65.8 1.6
58.4 2.5
38.6 0.8
88.6 1.9
75.6 2.4
66.8 2.5
54.3 1.6
45.8 1.8
11d
25
12.5
6.25
3.125
50
11e
25
12.5
6.25
3.125
50
11g
48.6 1.6
39.5 2.8
25.4 1.1
10.3 1.4
0.0 0.0
25
12.5
6.25
3.125
50
mandipropamid
dimethomorph
oxathiapiprolin
78.7 2.5
65.4 1.9
53.2 2.2
38.9 2.3
25.6 3.2
79.7 2.5
74.3 3.1
52.2 1.4
35.7 0.7
26.9 2.2
100 0.0
95.3 1.6
75.2 2.6
65.5 1.5
52.6 2.7
25
12.5
6.25
3.125
50
25
12.5
6.25
3.125
10
5
2.5
1.25
0.625
Li-Jie Gao − College of Animal Science & Technology, Forestry
College, Hebei Agricultural University, Baoding 071000,
China
Guo-Na Zhou − College of Animal Science & Technology,
Forestry College, Hebei Agricultural University, Baoding
071000, China
Shu-Jing Yu − National Pesticide Engineering Research Center
(Tianjin), State Key Laboratory of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jafc.0c07581
3856
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
Figure 4. In vivo antifungal activities of 11b and controls.
Figure 5. Scanning electron micrographs of the hyphae of P. capsici.
Funding
DEDICATION
■
We are grateful to the National Key Research and Development
Program of China (no. 2017YFD0200506), Key R&D Program
Projects in Hebei Province (no. 20326516D), National Key
R&D Program of China (nos. 2017YFD0201400 and
2017YFD0201403), and the Open Research Fund of National
Citrus Engineering Research Centre (No. NCERC2019002) for
generous financial support for our programs.
Dedicated to the 100th anniversary of Chemistry at Nankai
University.
REFERENCES
■
(1) Larroque, M.; Barriot, R.; Bottin, A.; Barre, A.; Rougé, P.; Dumas,
B.; Gaulin, E. The unique architecture and function of cellulose-
interacting proteins in oomycetes revealed by genomic and structural
analyses. BMC Genom. 2012, 13, 605.
Notes
The authors declare no competing financial interest.
3857
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
(2) Carlile, M. J.; Watkinson, S. C.; Gooday, G. W. The Fungi, 2nd ed.;
Academic Press: New York, 2001.
synthesis of primary amines via the spiroborate-catalyzed borane
reduction of oxime ethers. Org. Lett. 2007, 9, 1793−1795.
(23) Liu, Y.-X.; Zhang, P.-X.; Li, Y.-Q.; Song, H.-B.; Wang, Q.-M.
Design, synthesis, and biological evaluation of 2-benzylpyrroles and 2-
benzoylpyrroles based on structures of insecticidal chlorfenapyr and
natural pyrrolomycins. Mol. Diversity 2014, 18, 593−598.
(24) Yin, X.-D.; Sun, Y.; Lawoe, R. K.; Yang, G.-Z.; Liu, Y.-Q.; Shang,
X.-F.; Liu, H.; Yang, Y.-D.; Zhu, J.-K.; Huang, X.-L. Synthesis and anti-
phytopathogenic activity of 8-hydroxyquinoline derivatives. RSC Adv.
2019, 9, 30087−30099.
(3) Fisher, M. C.; Gurr, S. J.; Cuomo, C. A.; Blehert, D. S.; Jin, H.;
Stukenbrock, E. H.; Stajich, J. E.; Kahmann, R.; Boone, C.; Denning, D.
W.; Gow, N. A. R.; Klein, B. S.; Kronstad, J. W.; Sheppard, D. C.;
Taylor, J. W.; Wright, G. D.; Heitman, J.; Casadevall, A.; Cowen, L. E.
Threats posed by the fungal kingdom to humans, wildlife, and
agriculture. mBio 2020, 11, No. e00449.
(4) Lu, X. H.; Chen, L.; Liu, X. L. Research advances in carboxylic acid
amide fungicides. Chin. J. Pestic. Sci. 2010, 12, 1−12.
(5) Pasteris, R. J.; Hanagan, M. A.; Shapiro, R. Fungicidal azocyclic
amides. CN 101888843 B, 2015.
(6) Cohen, Y. Root treatment with oxathiapiprolin, benthiavalicarb or
their mixture provides prolonged systemic protection against oomycete
foliar pathogens. PloS One 2020, 15, No. e0227556.
(7) Miao, J.; Liu, X.; Li, G.; Du, X.; Liu, X. Multiple point mutations in
PsORP1 gene conferring different resistance levels to oxathiapiprolin
confirmed using CRISPR-Cas9 in Phytophthora sojae. Pest Manag. Sci.
2020, 76, 2434−2440.
(8) Peng, Q.; Wang, Z.; Liu, P.; Liang, Y.; Zhao, Z.; Li, W.; Liu, X.; Xia,
Y. Oxathiapiprolin, a novel chemical inducer activates the plant disease
resistance. Int. J. Mol. Sci. 2020, 21, 1223.
(9) Pasteris, R. J. Fungicidal heterocyclic compounds.
WO2010065579A2, 2010.
(10) Hanagan, M. A.; Pasteris, R. J. Fungicidal amides. WO
2009094407 A2, 2009.
(11) Cristau, P.; Rahn, N.; Herrmann, S.; Tsuchiya, T.; Wachendorf-
Neumann, U.; Voerste, A.; Benting, J.; Wasnaire, P.; Hoffmann, S.
Heterocyclyl-substituted thiazoles as plant protection agents. WO
2010037479 A1, 2010.
(12) Cristau, P.; Hoffmann, S.; Kluth, J.; Seitz, T.; Tsuchiya, T.;
Wasnaire, P.; Benting, J.; Wachendorff-neumann, U. Ketoheteroar-
ylpiperidine and-piperazine derivatives as fungicides. U.S. Patent
0,312,999 Al, 2011.
(13) Tsuchiya, T.; Wasnaire, P.; Hoffmann, S.; Cristau, P.; Seitz, T.;
Kluth, J.; Hillebrand, S.; Benting, J.; Portz, D.; Wachendorff-Neumann,
U. Heteroarylpiperidine and -piperazine derivatives as fungicides, CN
103180317 A, 2013.
(14) Pulici, M.; Traquandi, G.; Marchionni, C.; Scolaro, A.; Colombo,
N. Thiazolylphenyl-benzenesulfonamido derivatives as kinase inhib-
itors. WO 2012113774 A1, 2012.
(15) Davies, J. R.; Kane, P. D.; Moody, C. J. N-H Insertion reactions of
rhodium carbenoids. Part 5: A convenient route to 1,3-azoles.
Tetrahedron 2004, 60, 3967−3977.
(16) Inoue, Y.; Jones, T. K.; Kondo, H.; Nguyen, T. N.; Raheja, R.;
Ripka, W. C.; Slee, D. H.; Yu, J. H. Substituted thiazoles for treatment of
human diseases involving modulators of P-, L- and E- selectin. WO
2000034255 A1, 2000.
(17) Ohkawa, S.; Naruo, K.-I.; Miwatashi, S.; Kimura, H. Substituted
1,3-thiazole compounds, their production and use. WO 01074811 A2,
2001.
(18) Zhang, N.; Ayral-Kaloustian, S.; Mansour, T. S.; Nguyen, T. H.;
Niu, C. S.; Rosfjord, E. C.; Suayan, R.; Tsou, H.-R. 2-Aryl- and 2-
heteroarylthiazolyl compounds, methods for their preparation and use
thereof. WO 2009120826 A1, 2009.
(19) Shi, Y.; Zhang, W.; Li, L.; Tong, Z.; Bai, C. Design and synthesis
of novel triazolo-lapatinib hybrids as inhibitors of breast cancer cells.
Med. Chem. Res. 2018, 27, 2437−2445.
(20) Sulzer-Mosse, S.; Cederbaum, F.; Lamberth, C.; Berthon, G.;
Umarye, J.; Grasso, V.; Schlereth, A.; Blum, M.; Waldmeier, R.
Synthesis and fungicidal activity of N-thiazol-4-yl-salicylamides, a new
family of anti-oomycete compounds. Bioorg. Med. Chem. 2015, 23,
2129−2138.
(21) To, T. A.; Vo, Y. H.; Nguyen, A. T.; Phan, A. N. Q.; Truong, T.;
Phan, N. T. S. A new route to substituted furocoumarins via copper-
catalyzed cyclization between 4-hydroxycoumarins and ketoximes. Org.
Biomol. Chem. 2018, 16, 5086−5089.
(22) Huang, X.; Ortiz-Marciales, M.; Huang, K.; Stepanenko, V.;
́
Merced, F. G.; Ayala, A. M.; Correa, W.; De Jesus, M. Asymmetric
3858
https://doi.org/10.1021/acs.jafc.0c07581
J. Agric. Food Chem. 2021, 69, 3848−3858