Study on a new type of high efficient amide compound fungicides against soybean rust

Article abstract of DOI:10.1016/j.tetlet.2020.152745

Amide compounds have received considerable interest in agricultural chemistry due to a novel action mode, extremely high activity against a broad spectrum of soybean rust, low acute toxicity to mammals, and environmentally benign characteristics. A series

Full text of DOI:10.1016/j.tetlet.2020.152745

Tetrahedron Letters 64 (2021) 152745
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Study on a new type of high efficient amide compound fungicides
against soybean rust
a
b
b
a
b,
Pengmian Huang a, , Sheng Zhou , Yonglei Du , Hongwei Li , Yanbo Lv , Liang Lv
⇑
⇑
a School of Chemistry and Food Engineering, Changsha University of Science & Technology, Changsha 410114, China
b CAC Shanghai International Trading Co., Ltd., Shanghai 200335, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Amide compounds have received considerable interest in agricultural chemistry due to a novel action
mode, extremely high activity against a broad spectrum of soybean rust, low acute toxicity to mammals,
and environmentally benign characteristics. A series amide compounds were synthesized and character-
ized by 1H NMR and 13C NMR, which were evaluated against plant diseases caused by Phakopsora
Pachyrhizi. The results show that when the concentration of the amide compound was over 10 ppm,
the fungicidal activities on soybean rust were more than 90%. Especially, the fungicide 11 exhibits excel-
lent activity at a low concentration, which provides some hints for further investigation on structure
modification. Those amide compounds would play an important role in the control of agriculture and for-
estry, especially the pathogen of soybean rust in the foreseeable future.
Received 3 August 2020
Revised 14 November 2020
Accepted 7 December 2020
Available online 30 December 2020
Keywords:
Amide compounds
Fungicides
Fungicidal activity
Soybean rust
Ó 2020 Elsevier Ltd. All rights reserved.
Introduction
Phakopsora Pachyrhizi fungi was significantly reduced in Brazil
[7–9].
Soybean rust is caused by Phakopsora Pachyrhizi fungus, which
may lead to the loss of 10% to 15% of soybean production [1]. Seri-
ously, the loss may sharply decrease to 50% in rainy years. The dis-
ease was first found in Africa in the mid-1990s. The pathogen was
first discovered in Japan in 1902 and then throughout tropical and
subtropical Asia and Oceania in the early 20th century [1]. It then
explosively expanded to Paraguay and western Parana, Brazil, and
throughout South America within three years [2,3]. In 2004, soy-
bean rust also spread in the continental United States [4].
Claudia Godoy, the Embrapa scientist, said that soybean rust
pathogens were becoming less sensitive to different fungicides.
The activities of some pesticides have reduced to 20% from 90%.
In the worst case, farmers have to intensify spraying to ten times
in order to control the disease. In Brazil, more than three fungicides
need to be applied each season, which increase annual cost to $2
billion [5]. Undoubtedly, excessive use of fungicides will cause
serious consequences, such as increased resistance of fungal
strains. Recently research explained that excessive use of fungi-
cides has caused seriously resistance of Phakopsora Pachyrhizi fungi
and other fungal pathogens to pyrazole fungicides [6]. After using
fungicides for several years, the effectiveness of DMI against
Amide fungicides are widely used for the highly effective fungi-
cidal activity [10]. In terms of chemical structure classification they
can be divided into carboxylic acid amides, mandelic acid and
phenylamides and divided into biosynthesis inhibitors and biooxi-
dation inhibitors according to the mechanism of action. Amide
fungicides performed outstanding effects on downy mildew on
soybean, cucumber, millet, potato and eggplant caused by Phy-
tophthora. Unfortunately, after using for a period of time,the fungi-
cides will be gradually out of severce. Therefore, it is urgent to
develop some innovative compounds displaying excellent fungici-
dal activity against soybean rust.
Carboxin Standard was the earliest commercial product
launched of the Amide fungicides in 1966. Thereafter, many new
fungicides have being developed with good activity. So far, there
are 19 commercial fungicides, divided into 9 categories [11]. Due
to long-term use, many pathogens have exhibited extremely resis-
tant to carboxamide fungicides, such as Alternaria alternate
[12,13], Botrytis cinerea [14,15], Podosphaera xanthii [16], and
Mycosphaerella graminicola.[17–19] Thus, it is necessary to
develop new fungicides with excellent performance [20–24].
Xiong [25] has designed and synthesized a series of novel suc-
cinate ubiquinone oxidoreductase (SQR) inhibitors containing
pyrazole-carboxamide. The evaluation showed good SQR inhibi-
tory activities against Fusarium solani and Pythium brevis with
the concentration 200 mg/L. Specially, Compound A showed the
⇑
Corresponding authors.
E-mail addresses: huangpengmian@126.com (P. Huang), liang_lv@cacch.com
most excellent SQR inhibitory activity, with
a Ki value of
(L. Lv).
https://doi.org/10.1016/j.tetlet.2020.152745
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

P. Huang, S. Zhou, Y. Du et al.
Tetrahedron Letters 64 (2021) 152745
Table 1
Amide fungicides 1–12.
Product
1
Q
X
Y
Yielda (%)
37
Isopropyl
methyl
2
3
4
5
6
7
8
Isopropyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
85
87
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
76.7
59
73
75
49
9
Isopropyl
methyl
methyl
69.3
79
10
Tert-butyl
2

P. Huang, S. Zhou, Y. Du et al.
Tetrahedron Letters 64 (2021) 152745
Table 1 (continued)
Product
11
Q
X
Y
Yielda (%)
73.9
Tert-butyl
methyl
12
Tert-butyl
Isopropyl
77
a
Isolated yield.
0.081
(Ki = 0.307
l
M, which was about 4 times stronger than pentathion
M).
Results and discussion
l
Fungicidal activities of amide fungicides 1–12
The samples were dissolved in a little solvent and diluted with
water containing 0.1% Tween 80. Two-leaf stage soybean was cul-
tivated in a greenhouse as a test host plant of Phakopsora
Pachyrhizi. The results of the survey referred to the Key Manual of
Plant Disease. The activities against soybean rust of amide fungi-
cides 1–12 and compound A were tested in Table 2.
Relationship between fungicidal activities and structure of amide
fungicides
A series of novel 1,2,4-triazole derivatives with 4-(4-substituted
phenyl)piperazine side chain based on the structure of lanosterol
14a-demethylase (CYP51) were developed by Xu [26]. By measur-
In Fig. 1, the activities between amide fungicide 1 (thiazole) and
7 (pyrazole) were compared in A. At high concentrations, nearly no
significant differences of fungicidal activities played, but the fungi-
cidal activity of 7 at low concentration improved significantly.
Therefore, the fungicidal activity with pyrazole was higher than
that of the thiazole. In order to investigate the fungicidal activities
of halogen substitution on pyrazole the bactericidal activities of
amide fungicides 2, 4, and 9 were discussed. At high concentra-
tions, the fungicidal activities of the three compounds were equiv-
alent, but the fungicidal activities at low concentrations with Cl
and unsubstituted showed no activities. And the fungicidal activi-
ties with F substitution was 20, so the sequence of fungicidal activ-
ities of halogen substitution on pyrazole was F > Cl > unsubstituted.
Similarly, the activities of amide fungicides 2 with methyl, 5
with difluoromethyl and 7 with trifluoromethyl were also com-
pared that the activities of amide fungicide 5 with difluoromethyl
at low concentrations were better than that of trifluoromethyl and
methyl. Then the fungicidal activities of amide fungicides 6 and 9
substituted with alkane groups were also investigated in the pres-
ence of halogen substitution on pyrazole. The result showed that
ing the minimum inhibitory concentration, antifungal activities
against eight human pathogenic fungi are evaluated in vitro.
Nearly all the compounds are more resistant to Candida albicans
than fluconazole.
Depressively, these fungicides play poor activity at low concen-
tration. Therefore, it is very important to develop more effective
fungicides at low concentration. This paper presents the design
and synthesis for a class of amide compounds. Exhilaratingly, the
amide compounds perform unexpectedly high fungicidal activities
against plant diseases caused by oomycetes, ascomycetes, basid-
iomycetes or deuterium bacteria.
Experimental section
In this work, 12 novel amide compounds based on compound A
were designed and the related structures are in Table 1. The syn-
thetic process of amide fungicides are shown in Scheme 1.
Scheme 1. The synthesis of the amide fungicides 1–12. (R2 is difluoromethyl or a trifluoromethyl; X is selected among a C2-C12 alkyl; Y is selected among a C1-C6 alkyl; LG
represents a readily detachable group such as a chlorine or a bromine, alkoxy or acyloxy; L represents a group susceptible to nucleophilic reaction, such as fluorine or
chlorine).
3

P. Huang, S. Zhou, Y. Du et al.
Tetrahedron Letters 64 (2021) 152745
Table 2
the fungicidal activities of compound with difluoromethyl were
better than that with ethyl.
Fungicidal activity of amide fungicides 1–12 and compound A.
The fungicidal activities of amide fungicides 2, 10, and 12 sub-
stituted by phenoxy group were also studied. It displayed that at
the Y position the fungicidal activities with tertiary butyl radical
at low concentrations was better than Propyl radical. Similarly,
amide fungicides 10 and 12 were studied that the fungicidal activ-
ities of compound substituted with methyl at X position were
superior to isopropyl at low concentrations.
Therefore, the amide fungicide 11 exhibited higher fungicidal
activities than amide fungicides 4 and 10 (result shown in Fig. 2).
The structure differences between amide fungicides 4 and 11
were that amide fungicide 4 was substituted by isopropyl while
amide fungicide 11 was substituted by tert-butyl at the Y position
respectively. The amide fungicide 10 had no halogen on pyrazole,
while the amide fungicide 11 owned F. It could be speculated from
Product
Fungicidal activities at different concentrations
10 ppm
1 ppm
0.1 ppm
1
2
3
4
5
6
7
8
100
100
95
100
85
80
100
85
100
100
100
100
40
95
90
40
95
20
20
95
20
100
100
100
45
0
0
0
0
20
0
0
30
0
9
0
10
11
12
A
20
70
0
0
Fig. 1. Comparison of fungicidal activities between similar structures. (A) The comparison of the fungicidal activities between thiazole and pyrazole;(B) The comparison of
fungicidal activities of halogen substitution on the pyrazole; (C) R2 is the comparison of the fungicidal activities among methyl, difluoromethyl and trifluoromethyl; (D) R2 is
the comparison of the fungicidal activities between difluoromethyl and ethyl; (E) Y is the comparison of the fungicidal activities between tert-butyl and isopropyl; (F) X is the
comparison of the fungicidal activities between methyl and isopropyl.
4

P. Huang, S. Zhou, Y. Du et al.
Tetrahedron Letters 64 (2021) 152745
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152745.
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Declaration of Competing Interest
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The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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