Design, synthesis, and fungicidal activity of novel 1,3,4-oxadiazole derivatives

Article abstract of DOI:10.1016/j.cclet.2018.01.050

Employing the intermediate derivatization method (IDM), twenty novel 1,3,4-oxadiazole derivatives containing arylpyrazoloxyl moiety were designed and synthesized. The structures of the title compounds were identified by ¹H NMR, ¹³C NMR, MS and elemental analyses, compound 4 was further identified by single-crystal X-ray diffraction. Antifungal activities against rice sheath blight (RSB) and sorghum anthracnose (SA) were evaluated by the mycelium linear growth rate method. Compounds 4, 16 and 20 displayed significant activities against RSB (EC₅₀ = 0.88 mg/L, 0.91 mg/L and 0.85 mg/L, respectively), higher than the reference tebuconazole; While compound 3 exhibited higher activity against SA (EC₅₀ = 1.03 mg/L), equal to commercial pyraclostrobin (EC₅₀ = 1.06 mg/L). The study showed that compound 20 is a promising fungicide for further development.

Full text of DOI:10.1016/j.cclet.2018.01.050

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CCLET 4440 No. of Pages 4
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Design, synthesis, and fungicidal activity of novel 1,3,4-oxadiazole
derivatives
a,b
b,
b
b
a,
Fuqiang Yu , Aiying Guan *, Mengru Li , Lan Hu , Xiaowu Li *
a
Department of Materials Physics and Chemistry, School of Material Science and Engineering, and Key Laboratory for Anisotropy and Texture of Materials,
Ministry of Education, Northeastern University, Shenyang 110819, China
b
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Co., Ltd., Shenyang 110021, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 4 December 2017
Received in revised form 22 January 2018
Accepted 24 January 2018
Available online xxx
Employing the intermediate derivatization method (IDM), twenty novel 1,3,4-oxadiazole derivatives
containing arylpyrazoloxyl moiety were designed and synthesized. The structures of the title compounds
1
13
were identified by H NMR, C NMR, MS and elemental analyses, compound 4 was further identified by
single-crystal X-ray diffraction. Antifungal activities against rice sheath blight (RSB) and sorghum
anthracnose (SA) were evaluated by the mycelium linear growth rate method. Compounds 4, 16 and 20
displayed significant activities against RSB (EC50 = 0.88 mg/L, 0.91 mg/L and 0.85 mg/L, respectively),
higher than the reference tebuconazole; While compound 3 exhibited higher activity against SA
Keywords:
1,3,4-Oxadiazole derivatives
Intermediate derivatization method
Rice sheath blight
Sorghum anthracnose
(EC50 = 1.03 mg/L), equal to commercial pyraclostrobin (EC50 = 1.06 mg/L). The study showed that
compound 20 is a promising fungicide for further development.
©
2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Structure-activity relationship
Rice sheath blight (Rhizoctonia solani Kühn, RSB) is one of the
three important diseases (rice sheath blight, bacterial blight and
rice blast) of rice. Meanwhile, sorghum anthracnose (Colletotri-
chum graminicola (Cesati) Wilson, SA) is also a worldwide disease,
which occurs at all stages of sorghum growth. It was reported that
both RSB and SA can cause 10%–30% even 40%–50% production loss
in crops per year worldwide [1,2]. The use of fungicides can
effectively reduce crop loss and further to guarantee crop harvest.
At present, the existing pesticides for control of RSB are mainly
tebuconazole, pyraclostrobin and azoxystrobin; and thiram and
prochloraz for control of SA. However, the fungus will develop
resistance subsequently after these agrochemicals are used for a
while. The Fungicide Resistance Action Committee (FRAC) reported
that the fungicides with known modes of action are classified
according to target sites into more than 50 groups [3]. Unfortu-
nately over 80% target sites have already developed medium to
high resistance risk to many familiar classes of fungicides, which
involved the vast majority of fungicide structures. So it is an urgent
demand for developing continually novel and highly active
fungicides with different modes of action to address the
increasingly serious resistance problem.
1,3,4-Oxadiazole derivatives have been paid more and more
attention since Gibson reported cyclization mechanism of this type
of compounds in 1962 firstly [4]. The derivatives of 1,3,4-
oxadiazoles often exhibit broad biological activities in medicine
[5–9] and agriculture. For agrochemicals, Song et al. [10],
introduced phenoxymethyl moiety into 1,3,4-oxadiazole to afford
insecticides; Zhang et al. [11], discovered antimicrobial agents by
importing phenylpyrazolyl to 1,3,4-oxadiazole. Zhang et al. [12],
inserted piperazine to 1,3,4-oxadiazole and obtained compounds
which exhibited broad spectrum herbicidal and fungicidal activi-
ties. Some literatures also disclosed 1,3,4-oxadiazoles containing
phenyl [13], pyridyl [14], thiazole ring [14] as agrochemicals. On
the other side, the arylpyrazole derivatives have been playing an
important role both in medicinal [15,16] and crop protection fields
[17], too. The main varieties containing arylpyrazole substructure
include pyrametostrobin [18,19], pyraoxystrobin [20] and pyra-
clostrobin [21,22]. Although these three fungicides all belong to
strobilurin, they focus on different targets, rice sheath blight and
rice blast, downy mildew, and powdery mildew, respectively.
Scholars have been carrying out studies on taking arylpyrazole as
structural units of pesticides. Wang et al. [23], found pyridylpyr-
azole acid derivatives can be used as lead compounds for further
development of novel insecticides. Wu et al. [24], demonstrated
that arylpyrazole carboxamide derivatives exhibited broad-spec-
trum insecticidal activities. Wang et al. [25], achieved heterocyclic
compounds containing pyridylpyrazole not only displayed
*
Corresponding authors.
E-mail addresses: yufuqiang@sinochem.com (F. Yu), guanaiying@sinochem.com
(
A. Guan), xwli@mail.neu.edu.cn (X. Li).
https://doi.org/10.1016/j.cclet.2018.01.050
001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
1
Please cite this article in press as: F. Yu, et al., Design, synthesis, and fungicidal activity of novel 1,3,4-oxadiazole derivatives, Chin. Chem. Lett.
2018), https://doi.org/10.1016/j.cclet.2018.01.050
(

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CCLET 4440 No. of Pages 4
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F. Yu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
Scheme 1. An overview of the design of 1,3,4-oxadiazole derivatives.
excellent fungicidal activities, but also exhibited modest insecti-
cidal activities. Therefore, arylpyrazole is a magical and formidable
chemical group, which is worthy of being applied further.
In this study, to develop new fungicides with high biological
activity, based on the excellent performance of the above two kinds
of compounds, under the direction of the intermediate derivatiza-
tion methods (IDM) [26–32], we introduced arylpyrazoloxyl to
The crystal structure of target compound 4 was also determined
by X-ray diffraction analyses (The atomic coordinates for
compound 4 have been deposited at the Cambridge Crystallo-
graphic Data Centre. CCDC ID: 1572037 contain the supplementary
crystallographic data for this article. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.). Its crystal structure is
shown in Fig. 1.
The antifungal activities in vitro of all the synthesized
compounds against two plant pathogenic fungi (RSB and SA)
were conducted by the mycelium linear growth rate method as
previously reported [34]. The final concentration of the test
compound in the culture medium was 100, 50, 25, 12.5, 6.25 and
3.125 mg/L. For details, see Supporting information. The test results
of the fungicidal activities of compounds 1 to 20 against RSB and SA
are listed in Table 1.
1
,3,4-oxadiazole and designed a series of novel 1,3,4-oxadiazole
derivatives using 4-chlorophenylhydrazine as the starting material
Scheme 1). The detailed synthesis, bioassays and structure-
(
activity relationship of these derivatives were discussed below.
All chemicals such as starting materials and reagents were
commercially available (Sinopharm Chemical Reagent Co., Ltd.,
China) and used without further purification. Melting points were
determined on a Büchi M-569 melting point apparatus and were
1
13
uncorrected. H NMR and C NMR spectra were recorded with a
Mercury 300 MHz spectrometer with deuterochloroform (CDCl
or DMSO-d as the solvent and tetramethylsilane (TMS) as the
3
)
According to the scheme described in Scheme 2, twenty title
compounds were designed and synthesized, their chemical
structures were summarized in Table 1. The synthesized com-
6
internal standard. Elemental analyses were determined on an
elementar Vario EL cube instrument. The mass spectra were
acquired with an Agilent 1100 series LC/MSD Trap equipped with
electron spray ionization (ESI) source. X-ray structure determina-
tion was recorded with Bruker D8 Quest Single crystal X-ray
diffractometer. The isolation of the compounds was conducted by
Biotage Isolera Prime flash purification system.
1
13
pounds were characterized by H NMR, C NMR, MS and elemental
analyses. The chemical structure of compound 4 was also
unequivocally determined by X-ray crystallography (Fig. 1).
In vitro bioassays indicated that these compounds have
moderate to significant fungicidal activity against RSB and SA.
Especially, compounds 4, 16 and 20 displayed excellent activities
against RSB (EC50 = 0.88, 0.91 and 0.85 mg/L, respectively), higher
than the reference tebuconazole; While compound 3 exhibited
higher activity against SA (EC50 = 1.03 mg/L), equal to commercial
pyraclostrobin (EC50 = 1.02 mg/L). In general, the fungicidal activity
of the tested compounds against RSB is superior to that against SA,
The general synthetic methods for compounds 1–20 are shown
0
in Scheme 2. Intermediates A and B/B were prepared according to
the previously reported methods [33]. The general procedures for
synthesis of intermediates D, E, G and compounds 1–20 were listed
in Supporting information.
Scheme 2. Synthetic route of compounds 1–20.
Please cite this article in press as: F. Yu, et al., Design, synthesis, and fungicidal activity of novel 1,3,4-oxadiazole derivatives, Chin. Chem. Lett.
2018), https://doi.org/10.1016/j.cclet.2018.01.050
(

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F. Yu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
3
Table 1
Chemical structures and fungicidal activity of 1,3,4-oxadiazole derivatives (compounds 1–20).
Compd.
R
Q
RSB
SA
EC50 (mg/L)
95% da
EC50 (mg/L)
95% da
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
H
3
3
3
3
Phenyl
25.87
2.94
1.57
0.88
0.89
2.16
1.97
1.63
1.92
1.59
12.46
2.87
1.45
11.12
1.78
0.91
16.5
4.28
4.27
0.85
1.02
0.81
13.94–48.02
1.79–4.86
0.83–2.98
0.30–2.54
0.32–2.55
1.03–4.54
1.07–3.62
0.82–3.24
0.92–3.97
0.72–3.51
9.38–16.54
1.78–4.61
0.58–3.58
8.69–14.23
0.94–3.40
0.59–2.96
12.26–22.29
2.91–6.30
2.87–6.36
0.27–2.70
0.41–2.54
0.25–2.59
14.8
2.20
1.03
1.78
5.00
15.99
3.90
3.73
2.39
1.60
17.16
26.21
7.00
2.41
11.75
10.75
43.38
12.7
3.47
3.42
//
12.18–17.98
0.91–5.35
0.36–2.93
1.02–3.13
3.71–6.72
9.85–25.95
1.86–8.17
2.74–5.09
1.26–4.53
0.68–3.74
12.60–23.38
17.35–39.58
5.45–9.00
1.51–3.86
9.85–14.01
7.81–14.78
31.04–60.61
9.99–16.39
2.19–5.70
1.79–6.54
//
4-Fluorophenyl
4-Chlorophenyl
4-(Trifluoromethyl)phenyl
4-(Trifluoromethyl)phenyl
4-Nitrophenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-(t-Butyl)phenyl
4-(t-Butyl)phenyl
2,4,6-(Trimethyl)phenyl
Cyclopropyl
Cyclopropyl
n-Propyl
n-Propyl
Phenylethyl
2-Thiophenyl
2-Thiophenyl
2-Pyridinyl
3-Pyridinyl
CH
CH
H
3
3
CH
H
3
1
0
1
1
CH
CH
H
3
1
2
3
1
3
1
4
CH
H
3
1
5
1
6
CH
CH
H
3
1
7
3
1
8
1
9
CH
CH
3
2
0
3
Tebuconazole
Pyraclostrobin
1.06
0.44–2.61
/
/: no data.
Confidence limit.
a
prominent control effect with EC50 of 0.91 mg/L and 0.85 mg/L,
respectively,nearlyclosetocommercialpyraclostrobin(0.81 mg/L),a
little higher than tebuconazole, which implied that compounds
bearing Q of phenylethyl and 3-pyridinyl are worthy of being novel
leadsforfurther studyas well. As forR substituent, by comparing the
relevant compound pairs, we found the activity of compounds
possessingRofHagainstRSBisusuallybetterthanthatofcompounds
imparting R of methyl except compound pair of 4 and 5 showing
comparative EC50 values (0.88 mg/L and 0.89 mg/L, respectively).
In summary, twenty novel 1,3,4-oxadiazole derivatives were
designed and synthesized. In vitro bioassays showed that these
compounds have moderate to significant fungicidal activity against
RSB and SA. Three compounds (4, 16 and 20) were discovered
preliminarily after hit–to–lead optimization with EC50 values of
Fig. 1. X-ray single-crystal diffraction of compound 4.
so the following structure–activity relationships (SAR) were
mainly unfolded around RSB.
Initially, in order to verify the feasibility of our design concept,
compounds 1–3 were designed and synthesized employing simple
raw materials available in our lab. Fortunately, they indicated
certain fungicidal activity with EC50 values of 25.87 mg/L, 2.94 mg/
L and 1.57 mg/L, respectively. The results suggested that phenyl,
particularly the p-substituted phenyl, maybe play an important
role in the interaction of active molecules with targets. Encouraged
by this finding, further structural modifications around p-position
on phenyl were carried out. The typical electron-withdrawing
0
.85–0.91 mg/L against RSB, comparable to tebuconazole (1.02 mg/
L). Compound 3 displayed higher activity against SA (EC50 = 1.03
mg/L), which is also equal to commercial pyraclostrobin (EC50
.06 mg/L). This study demonstrated that 1,3,4-oxadiazole deriv-
=
1
atives can be further studied as lead compounds for control of rice
sheath blight and/or sorghum anthracnose. Compound 20 is a
promising fungicide for further development. Further syntheses
and structural optimization studies are in progress.
groups (CF
designed. The bioassay results showed that the EC50 values were
.88 mg/L and 2.16 mg/L respectively, especially compound 4
showed higher activity than the reference tebuconazole (EC50
.88 mg/L versus 1.02 mg/L). However, the introduction of the NO
compound 6), a stronger electron-withdrawing group led to a
decrease of the activity (EC50 = 2.16 mg/L). On the contrary, the
replacement of electron-donating group methoxyl (compound 7,
EC50 = 1.97 mg/L), bulky moiety t-butyl (compound 9, EC50 = 1.92
mg/L) and greater steric group 2,4,6-(trimethyl) (compound 11,
EC50 = 12.46 mg/L) did not make any contribution on bioactivity
compared with compound 4.
3 2
and NO , compounds 4 and 6 respectively) were
Acknowledgment
0
This work was financially supported partially by the Open
Foundation of Key Laboratory for Anisotropy and Texture of
Materials, Ministry of Education, Northeastern University, China
=
0
(
2
(
No. ATM20170001).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.cclet.2018.01.050.
Next, to determine if changing other representative substitu-
ents to replace Q would bring enhanced fungicidal activity, we
synthesized compounds 12 (Q = cyclopropyl), 14 (Q = n-propyl), 16
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2018), https://doi.org/10.1016/j.cclet.2018.01.050
(