Synthesis, fungicidal activity, and 3D-QSAR of tetrazole derivatives containing phenyloxadiazole moieties

Article abstract of DOI:10.1016/j.bmcl.2020.127762

In an effort to discover new agents with good fungicidal activities against CDM (cucumber downy mildew), a series of tetrazole derivatives containing phenyloxadiazole moieties were designed and synthesized. The EC₅₀ values for fungicidal activities against CDM were determined. Bioassay results indicated that most synthesized compounds exhibited potential in vivo fungicidal activity against CDM. A CoMFA (comparative molecular field analysis) model based on the bioactivity was developed to identify some primary structural quality for the efficiency. The values of q² and r² for the established model were 0.791 and 0.982 respectively, which reliability and predict abilities were verified. Three analogues (q3, q4, q5) were designed and synthesized based on the model. All these compounds exhibited significant fungicidal activity on CDM with the EC₅₀ of 1.43, 1.52, 1.77 mg·L^?1. This work could provide a useful instruction for the further structure optimization.

Full text of DOI:10.1016/j.bmcl.2020.127762

Bioorg. Med. Chem. Lett. 34 (2021) 127762
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, fungicidal activity, and 3D-QSAR of tetrazole derivatives
containing phenyloxadiazole moieties
,b,
Yi-Tao Lia, Wen-Qiang Yaoa, Si Zhoua, Jun-Xing Xua, Hui Lua, Jian Lina *, Xiao-Yun Hua,
Shao-Kai Zhanga
a Dongguan HEC Pesticides R&D Co., Ltd, Dongguan 523871, PR China
b College of Chemistry Biology and Environmental Engineering, Xiangnan University, Chenzhou 423000, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
In an effort to discover new agents with good fungicidal activities against CDM (cucumber downy mildew), a
series of tetrazole derivatives containing phenyloxadiazole moieties were designed and synthesized. The EC50
values for fungicidal activities against CDM were determined. Bioassay results indicated that most synthesized
compounds exhibited potential in vivo fungicidal activity against CDM. A CoMFA (comparative molecular field
analysis) model based on the bioactivity was developed to identify some primary structural quality for the ef-
ficiency. The values of q2 and r2 for the established model were 0.791 and 0.982 respectively, which reliability
and predict abilities were verified. Three analogues (q3, q4, q5) were designed and synthesized based on the
model. All these compounds exhibited significant fungicidal activity on CDM with the EC50 of 1.43, 1.52, 1.77
mg⋅Lꢀ 1. This work could provide a useful instruction for the further structure optimization.
Tetrazole
Cucumber downy mildew
Phenyloxadiazole
Fungicidal activity
CoMFA
Downy mildew, caused by the oomycete pathogen, is a major foliar
damage of cucumber.1 The product of cucumber could be severely
lessened by more than 50% without effective control.2 The application
of chemical fungicides is one of the most efficient methods for the
treatment of CDM. For instance, the active ingredients azoxystrobin,
dimethomorph and cymoxanil registered have high activity against
CDM.3,4 However, the enormous application of one fungicide may in-
crease the risk of resistance and therefore the deficient efficacy.5–10
Thus, it is crucial to discover the new active agent against CDM. Our
previous work is mainly to study the distinct chemicals with different
modes of action in the control of CDM, such as triazole disulfonamide
derivatives and tetrazole compounds.11
had a wide range of applications.23,24 Tetrazole group, which is an
efficient pharmacophore, can be applied in the discovery of inhibitors
against CDM.
Compounds containing oxadiazole have demonstrated to display
great biological activity in medicine, materials and agriculture chem-
istry.25–30 Compounds with phenyloxadiazole fragment also played a
great role in the creation of new pesticides.31–35 Yu et al reported that
the synthesized phenyloxadiazole analogues exhibited activity against
Candida albicans.36 Research has shown good insecticidal activities of
compounds with phenyloxadiazole on Pseudaletia separata Walker.37 The
incorporation of phenyloxadiazole into the tetrazole skeleton is
considered to discover a new fungicide agent. In this study, a series
tetrazole derivatives incorporation of phenyloxadiazole potential for
CDM was designed and synthesized. Due to the limitations of the unclear
mechanism of compounds and the inefficiency of the modification, 3D-
QSAR studies were performed to predict the correlation between
structure and activity for structure optimization. CoMFA is an effective
technique to build statistical and graphical models in 3D-QSAR which
has made a great contribution to ligand-based drug design and is used
widely.38–41 We also discussed CoMFA based on the fungicidal activity
of synthesized compounds on CDM. It exhibited the appropriate modi-
fication in phenyl of compounds with high fungicidal activity. We
Tetrazoles were widely applied in organic chemistry, coordination
chemistry and pharmaceutical chemistry with the highest nitrogen
content in stable heterocycles.12–17 Tetrazole derivatives also attracted
considerable attention in the field of agriculture due to the promising
biological activity and low toxicity to the environment. Relevant re-
searches and achievements have been made for their insecticidal,
bactericidal, herbicidal activities.18–20 For example, picarbutrazox
posed an increasing interest in the current research of fungicide for its
novel tetrazole structure and mechanism of action.21,22 The high selec-
tivity herbicide azimsulfuron and effective fungicide metyltetraprole
* Corresponding author at: Dongguan HEC Pesticides R&D Co., Ltd, Dongguan 523867, PR China.
E-mail address: linjian@hec.cn (J. Lin).
https://doi.org/10.1016/j.bmcl.2020.127762
Received 19 November 2020; Received in revised form 14 December 2020; Accepted 20 December 2020
Available online 24 December 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.

Y.-T. Li et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127762
O
NHNH2
(2)
COOCH3
R
R
R
O
(1)
O
(3)
(4)
O
O
R
R
N
N
N
OEt
N
N
OH
Br
N
N
N
R
O
d
b
e
c
(9)
a
O
N
N
OH
N
O
Cl
N
N
O
O
O
N
H
N
N
O
N
(6)
(7)
N
(5)
(8)
N
N
O
N
N
O
k
O
N
N
g
j
h
f
i
N
N
N
N
Br
(10)
O
O
R
O
N
O
N
N
N
N
N
N
N
N
N
p
k
Scheme 1. Synthetic route of compounds k1-k6 and p1-22. Reagents and conditions: (1) N2H4⋅H2O, CH3OH, 80 ◦C, 4 h; (2) Ethyl oxalyl monochloride, NEt3, DCM,
rt, 6 h, TsCl, NEt3, rt, 18 h; (3) NaBH4, CaCl2, EtOH, rt, 18 h; (4) PBr3, DCM, rt, 4 h; (5) CH3NH2, CH3OH, rt, 2 h; (6) SOCl2, CHCl3, DMF, reflux, 12 h; (7) NaN3, TBA
bromide, Toluene, H2O, rt, 2 h; (8) NH2OH⋅HCl, EtOH, 48 ◦C, 12 h; (9) K2CO3, DMF, rt, 6 h; (10) K2CO3, ethylene glycol dimethyl ether/methanol/water (V/V/V) =
4/1/1, palladium acetate.
N
N
R
O
CN
O
N
O
CN
COOMe
N
COOH
R
O
O
(11)
O
(1-9)
N
(12)
(13)
R
N
R'
R'
R
R'
R'
N
m
n
o
l
q
Scheme 2. Synthetic route of compounds q1-q5. Reagents and conditions: (11) K2CO3, DMF, 110 ◦C, 5 h; (12) 30%H2O2, KOH, CH3OH, EtOH, 80 ◦C, 4 h; (13)
H2SO4, CH3OH, 80 ◦C, 6 h.
synthesized compounds q3, q4, q5 according to the structure–activity
relationship reflected by the counter map. All these compounds
exhibited better fungicidal activity on CDM.
obtain target compounds by repeating the synthesis method of series k
(Scheme 2). The 1H NMR and 13C NMR of synthesized compounds were
collected in Supplementary data.
According to Scheme 1, compound b was obtained from methyl
benzoate derivatives using hydrazine hydrate reaction. Then product b
was reacted with oxalyl chloride monoethyl ester in basic condition
(triethylamine), and the intermediate is cyclized to give c by catalyst (p-
toluenesulfonyl chloride). Compound c is reduced by sodium borohy-
dride and then substituted to obtain the key intermediate e. Otherwise,
methyl benzoylformate f was reacted with methylamine water solution
to give the intermediate g, and then obtained h by substitution reaction.
Compound h is cyclically closed with sodium azide and reacted with
hydroxylamine hydrochloride to provide the intermediate j in good
yields. Subsequently, the reaction of intermediate e and J in alkaline
condition (potassium carbonate) to give the series compounds k. This
synthesis route is the common step of synthesizing series p and q. Target
compound p1-22 can be obtained by coupling reaction of compound k
with corresponding substituted phenylboronic acid using palladium
acetate as catalyst. For the synthesis of target compound q, compound m
is obtained by coupling reaction between benzonitrile derivative l and
phenol derivative. Compound m was hydrolyzed and then esterified to
obtain intermediate o, which acted as methyl benzoate derivatives to
We systematically tested the fungicidal activities of all compounds
against CDM. The fungicidal activities were recorded in Table 1. Com-
mercial fungicide azoxystrobin and cymoxanil were used as control. The
test results showed that target compounds have desirable inhibitory
activity against CDM with EC50 from 1.78 to 53.95 mg⋅Lꢀ 1. In particular,
compounds k1, k2, k3, p22 exhibited significant fungicidal activities
against CDM with EC50 values of 1.78, 2.72, 2.58 and 2.71 mg⋅Lꢀ 1. All of
these compounds displayed better activities than control compounds.
The introduction of a smaller negative groups at the 4-position of the
benzene exhibited higher activities against CDM, such as compound k5,
k6 with the EC50 values of 5.16, 5.15 mg⋅Lꢀ 1, respectively. The EC50
value of compound with various substitutes at the individual position of
benzene ring was quite different. For example, the compounds with a
bulky group at the 4-position displayed reduced fungicidal activities.
Whereas the compound with an appropriate large substitute at the 2-po-
sition was likely to increase the fungicidal activities.
Based on the biological activities on CDM, CoMFA model was built to
analyze the relationship between the structure and the fungicidal ac-
tivity. Compound k1 was chosen as a template for superimposition
2

Y.-T. Li et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127762
Table 1
N
N
R1
O
O
N
Fungicidal activity of compounds against CDM.
N
N
N
N
Compound
R1
EC50(mg/L)
95% confidence interval (mg/L)
k1
3-CF3
1.78
2.72
1.676–1.972
1.623–4.451
2.387–2.748
2.838–5.973
1.461–4.958
2.021–4.383
5.653–9.709
7.160–15.384
4.188–12.291
8.549–14.969
13.116–26.291
1.651–6.592
9.226–11.135
16.314–19.145
5.298–7.152
6.769–11.716
17.063–42.142
0.373–6.507
19.248–32.420
23.650–46.079
2.824–12.209
6.332–15.726
9.521–11.738
13.982–24.459
18.844–21.975
14.725–23.947
2.770–3.581
2.177–3.297
3.300–6.286
2.094–3.601
1.281–1.577
1.347–1.704
1.575–1.981
9.421–14.562
k2
3, 5-2CF3
k3
3-F-4-CH3
2.58
k4
2-NO2-5-CH3
4.12
k5
4-OCH2CH3
2.78
k6
4-Br
3.14
a p1
p2
4-pheyl
7.75
4-(3′-F-4′-Me-phenyl)
4-(4′-ethyl-phenyl)
4-(4′-ethoxy-phenyl)
4-(4′-CF3-phenyl)
4-(4′-ethoxy-phenyl)
4-(4′-propyl-phenyl)
4-(4′-methoxy-phenyl)
4-(4′-Me-phenyl)
4-(2′,5′-2Me- phenyl)
4-(4′-NO2-phenyl)
4-(2′,3′-2Me- phenyl)
4-(3′-NO2-4′-Me-phenyl)
3-(4′-CF3-phenyl)
4-(4′-F-phenyl)
10.90
8.40
p3
p4
11.66
18.96
4.61
p5
a p6
p7
10.16
17.68
6.29
p8
a p9
p10
p11
p12
p13
a p14
p15
p16
a p17
p18
p19
p20
p21
p22
q1
9.20
26.78
3.89
24.99
32.98
7.74
3-(3′-ethoxy-phenyl)
3-(4′-propyl-phenyl)
3-(2′,3′-2Me- phenyl)
3-(3′-NO2-4′-Me-phenyl)
3-(2′,5′-2Me- phenyl)
2-(3′-ethoxy-phenyl)
2-(2′,4′-2F- phenyl)
2-(3′-fluorophenoxy)
2-(2′-fluorophenoxy)
5-Br-2-(2′-fluorophenoxy)
5-Cl-2-(3′-fluorophenoxy)
10.52
10.61
18.07
20.38
18.86
3.17
2.71
4.66
q2
2.83
q3
1.43
q4
1.52
q5
5-Cl-2-(4′-fluorophenoxy)
1.77
O
cymoxanil
12.54
NH
N
O
NH
O
N
N
N
Azoxystrobin
3.28
2.067–4.840
O
O
O
O
N
O
a
Test set.
because of the highest fungicidal efficacy (Fig. 1). The cross-validated
correlation coefficients q2 and the regression coefficients r2 for the
training set were 0.791 and 0.982 with the SEE (standard error of esti-
mation) of 0.035. And the relative contributions of steric and electro-
static of the CoMFA model were 0.619 and 0.381. The parameters
evaluated by the CoMFA model (Table 2) suggest the reliability of this
model. The correlations between the predicted pEC50 and experimental
pEC50 are represented in Fig. 2, which shows a good prediction of the
data for training and test sets (Table 3).
The contour map was generated to determine the steric and elec-
trostatic contributions for fungicidal activity (Fig. 3). The field of green
contour indicates that a bulky substituent was associated with higher
Fig. 1. Molecular alignment for the CoMFA study: (A) molecular alignment template; (B) the result of superimposition.
3

Y.-T. Li et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127762
Table 2
The statistical parameters for the CoMFA model.
Statistical parameters
q2
r2
n
4
SEE
F
Field contribution
steric
electrostatic
0.381
Value
0.791
0.982
0.035
267.521
0.619
q2: cross validated correlation coefficient; r2: Non-cross validated correlation coefficient; n: optimum number of components; SEE: standard error of estimate; F: F-test
value.
Table 3
Experimental and predicted activity (pEC50) by the CoMFA model.
Number
Experiment pEC50
Predicted pEC50
residual
k1
5.383
5.262
5.183
5.009
5.163
5.147
4.751
4.634
4.743
4.616
4.426
5.019
4.673
4.422
4.856
4.704
4.255
5.077
4.298
4.185
4.769
4.660
4.655
4.411
4.386
4.392
5.181
5.242
5.005
5.222
5.586
5.521
5.456
5.426
5.239
5.125
4.992
5.166
5.147
4.929
4.739
4.731
4.560
4.392
4.998
4.717
4.557
4.827
4.657
4.317
5.069
4.255
4.483
4.701
4.683
4.63
0.043
0.023
0.058
0.017
0.003
0
k2
k3
k4
k5
k6
p1
0.178
0.105
0.012
0.056
0.034
0.021
0.044
0.135
0.029
0.047
0.062
0.008
0.043
0.298
0.068
0.023
0.025
0.030
0.016
0.005
0.003
0.027
0.013
0.012
0.025
0.006
0.206
p2
p3
p4
p5
p6
p7
p8
Fig. 2. The correlations between experimental and predicted activities
p9
of compounds.
p10
p11
p12
p13
p14
p15
p16
p17
p18
p19
p20
p21
p22
q1
activity, while the yellow field indicates an area where an increase in
substituent bulk was unfavorable. A blue region suggests that the
introduction of the positive charge will lead to an increase in activity,
while the red contour means the contrary. A small green contour with a
yellow contour closed to the 4-position of phenyl, which suggested an
appropriate large group should be suitable. For example, compound p1
(4-phenyl) shows higher activity than p7 (4-(4′-propyl-phenyl)). A green
contour near the 2-position of phenyl suggests that the bulky groups in
this position will increase the fungicidal activity. Compounds p21, p22
exhibits higher activity with EC50 of 5.181, 5.242 mg⋅Lꢀ 1, respectively.
A red contour indicated a negative charge group near the 3-position of
phenyl is favored. Besides, a proper positive charge group at the 4-posi-
tion of phenyl substituents should be suitable for the fungicidal activity
(Fig. 4). This model revealed the structural features efficient for the
fungicidal activity and displayed a structure–activity relationship useful
for further structural optimization .
4.441
4.37
4.397
5.178
5.215
5.018
5.210
5.561
5.527
5.250
q2
q3
q4
q5
A series of tetrazole derivatives containing phenyloxadiazole moi-
eties were synthesized and their fungicidal activities against CDM were
tested. The bioassay results indicated that some of the target compounds
exhibited notable activities against CDM, especially compound k1 with
the EC50 of 1.78 mg⋅Lꢀ 1. The CoMFA study for compounds on CDM was
also discussed. It revealed that the presence of a bulky group at the 2-po-
sition of benzene and a negatively charged group at the 3-position of
benzene could enhance fungicidal activity. Three analogues were
designed and synthesized according to the model. All these compounds
exhibited better fungicidal activity on CDM. This work could provide a
theoretical support for understanding the structure–activity relationship
and further optimizing these compounds.
With the result of contour maps, we designed and synthesized three
compounds (q3, q4, q5). Their pEC50 values were predicted and tested.
A bulky group at the 2-position and a negatively charged group at the 3-
position of benzene will be benefit for the fungicidal activity against
CDM. We retained the bulky group phenyl ether at the 2-position of q1
with the high activity. And we also introduced a negatively charged
group such as halogen atom at the 3-position of benzene. The predicted
pEC50 of compounds q3, q4, q5 according to CoMFA model are 5.561,
5.527 and 5.250, respectively. The pEC50 values of bioassay are 5.586,
5.521, 5.456, which displayed higher fungicidal activities against CDM.
As shown in Fig. 5, the three compounds exhibited notably in vivo ac-
tivity at a concentration of 3.125 mg⋅Lꢀ 1. The pEC50 values predicted
were typically in accordance with the experiment data. All the results
showed that the steric and electrostatic considered in the model have a
significant effect on bioactivity against CDM of these compounds, and
the reliability of the model has been validated.
Declaration of Competing Interest
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.
4

Y.-T. Li et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127762
Fig. 3. The 3D steric and electrostatic maps of the CoMFA model with the compound k1.
Fig. 4. The contour map of CoMFA with compounds (A) steric contour map: the activity of compound p1 (red) higher than that of p7 (gray); (B) electrostatic contour
map: the activity of compound p9 (red) higher than that of p11 (gray); (C) steric contour map: the activity of compound p21 (red) higher than that of p16 (gray); (D)
electrostatic contour map: the activity of compound k1 (red) higher than that of p4 (gray).
Fig. 5. In vivo activity of compounds against CDM at a concentration of 3.125 mg⋅Lꢀ 1
.
Acknowledgment
org/10.1016/j.bmcl.2020.127762.
The authors acknowledge Dr Guang-Fu Yang, the professor of Col-
lege of Chemistry, Central China Normal University, for providing the
assistance of computation.
References
1 Gabaston J, Cantos-Villar E, Biais B, Waffo-Teguo P, et al. Stilbenes from Vitis
vinifera L. waste: A sustainable tool for controlling Plasmopara Viticola. J Agric Food
Chem. 2017;65(13):2711–2718. https://doi.org/10.1021/acs.jafc.7b00241.s001.
2 Li Y, Lin J, Yao W, Gao G, Jing D, Wu Y. Discovery of a new fungicide by screening
triazole sulfonylhydrazone derivatives and its downy mildew inhibition in cucumber.
J Heterocyclic Chem. 2020;57(5):2128–2138. https://doi.org/10.1002/jhet.3932.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
5

Y.-T. Li et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127762
´
ˇ
´
´
3 Bagi FF, Budakov DB, Bursic VP, Stojsin VB, Lazic SD, Vukovic SM. Efficacy of
azoxystrobin for the control of cucumber downy mildew (Pseudoperonospora
cubensis) and fungicide residue analysis. Crop Prot. 2014;61:74–78. https://doi.org/
10.1016/j.cropro.2014.03.012.
24 Matsuzaki Y, Kiguchi So, Suemoto H, Iwahashi F. Antifungal activity of
metyltetraprole against the existing QoI-resistant isolates of various plant pathogenic
fungi: Metyltetraprole against QoI-R isolates. Pest Manag Sci. 2020;76(5):1743–1750.
https://doi.org/10.1002/ps.5697.
4 Young DH, Wilson WJ, Egan AR, Luis ME. Fungicidal compositions containing N-
acetonylbenzamides. 2000; US 6319936.
25 Paidi KR, Kolli MK, Reddy EK, Pedakotla VR. Sodium hypochlorite-mediated
synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from hydrazides and aldehydes.
Chem Heterocycl Comp. 2020;56(3):371–376. https://doi.org/10.1007/s10593-020-
02669-6.
5 Chen YM, Gu LL, Lin SX, Wang P, Ding L, Wu SJ. Cucumber Downy Mildew: Research
progress and registered fungicides. J Agric. 2019;11:60–67.
6 Guan A, Wang M, Yang J, et al. The discovery of a new fungicide candidate through
lead optimization of pyrimidinamine derivatives and their activity against cucumber
downy mildew. J Agric Food Chem. 2017;65:10829–10835.
26 Macaev F, Rusu G, Pogrebnoi S, Gudima A, Stingaci E, Vlad L, et al. Synthesis of
novel 5-aryl-2-thio-1,3,4-oxadiazoles and the study of their structure–anti-
mycobacterial activities. Bioorg Med Chem. 2005;13(16):4842–4850. https://doi.org/
10.1016/j.bmc.2005.05.011.
7 Ishii H, Fraaije BA, Sugiyama T, Noguchi K, et al. Occurrence and molecular
characterization of strobilurin resistance in cucumber powdery mildew and downy
mildew. Phytopathology®. 2001;91(12):1166–1171. https://doi.org/10.1094/
PHYTO.2001.91.12.1166.
27 Zou X-J, Lai L-H, Jin G-Y, Zhang Z-X. Synthesis, fungicidal activity, and 3D-QSAR of
Pyridazinone-Substituted 1,3,4-oxadiazoles and 1,3,4-thiadiazoles. J Agric Food
Chem. 2002;50(13):3757–3760. https://doi.org/10.1021/jf0201677.
28 Milinkevich KA, Yoo CL, Sparks TC, Lorsbach BA, Kurth MJ. Synthesis and biological
activity of 2-(4,5-dihydroisoxazol-5-yl)-1,3,4-oxadiazoles. Bioorg Med Chem Lett.
2009;19(19):5796–5798. https://doi.org/10.1016/j.bmcl.2009.07.139.
29 Zhang K, Tao Y, Yang C, et al. Synthesis and properties of carbazole main chain
copolymers with oxadiazole pendant toward bipolar polymer host: tuning the
HOMO/LUMO level and triplet energy. Chem Mater. 2008;20(23):7324–7331.
https://doi.org/10.1021/cm802240q.
8 Wang F, Yang JF, Wang MY, et al. Graph attention convolutional neural network
model for chemical poisoning of honey bees’ prediction. Sci Bull. 2020;65:
1184–1191.
9 Yang JF, Wang F, Chen YZ, Hao GF, Yang GF. LARMD: integration of bioinformatic
resources to profile ligand-driven protein dynamics with a case on the activation of
estrogen receptor. Brief Bioinform. 2020;21:2206–2218.
10 Wu FX, Wang F, Yang JF, et al. AIMMS suite: a web server dedicated for prediction of
drug resistance on protein mutation. Brief Bioinform. 2018;21:318–328.
11 Lin J, Zhou Si, Xu J-X, Yao W-Q, Hao G-F, Li Y-T. Design, synthesis, and
structure–activity relationship of economical triazole sulfonamide aryl derivatives
with high fungicidal activity. J Agric Food Chem. 2020;68(25):6792–6801. https://
doi.org/10.1021/acs.jafc.9b07887.s001.
30 Madhavi S, Sreenivasulu R, Raju RR. Synthesis and biological evaluation of
oxadiazole incorporated ellipticine derivatives as anticancer agents. Monatsh Chem.
2017;148(5):933–938. https://doi.org/10.1007/s00706-016-1790-y.
31 Li P, Tian P, Chen Y, Song X, Xue W, et al. Novel bisthioether derivatives containing a
1,3,4-oxadiazole moiety: design, synthesis, antibacterial and nematocidal activities:
Antibacterial and nematocidal activities of novel bisthioether derivatives. Pest Manag
Sci. 2018;74(4):844–852. https://doi.org/10.1002/ps.4762.
´
´
´
12 Roh J, Vavrova K, Hrabalek A. Synthesis and Functionalization of 5-Substituted
Tetrazoles. Eur J Org Chem. 2012;2012(31):6101–6118. https://doi.org/10.1002/
ejoc.201200469.
32 Wu Y-Y, Shao W-B, Zhu J-J, Long Z-Q, et al. Novel 1,3,4-oxadiazole-2-carbohydra-
zides as prospective agricultural antifungal agents potentially targeting succinate
dehydrogenase. J Agric Food Chem. 2019;67(50):13892–13903. https://doi.org/
10.1021/acs.jafc.9b05942.s001.
¨
13 Pihko PM, Majander I, Erkkila A. Enamine catalysis. Topics Curr Chem. 2010;291:
29–75.
14 Upadhayaya RS, Jain S, Sinha N, Kishore N, Chandra R, Arora SK. Synthesis of novel
substituted tetrazoles having antifungal activity. Eur J Med Chem. 2004;39(7):
579–592. https://doi.org/10.1016/j.ejmech.2004.03.004.
33 Cui Z-N, Shi Y-X, Zhang Li, et al. Synthesis and fungicidal activity of novel 2,5-
disubstituted-1,3,4-oxadiazole derivatives. J Agric Food Chem. 2012;60(47):
11649–11656. https://doi.org/10.1021/jf303807a.
15 Jedhe GS, Paul D, Gonnade RG, et al. Correlation of hydrogen-bonding propensity
and anticancer profile of tetrazole-tethered combretastatin analogues. Bioorg Med
Chem Lett. 2013;23:4680–4684.
34 Xu W-M, Han F-F, He M, et al. Inhibition of tobacco bacterial wilt with sulfone
derivatives containing an 1,3,4-oxadiazole moiety. J Agric Food Chem. 2012;60(4):
1036–1041. https://doi.org/10.1021/jf203772d.
16 Ionescu C, Sippelli S, Toupet L, Barragan-Montero V. New mannose derivatives: The
tetrazole analogue of mannose-6-phosphate as angiogenesis inhibitor. Bioorg Med
Chem Lett. 2016;26(2):636–639. https://doi.org/10.1016/j.bmcl.2015.11.059.
17 Kavitha HP. Synthesis and antimicrobial activity of 1-(9-acridinyl)-5-(4- substituted
phenyl) tetrazoles. Asian J Chem. 2004;16:1191–1193.
35 Hao G-F, Jiang W, Ye Y-N, et al. ACFIS: a web server for fragment-based drug
discovery. Nucleic Acids Res. 2016;44(W1):W550–W556. https://doi.org/10.1093/
nar/gkw393.
36 Yu DT, Macina OT, Sircar I, Sircar, JC, Oxadiazole antifungal agents. 2001; US patent
6277873.
18 Dai L, Cui S, Damu GLV, Zhou C. Recent Advances in the Synthesis and Application of
Tetrazoles. Chin J Org Chem. 2013;33(2):224. https://doi.org/10.6023/
cjoc201208036.
37 Shi W, Qian X, Zhang R, Song G. Synthesis and quantitative structureꢀ activity
relationships of new 2,5-disubstituted-1,3,4-oxadiazoles. J Agric Food Chem. 2001;49
(1):124–130. https://doi.org/10.1021/jf0007941.
19 Koldobskii GI, Ostrovskii VA, Popavskii VS. Advances in the chemistry of tetrazoles
(review). Chem Heterocycl Compd. 1981;17(10):965–988. https://doi.org/10.1007/
BF00503523.
38 Mao B, Gao M, Chen C, Li Z, Zhang H-Y, Zhang Q. Design, synthesis and biological
evaluation of novel N-nitrophenyl derivatives based on the structure of
acetohydroxyacid synthase. Pestic Biochem Physiol. 2018;145:100–107. https://doi.
org/10.1016/j.pestbp.2018.01.011.
20 Luo Y-P, Yang G-F. Discovery of a new insecticide lead by optimizing a target-diverse
scaffold: Tetrazolinone derivatives. Bioorg Med Chem. 2007;15(4):1716–1724.
https://doi.org/10.1016/j.bmc.2006.12.002.
39 Acharya C, Coop A, Polli JE, Mackerell AD. Recent advances in ligand-based drug
design: relevance and utility of the conformationally sampled pharmacophore
approach. Curr Comput Aided Drug Des. 2011;7:10–22.
21 Jeanmart S, Edmunds AJF, Lamberth C, Pouliot M. Synthetic approaches to the
2010–2014 new agrochemicals. Bioorg Med Chem. 2016;24(3):317–341. https://doi.
org/10.1016/j.bmc.2015.12.014.
40 Zang Y-Y, Li Y-M, Yin Y, Chen S-S, Kai Z-P. Discovery and quantitative structure-
activity relationship study of lepidopteran HMG-CoA reductase inhibitors as selective
insecticides: Lepidopteran HMG-CoA reductase inhibitors as selective insecticides.
Pest Manag Sci. 2017;73(9):1944–1952. https://doi.org/10.1002/ps.4561.
41 Wang YL, Wang F, Shi XX, Jia CY, Wu FX, Hao GF, Yang GF. Cloud 3D-QSAR: a web
tool for the development of quantitative structure-activity relationship models in
drug discovery. Brief Bioinform. 2020. https://doi.org/10.1093/bib/bbaa276.
22 Ichinari D, Nagaki A, Yoshida J-I. Generation of hazardous methyl azide and its
application to synthesis of a key-intermediate of picarbutrazox, a new potent
pesticide in flow. Bioorg Med Chem. 2017;25(23):6224–6228. https://doi.org/
10.1016/j.bmc.2017.07.005.
23 Pinna MV, Zema M, Gessa C, Pusino A. Structural elucidation of phototransformation
products of azimsulfuron in Water. J Agric Food Chem. 2007;55(16):6659–6663.
https://doi.org/10.1021/jf070897k.s001.
6