Design, synthesis, and bioactivities of novel oxadiazole-substituted pyrazole oximes

Article abstract of DOI:10.1016/j.bmcl.2016.12.083

A series of novel pyrazole oxime derivatives containing a substituted oxadiazole group were designed and synthesized. The bioassay results indicated that some title compounds displayed good acaricidal and insecticidal activities against Tetranychus cinnabarinus, Aphis medicaginis, Oriental armyworm, and Nilaparvata lugens. Especially, compounds 7a, 7b, and 7c had 80%, 90%, and 90% insecticidal activities against A. medicaginis at 20 μg/mL, respectively. Interestingly, some of the designed compounds displayed wonderful fungicidal activities in vivo against cucumber Pseudoperonospora cubensis. Furthermore, compounds 7a (EC₅₀= 4.97 μg/mL) and 7h (EC₅₀= 0.51 μg/mL) showed excellent fungicidal activity against P. cubensis comparable or better than that of the control Pyraclostrobin (EC₅₀= 4.59 μg/mL).

Full text of DOI:10.1016/j.bmcl.2016.12.083

Accepted Manuscript
Design, synthesis, and bioactivities of novel oxadiazole-substituted pyrazole
oximes
Hong Dai, Jia Chen, Gang Li, Shushan Ge, Yujun Shi, Yuan Fang, Yong Ling
PII:
S0960-894X(16)31361-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.12.083
BMCL 24572
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
11 October 2016
18 December 2016
29 December 2016
Please cite this article as: Dai, H., Chen, J., Li, G., Ge, S., Shi, Y., Fang, Y., Ling, Y., Design, synthesis, and
bioactivities of novel oxadiazole-substituted pyrazole oximes, Bioorganic & Medicinal Chemistry Letters (2016),
doi: http://dx.doi.org/10.1016/j.bmcl.2016.12.083
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Design, synthesis, and bioactivities of novel oxadiazole-substituted
pyrazole oximes
Hong Dai a, Jia Chen a, Gang Li a, Shushan Ge b, Yujun Shi a,*, Yuan Fang a, Yong Ling b,*
a College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, People’s
Republic of China
b School of Pharmacy, Nantong University, Nantong 226001, People’s Republic of China
Corresponding Author Emails: yjshi2015@163.com; yling2015@aliyun.com;
Tel: +86-513-85012851
ABSTRACT
A series of novel pyrazole oxime derivatives containing a substituted oxadiazole group were
designed and synthesized. The bioassay results indicated that some title compounds displayed
good acaricidal and insecticidal activities against Tetranychus cinnabarinus, Aphis medicaginis,
Oriental armyworm, and Nilaparvata lugens. Especially, compounds 7a, 7b, and 7c had 80%,
90%, and 90% insecticidal activities against A. medicagini at 20 µg/mL, respectively. Interestingly,
some of the designed compounds displayed wonderful fungicidal activities in vivo against
cucumber Pseudoperonospora cubensis. Furthermore, compounds 7a (EC50 = 4.97 µg/mL) and 7h
(EC50 = 0.51 µg/mL) showed excellent fungicidal activity against P. cubensis comparable or better
than that of the control Pyraclostrobin (EC50 = 4.59 µg/mL).
Keywords: Oxadiazole, Pyrazole oxime, Synthesis, Biological activity
In recent years, pyrazole derivatives have attracted considerable interest due to their versatile
pharmacological and biological properties.1 Particularly, in agricultural field, pyrazole ring is

usually considered as an important active component of some insecticidal,2 acaricidal,3
fungicidal,4,5 and antiviral molecules.6 For example, commerial insecticide Tebufenpyrad and
Tolfenpyrad,7 and fungicide Pyraclostrobin,8 are structurally embedded with
a
pyrazole-5-carboxamide or pyrazole-3-ether unit (Fig. 1), respectively. Fenpyroximate (Fig. 1),
another pyrazole derivative characterized by the unique pyrazole oxime scaffold, was a
well-known acaricide developed by Nihon Nohyaku Co. in 1991. Over the years, Fenpyroximate
has been widely used in protecting various crops due to its high efficiency against agricultural
mites such as Polyphagotarsonemus latus Banks and Tetranychus urticae Koch, and low toxicity
to mammals.9,10 However, several field populations of T. urticae have already developed high
levels of Fenpyroximate resistance with its continuous application.11 Thereafter, numerous
researches on structural modification of Fenpyroximate, and corresponding bioactivities were
carried out.12,13 In the process of developing new Fenpyroximate derivatives, modification of
phenyl B (Fig. 1) and its substituents was mainly focused on with the 4-pyrazole oxime moiety
retained. For example, by replacing the phenyl B (Fig. 1) group with a pyridyl or thiazole ring, Fu
and Yang reported some pyrazole oxime derivatives with good acaricidal or insecticidal properties,
respectively.14,15 Dai and coworkers obtained several classes of acaricidal or insecticidal
Fenpyroximate mimics by replacing the phenyl B (Fig. 1) with a thiazole,16 oxazole,17 or pyridyl
group.18 More recently, Dai et al. also found some pyrazole oximes possessing interesting
insecticidal activity beyond acaricidal activity through modification of 4-position on the phenyl B
(Fig. 1) of Fenpyroximate with a thiazolylmethoxy or pyridyloxy group.19,20 As a result, structural
optimization about the phenyl B of Fenpyroximate (Fig. 1) to explore new biologically active
pyrazole oxime molecules is a reasonable design.
On the other hand, the oxadiazole ring is another significant five-membered aromatic
heterocycle carrying one oxygen atom and two nitrogen atoms, which plays an important role in
many bioactive compounds.21,22 In recent years, lots of oxadiazole-based derivatives have been
found to display insecticidal,23 fungicidal,24 herbicidal,25 antiviral,26 antineoplastic,27
antitubercular,28 and antibacterial activities.29 The widespread use of oxadiazole-based compounds
as a sketelon in the field of agricultural and medicinal chemistry establishes the oxadiazole ring as
a vital structural class.

Inspired by the above viewpoints, we envisioned that the introduction of oxadiazole moiety to
the parent pyrazole oxime scaffold may lead to some new compounds possessing multiple
bioactivities. In this research, we replaced the phenyl B of Fenpyroximate with a substituted
oxadiazole ring for the first time, meanwhile substituents on phenyl A were screened. Acaricidal,
insecticidal, and fungicidal activities of the obtained new compounds were evaluated and
discussed.
Cl
N
N
Cl
O
Cl
O
H
N
H
N
N
N
N
N
O N
O
O
O
O
Tebufenpyrad
Tolfenpyrad
Pyraclostrobin
R1
N
O
N
O
B
N
N
N
N
N
O
O
O
N
R2
O
O
A
A
R3
R1 =F, Cl, CF3
R2 =Me, 4-MeC6H4, 4-ClC6H4
R3 =Me, F, Cl, Br, I, etc.
Fenpyroximate
Target Molecules
Figure 1. Chemical structure and the design of the target molecules.
The synthetic route of the title compounds 7a-7u was outlined in Scheme 1. Compound 1 was
easily reacted with hydroxylamine hydrochloride under basic condition to give compound 2.25
Further reaction with chloroacetyl chloride afforded 5-chloromethyl-3-aryl-1,2,4-oxadiazole (3) in
satisfactory yields. The key intermediates 6 were conveniently synthesized by two steps from
1-methyl-3-methyl (aryl)-5-chloro-1H-pyrazole-4-carbaldehyde (4). Benefiting from the activated
C-Cl bond by the electron-withdrawing aldehyde group at the 4-position of pyrazole ring, the
introduction of substituted phenol nucleophile into compound 4 was performed smoothly, and
produced 5-aryloxy pyrazole-4-carbaldehydes (5).30 Subsequently, intermediates 5 were easily

transformed into pyrazole oximes 6 by condensation with hydroxylamine hydrochloride using
potassium hydroxide as the base. Finally, the reaction of the key intermediates 6 with
5-chloromethyl-3-aryl-1,2,4-oxadiazole (3) proceeded successfully by the addition of a catalytic
amount of potassium iodide and provided the target compounds 7a-7u in good yields. All the title
compounds were structurally analyzed and confirmed through 1H NMR, 13C NMR and elemental
analyses (detailed information see Supplementary data).
Cl
O
N
N
N OH
NH2
a
R1
O
b
R1
C N
R1
R1 =F, Cl, CF3
3
2
1
OH
O
N
H
H
R3
c
d
R3
N
O
N
N
Cl
N
O
N
N
R2
R2
R2
R1
5
6
4
N
N
e
O
O
N
R3
N
O
N
R2
7a-7u
7o: R1 =Cl, R2 =Me, R3 =2,4-F2
7p: R1 =CF3, R2 =Me, R3 =4-F
7q: R1 =CF3, R2 =Me, R3 =4-I
7r: R1 =CF3, R2 =Me, R3 =3-CF3
7s: R1 =F, R2 =4-MePh, R3 =4-Me
7a: R1 =F, R2 =Me, R3 =4-Cl
7b: R1 =F, R2 =Me, R3 =4-Br
7c: R1 =F, R2 =Me, R3 =4-I
7d: R1 =F, R2 =Me, R3 =3-CF3
7e: R1 =F, R2 =Me, R3 =3-Me
7h: R1 =Cl, R2 =Me, R3 =4-F
7i: R1 =Cl, R2 =Me, R3 =4-Cl
7j: R1 =Cl, R2 =Me, R3 =4-OCF3
7k: R1 =Cl, R2 =Me, R3 =4-OMe
7l: R1 =Cl, R2 =Me, R3 =4-Me
7t: R1 =Cl, R2 =4-MePh, R3 =4-Me
7u: R1 =Cl, R2 =4-ClPh, R3 =4-OCF3
7m: R1 =Cl, R2 =Me, R3 =3-CF3
7n: R1 =Cl, R2 =Me, R3 =2,4-Cl2
7f: R1 =F, R2 =Me, R3 =4-OCF3
7g: R1 =F, R2 =Me, R3 =2,4-Cl2
Scheme 1. Synthesis of compounds 7a-7u. Reagents and conditions: (a) NH2OH·HCl, NaOH, C2H5OH-H2O,
reflux, 4 h; (b) chloroacetyl chloride, toluene, 0 oC, 15 min, reflux, 4 h; (c) substituted phenols, KOH, DMF or
DMSO, 40oC, 2 h, 105 oC, 5-18 h; (d) NH2OH·HCl, KOH, CH3OH or C2H5OH, reflux, 4-16 h; (e) compound 3,
Na2CO3, KI, CH3CN, reflux, 10-16 h.
The synthesized compounds 7a-7u were evaluated for insecticidal activities against Aphis

medicaginis, Oriental armyworm and Nilaparvata lugens, and acaricidal activity against
Tetranychus cinnabarinus using known procedures,31,32 and Imidacloprid, Abamectin and
Fenpyroximate were used as the positive controls, respectively. As shown in Table 1, some title
compounds exhibited good to excellent acaricidal activity against T. cinnabarinus at a
concentration of 500 µg/mL. Among these compounds, the mortalities of compounds 7a, 7h, 7p,
and 7q were 100%, 100%, 90%, and 90%, respectively, which were similar to that of the control
Fenpyroximate. Based on the structure-potency data, we can find that when R2 is a substituted
benzene ring, compounds 7s, 7t, and 7u showed no acaricidal activity against T. cinnabarinus.
Besides acaricidal potencies, most of the designed compounds demonstrated good insecticidal
activities against A. medicaginis at a concentration of 500 µg/mL, for instance, compounds 7a, 7b,
7c, 7d, 7e, 7h, 7i, 7k, 7l, 7p, and 7q had 100%, 90%, 90%, 100%, 100%, 100%, 100%, 100%,
100%, 100%, and 100% inhibition rates, respectively, which were comparable to that of the
control Imidacloprid. Moreover, some of the obtained compounds displayed potent insecticidal
activities against A. medicaginis when the concentration was reduced to 100 µg/mL. For example,
compounds 7a, 7b, 7c, 7d, 7e, 7h, 7i, 7k, 7l, 7p, 7q, and 7r had a ≥80% inhibition rate against A.
medicaginis. When the dosage was lowered to 20 µg/mL, the mortalities of compounds 7a, 7b, 7c,
7l, and 7m were 80%, 90%, 90%, 70%, and 70%, respectively. From the above insecticidal
activity data, we can infer that the substituents (R3) on the phenyl ring A may have an impact on
the activities. When R2 is methyl, the substituent (R3) at 4-position of phenyl ring A was halogen
(7a, 7b, 7c, 7h, 7i, 7p, and 7q), methoxy (7k) or methyl (7l), or 3-position of phenyl ring was
trifluoromethyl (7m), it was more favorable to the insecticidal activity against A. medicaginis at
20 µg/mL. Table 1 exhibited that some title compounds indicated perfect larvicidal activity against

Oriental armyworm at a concentration of 500 µg/mL. Furthermore, some of them displayed
moderate to good larvicidal activity against Oriental armyworm when the dosage was reduced to
100 µg/mL, compounds 7b and 7c possessed 80% and 100% inhibition rates, respectively.
Encouragingly, most title compounds showed satisfactory insecticidal activity against N. lugens
besides good insecticidal activities against A. medicaginis (Table 1). For example, compounds 7a,
7b, 7c, 7d, 7e, 7h, 7i, 7k, 7l, 7p, and 7q all achieved a 100% inhibition rate against N. lugens at a
concentration of 500 µg/mL. Among them, compounds 7a, 7b, 7c, 7l, and 7q were still active
against N. lugens at 100 µg/mL with inhibitory values of 100%, 90%, 90%, 90%, and 100%,
respectively, which were near to that of Abamectin (100%). From the data listed in Table 1, we
found that the structure-insecticidal activity relationship of some designed compounds against N.
lugen is similar to structure-insecticidal activity relationship of some title compounds against A.
medicaginis. When R2 is methyl, 4-position of phenyl ring A possessing halogen (7a, 7b, 7c, 7h,
7i, 7p, and 7q) or methyl (7l) was more advantageous to increase the insecticidal activity against
N. lugen at 100 µg/mL than other substituents (R3). When R2 is 4-methylphenyl, compounds 7s,
and 7t showed no acaricidal or insecticidal activity against A. medicaginis, Oriental armyworm
and N. lugen at the concentration of 500 µg/mL, which were lower than that of compound 7l (R2 =
Me). The data presented in Table 1 also indicated that compound 7a, 7b, and 7c had good
insecticidal effects against Oriental armyworm and N. lugen beyond potent insecticidal activities
against A. medicaginis at the concentration of 100 µg/mL. In addition, Table 2 indicated the
results of further toxicity assay about the typical candidates 7b and 7c, and the control
Imidacloprid against A. medicaginis. The data shown in Table 2 exhibited that compounds 7b and
7c displayed potent insecticidal activity against A. medicaginis, and the 50% lethal concentration

( LC50) values of compounds 7b and 7c were 2.81 and 5.02 µg/mL, respectively, which were
lower than that of the control Imidacloprid (LC50 = 0.15 µg/mL).
The fungicidal activities of compounds 7a–7u against cucumber Pseudoperonospora cubensis
in vivo were evaluated by a reported procedure,33 and Pyraclostrobin was selected as the control.
As indicated in Table 3, some of the aimed compounds showed good in vivo fungicidal activity
against P. cubensis at a concentration of 200 µg/mL. Especially, the inhibitory rates of compounds
7a, 7b, 7c, 7h, 7i, 7k, and 7l were 100%, 95%, 100%, 100%, 100%, 100%, and 95%, respectively,
which were equal to that of the control Pyraclostrobin (100%). Moreover, some of them possessed
satisfactory fungicidal activity against P. cubensis when the dosage was lowered to 50 µg/mL.
Compounds 7a and 7h displayed perfect inhibitory effects against P. cubensis at the dosages of 40
µg/mL, 20 µg/mL, and 10 µg/mL. Even when the concentration was reduced to 5 µg/mL,
compounds 7a and 7h were still active against P. cubensis with the values of 50%, and 80%,
respectively, which were comparable or much better than that of Pyraclostrobin (50%). From the
data listed in Table 3, we can find that the substituents (R3) on the phenyl ring A also have an
impact on the fungicidal activities. When R2 is methyl, 3- or 4-position of phenyl ring A having
halogen (7a, 7b, 7c, 7h, 7i, 7p, and 7q), methoxy (7k) or methyl (7e and 7l), or 2,4-position of
phenyl ring A possessing fluoro atom (7o) was advantageous to increase the fungicidal activity
against P. cubensis at 200 µg/mL. Then, the EC50 values of compounds 7a and 7h were tested and
given in Table 4, which showed that the EC50 value of compound 7a (4.97 µg/mL) was near to
that of the control Pyraclostrobin (4.59 µg/mL), and the EC50 value of compound 7h (0.51 µg/mL)
was about 10-folds as high as that of Pyraclostrobin.
In summary, a number of pyrazole oximes bearing an oxadiazole moiety were prepared in good

yields. Bioassays showed that some title compounds exhibited good acaricidal activity against T.
cinnabarinus at the concentration of 500 µg/mL. Moreover, some target compounds had potent
insecticidal activity against A. medicaginis, Oriental armyworm, and N. lugens at 500 and 100
µg/mL. Insecticidal activity against A. medicaginis of compounds 7a, 7b, and 7c were 80%, 90%,
and 90%, respectively, at 20 µg/mL. In addition, we are pleased to find that some compounds also
showed good in vivo fungicidal activity against P. cubensis. The EC50 values of compounds 7a
and 7h against P. cubensis were 4.97 µg/mL and 0.51 µg/mL, respectively, which were
comparable or much better than that of the control Pyraclostrobin (4.59 µg/mL). Further studies on
these compounds are in progress in our laboratory.
Table 1 Acaricidal and insecticidal activities of compounds 7a–7u
Acaricidal and insecticidal activity (%) at concn (µg/mL)
Compd
T. cinnabarinus
A. medicaginis
Oriental armyworm
N. lugens
500
100
0
100
0
—
—
—
0
—
—
0
—
—
0
500
100
90
100
80
100
100
80
90
0
—
80
80
—
80
100
70
—
—
80
80
20
500
100
100
100
50
0
0
0
0
0
100
50
80
100
0
20
0
0
500
100
100
100
100
100
80
100
100
90
90
0
20
0
0
80
90
90
0
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
0
90
0
0
0
80
0
0
100
0
100
100
80
—
—
—
—
—
—
0
—
—
—
—
—
—
—
—
0
—
—
0
0
—
0
0
—
—
—
—
—
30
—
—
—
—
—
—
—
60
0
—
—
50
50
—
60
70
70
—
—
50
30
0
0
—
80
80
—
50
90
0
—
0
80
100
100
100
0
100
100
80
0
0
100
100
100
100
0
100
100
80
0
50
100
100
0
80
0
80
70
0
0
0
0
50
0
0
0
0
0
—
—
—
0
—
—
—
0
90
90
0
0
0
7r
0
—
80
80
0
0
—
—
80
0
—
0
0
0
100
—
—
—
—
—
100
—
—
0
0
0
—
100
—
—
—
—
—
100
—
—
—
—
—
100
—
0
0
0
—
—
100
—
—
—
—
—
100
—
—
—
—
—
100
0
0
0
—
—
100
—
—
—
—
—
100
—
—
—
—
—
100
7s
7t
7u
Fenpyroximate
Imidacloprid
Abamectin
“—” refers to “not tested”.
Table 2 Toxicities of compounds 7b and 7c, and Imidacloprid against A. medicaginis
Compd
7b
7c
Regression equation
y = 4.12 + 1.95x
y = 3.57 + 2.04x
LC50 (µg/mL)
2.81
5.02
r
0.99
0.99

Imidacloprid
y = 7.47 + 2.99x
0.15
0.94
Table 3 Fungicidal activities of compounds 7a–7u in vivo
Fungicidal activity (%) against P. cubensis at concn (µg/mL)
Compd
200
50
40
20
10
5
100
95
100
50
100
—
96
—
70
—
50
—
7a
7b
100
0
0
—
—
—
—
—
—
—
—
7c
7d
—
75
0
10
100
100
0
100
95
0
0
—
—
100
0
—
30
0
—
—
—
100
—
—
—
—
—
—
—
—
—
100
—
—
—
—
—
—
—
—
—
93
—
—
—
—
—
—
—
—
—
80
—
—
—
—
—
—
7e
7f
7g
7h
7i
7j
7k
7l
—
—
7m
7n
0
80
0
—
—
—
—
7o
40
50
0
—
—
—
—
—
—
—
—
—
—
98
—
—
—
—
—
—
72
—
—
—
—
—
—
50
7p
7q
—
—
7r
0
—
—
—
—
7s
0
7t
7u
0
100
—
100
—
100
Pyraclostrobin
“—” refers to “not tested”.
Table 4 EC50 values of compounds 7a and 7h, and Pyraclostrobin against P. cubensis in vivo
Compd
Regression equation
y = 3.33 + 2.40x
y = 5.29 + 1.01x
y = 3.40 + 2.41x
EC50 (µg/mL)
4.97
0.51
r
0.98
0.95
0.96
7a
7h
Pyraclostrobin
4.59
Acknowledgments
This work was funded by the National Natural Science Foundation of China (Nos. 21202089,
21372135), the Research Foundation of the Six People Peak of Jiangsu Province (No.
2013-SWYY-013), the Technology Project Fund of Nantong City (Nos. AS2014011, CP12013002,
MS22015020).
Supplementary data
Supplementary data (which contain information on the synthesis, characterization, and

bioactivity test methods of the title compounds) associated with this article can be found, in the
online version, at http://dx.doi.org.
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The present work reported that novel pyrazole oxime derivatives containing a
substituted oxadiazole moiety displayed good fungicidal activity beyond satisfactory
insecticidal and acaricidal activities.
R1
N
O
N
N
N
N
N
O
O
O
O
N
N
R2
O
O
R3
7a-7u
R1 =F, Cl, CF3
Fenpyroximate
R2 =Me, 4-MeC6H4, 4-ClC6H4
R3 =Me, F, Cl, Br, I, etc.