Synthesis and biological activities of novel 1,3,4-thiadiazole-containing pyrazole oxime derivatives

Article abstract of DOI:10.1016/j.bmcl.2016.04.094

A new library of 1,3,4-thiadiazole-containing pyrazole oximes was designed and synthesized. Their acaricidal and insecticidal activities were evaluated. Bioassay results indicated that some target compounds exhibited good acaricidal and insecticidal properties. Especially, compound 8m had 80% acaricidal activity against Tetranychus cinnabarinus at the concentration of 50?μg/mL, compound 8f displayed 100% insecticidal activities against Aphis craccivora at the concentration of 50?μg/mL, compounds 8r and 8w showed 100% insecticidal activities against Plutella xylostella at the concentration of 50?μg/mL. Furthermore, compounds 8r (LC₅₀?=?19.61?μg/mL) and 8w (LC₅₀?=?9.78?μg/mL) possessed comparable or even better insecticidal activities than the control Pyridalyl (LC₅₀?=?17.40?μg/mL) against P. xylostella.

Full text of DOI:10.1016/j.bmcl.2016.04.094

Accepted Manuscript
Synthesis and biological activities of novel 1,3,4-thiadiazole-containing pyra-
zole oxime derivatives
Hong Dai, Gang Li, Jia Chen, Yujun Shi, Shushan Ge, Chongguang Fan,
Haibing He
PII:
S0960-894X(16)30492-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.04.094
BMCL 23867
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 April 2016
25 April 2016
28 April 2016
Please cite this article as: Dai, H., Li, G., Chen, J., Shi, Y., Ge, S., Fan, C., He, H., Synthesis and biological activities
of novel 1,3,4-thiadiazole-containing pyrazole oxime derivatives, Bioorganic & Medicinal Chemistry Letters
(2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.04.094
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Synthesis
and
biological
activities
of
novel
1,3,4-thiadiazole-containing pyrazole oxime derivatives
Hong Dai, Gang Li, Jia Chen, Yujun Shi*, Shushan Ge, Chongguang Fan and Haibing He*
College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, People’s
Republic of China
Corresponding Author Emails: yjshi2015@163.com; gaohbhe2015@aliyun.com; Tel:
+86-513-85012851
ABSTRACT
A new library of 1,3,4-thiadiazole-containing pyrazole oximes were designed and synthesized.
Their acaricidal and insecticidal activities were evaluated. Bioassay results indicated that some
target compounds exhibited good acaricidal and insecticidal properties. Especially, compound 8m
had 80% acaricidal activity against Tetranychus cinnabarinus at the concentration of 50 μg/mL,
compound 8f displayed 100% insecticidal activities against Aphis craccivora at the concentration
of 50 μg/mL, compounds 8r and 8w showed 100% insecticidal activities against Plutella
xylostella at the concentration of 50 μg/mL. Furthermore, compounds 8r (LC50 = 19.61 μg/mL)
and 8w (LC50 = 9.78 μg/mL) possessed comparable or even better insecticidal activities than the
control Pyridalyl (LC50 = 17.40 μg/mL) against Plutella xylostella.
Keywords: 1,3,4-Thiadiazole, Pyrazole oxime, Synthesis, Bioactivity
In recent years, the development of heterocyclic agrochemicals has become a main trend for
their flexible structure, low mammalian toxicity, and high activity in the research on pesticides. As
an important five-member of heterocycle, literature survey has been revealed that 1,3,4-thiadiazole
derivatives possess broad spectrum biological activities such as insecticidal,1,2 fungicidal,3,4 and
herbicidal activity.5 At present, many commercial marketed pesticides such as Tebuthiuron and

Thiazafluron (Figure 1), containing a 1,3,4-thiadiazole ring, have been widely used in agriculture.
Furthermore, the research of 1,3,4-thiadiazole compounds in medicinal and pharmaceutical
chemistry is also unfolded rapidly.6 Many 1,3,4-thiadizole-containing compounds are found to
possess potent anticancer,7,8 and anti-proliferative activity.9 This endowed a great impetus to the
study of biologically active 1,3,4-thiadiazole derivatives.
On the other hand, pyrazole oxime unit plays a vital role in bioactive molecules. Lots of
pyrazole oxime derivatives are reported to possess diverse bioactivities including fungicidal,10
insecticidal,11 acaricidal,12 anti-TMV,13 and antitumor properties.14 For example, Fenpyroximate
(Figure 1), an excellent acaricide bearing a pyrazole oxime unit, is used to control some
phytophagous mites such as Tetranychus urticae Koch and Polyphagotarsonemus latus Banks.15,16
Furthermore, a series of Fenpyroximate analogues have displayed satisfactory antitumor activity.17
Recently, Dai and co-workers have obtained a variety of novel pyrazole oxime derivatives by
replacing the esterified aryl group of Fenpyroximate with different heterocycles such as thiazole,18
pyridine,19 and oxazole ring.20 Some of them exhibited promising fungicidal activity beyond good
insecticidal and acaricidal activity. Very recently, Dai et al. also found some pyrazole oximes
possessed interesting insecticidal activity besides potent acaricidal activity through modification
of the esterified group of Fenpyroximate with thiazolylmethoxy unit.21 Thus, we have reason to
believe that the pyrazole oxime moiety can be used as a significant skeleton in exploring new
bioactive compounds.
Considering the facts mentioned above, we speculated that the introduction of a substituted
1,3,4-thiadiazole pharmacophore into pyrazole oximes might produce some new compounds with
multiple bioactivities. Herein, we describe the design and synthesis of a series of novel pyrazole

oximes carrying a substituted 1,3,4-thiadiazole ring. Moreover, all the new compounds were
investigated for their acaricidal and insecticidal activities.
O
N
N
N
N
R1
O
N
N
O
O
S
O
N
N
R2
O
O
R3
Fenpyroximate
R1 =Me, Et
R2 =Me, 4-MeC6H4
R3 =Me, F, Cl, Br, etc.
O
N
N
N
N
H
F3C
S
Target Molecules
Thiazafluron
Figure 1. The design of the target molecules.
The general synthetic route of the target compounds 8a-8z was outlined in Scheme 1.
Intermediate 2-chloromethyl-5-alkoxy-1,3,4-thiadiazole (4) was synthesized from alcohols (1).
Compound 1 reacted with carbon disulfide under basic condition, and further subjected to
hydrazinolysis to give intermediate 2.22 The condensation of compound 2 with chloracetyl chloride
produced
compound
3
successfully,
which
was
then
cyclized
to
form
2-chloromethyl-5-alkoxy-1,3,4-thiadiazole (4). 5-aryloxy pyrazole oximes (7) were prepared from
compound 5. Introduction of substituted phenols into 5-chloropyrazole-4-carbaldehyde (5) by
nucleophilic aromatic substitution gave 5-aryloxy substituted pyrazole carbaldehyde (6)
successfully.23 Further reaction of 5-aryloxypyrazole carbaldehyde (6) with hydroxylamine
hydrochloride in methanol or ethanol medium afforded 5-aryloxy pyrazole oximes (7) in
satisfactory
yields.
The
treatment
of
intermediate
7
with
2-chloromethyl-5-alkoxy-1,3,4-thiadiazole (4) in acetonitrile medium using potassium carbonate
as alkali produced corresponding pyrazole oximes containing a substituted 1,3,4-thiadiazole
moiety smoothly (Scheme 1). The structures of the newly synthesized compounds 8a-8z were well

characterized by 1H NMR, 13C NMR, and elemental analyses (detailed information see
Supplementary data).
S
C
S
C
a
NH2
NH
b
R1OH
R1O
N
R1O
N
H
H
Cl
O
1
3
2
N N
c
R1
Cl
O
S
R1 =Me, Et
4
O
O
H
OH
H3C
N
H3C
H3C
H
N
f
e
d
R3
N
R3
N
Cl
O
N
N
O
N
R2
5
R2
6
R2
7
R1
O
N
S
N
O
H3C
N
R3
N
O
N
R2
8a-8z
Scheme 1. Synthesis of compounds 8a-8z. Reagents and conditions: (a) (i) CS2, NaOH-H2O, 20oC, 3 h; (ii)
NH2NH2-H2O, 30 oC, 2 h; (b) CH3COONa-H2O, 1,4-dioxane, chloroacetyl chloride, 0 oC to rt, 4 h; (c) H2SO4, 0oC,
3 h; (c) substituted phenols, KOH, DMF or DMSO, 45 oC, 2 h, 110oC, 6-22 h; (e) NH2OH·HCl, KOH, CH3OH or
CH3CH2OH, reflux, 5-20 h; (f) compound 4, K2CO3, CH3CN, reflux, 8-17 h.
In this study, the title compounds 8a-8z were tested for their insecticidal activities against Aphis
craccivora and Plutella xylostella and acaricidal activity against Tetranychus cinnabarinus using
known procedures,24-26 and Imidacloprid, Pyridalyl and Fenpyroximate were used as the positive
controls, respectively. As shown in Table 1, some title compounds possessed excellent acaricidal
activities against T. cinnabarinus at a concentration of 200 μg/mL. For instance, the mortalities of
compounds 8m, 8n, 8p, 8r, 8s, and 8t against T. cinnabarinus were 100%, 100%, 100%, 95%,
100%, and 100%, respectively, which were similar to that of the control Fenpyroximate. Some of
them displayed good acaricidal properties against T. cinnabarinus when the concentration was

reduced to 100 μg/mL, compounds 8m, 8n, 8p, 8r, 8s, and 8t had 100%, 100%, 90%, 80%, 80%,
and 80% inhibition rates, respectively. Among them, compounds 8m, 8s, and 8t were still active
against T. cinnabarinus even when the concentration was reduced to 50 μg/mL with inhibitory
values of 80%, 50%, and 65%, respectively. Based on the structure-potency data, we can find that
when R1 is Me and R2 is Me, most of the target compounds showed no acaricidal activity against T.
cinnabarinus except compound 8a possessing 60% morality at 200 μg/mL. When R1 is ethyl
(R2=Me), some designed compounds displayed relatively better acaricidal activity against T.
cinnabarinus than did the corresponding methyl derivatives (R2=Me). For example, compounds
8a, 8b, 8e, 8f, 8l, 8n, 8r, and 8s exhibited 60%, 0%, 0%, 0%, 80%, 100%, 95%, and 100%
acaricidal activity against T. cinnabarinus at the concentration of 200 μg/mL, respectively.
Moreover, we can also see that when R1 is ethyl (R2=Me), the substituent at 4-position of phenyl
ring was halogen (8s and 8t) or trifluoromethoxy (8m), it was advantageous to increase the
acaricidal activity at 50 μg/mL except 4-fluoro derivative (8q). From the data presented in Table 1,
we found that most of the obtained compounds displayed perfect insecticidal activities against A.
craccivora at the concentration of 200 μg/mL. Furthermore, some of them showed good
insecticidal activities against A. craccivora when the concentration was lowered to 100 μg/mL,
compounds 8f, 8j, 8l, 8m, 8n, 8p, 8r, 8s, and 8t possessed 100%, 100%, 95%, 100%, 90%, 100%,
90%, 100%, and 95% inhibition rates, respectively, which were comparable to that of the control
Imidacloprid. Interestingly, even when the concentration was reduced to 50 μg/mL, compounds 8f,
8l, 8m, 8p, 8r, 8s, and 8t showed 100%, 90%, 95%, 95%, 90%, 95%, and 90% insecticidal
activities against A. craccivora, respectively, which were similar to that of the control
Imidacloprid. From the above insecticidal activity data, we can infer that the substituents on the

benzene ring also have an impact on the activities, when 3- or 4-position of phenyl ring bears a
halogen atom (8f, 8l, 8p, 8r, 8s, and 8t), methoxy (8l) or trifluoromethoxy (8m), it would be more
favorable to the insecticidal activities against A. craccivora except compounds 8e and 8q. Table 1
exhibited that some of the designed compounds had satisfactory insecticidal activities against P.
xylostella beyond good insecticidal activities against A. craccivora. For example, the mortalities
of compounds 8l, 8m, 8n, 8p, 8q, 8r, 8s, 8t, 8v, and 8w against P. xylostella were all 100% at 200
μg/mL, which were similar to that of the control Pyridalyl. Moreover, the insecticidal activities of
compounds 8r (100%) and 8w (100%) against P. xylostella at 50 μg/mL even reached the level of
Pyridalyl (100%). From the data listed in Table 1, we can find that structure-insecticidal activity
relationship of some compounds against P. xylostella were similar to structure-acaricidal activity
relationship against T. cinnabarinus. When R1 is ethyl (R2=Me), some title compounds showed
relatively higher insecticidal activity against P. xylostella than did the corresponding methyl
derivatives (R2=Me), and 3-, 4- or 2, 4-position of phenyl ring possessing methoxy (8l), hydrogen
(8n) or halogen (8p, 8q, 8r, 8s, 8t, 8v, and 8w) was more favorable to the insecticidal activity
against P. xylostella at 50 μg/mL than other substituents. When R2 is 4-MeC6H4 (R1=Et),
compounds 8y and 8z displayed poor insecticidal activities against A. craccivora and P. xylostella
at the concentration of 200 μg/mL, which were lower than those of compounds 8q and 8s (R2=Me
and R1=Et). The data presented in Table 1 also showed that 4-chloro substituted compound 8s and
4-bromo substituted analogue 8t possessed good insecticidal activities against P. xylostella and A.
craccivora beyond potent acaricidal properties against T. cinnabarinus from the concentrations of
200 μg/mL to 50 μg/mL. In addition, Table 2 indicated the results of further toxicity assay about
the typical candidates 8q, 8r and 8w, and the control Pyridalyl against P. xylostella. The data listed

in Table 2 displayed that compounds 8r and 8w had good potency against P. xylostella, and the 50%
lethal concentration ( LC50) values of compounds 8r and 8w were 19.61 and 9.78 μg/mL,
respectively, which were comparable or even better than that of the control Pyridalyl (LC50 =
17.40 μg/mL). All the above data implied that the biological activity spectrum of pyrazole oxime
derivatives was importantly improved via the introduction of a substituted 1,3,4-thiadiazole ring.
These studies represent a significant basis for the development of novel pesticides in future.
Table 1. Insecticidal and acaricidal activities of compounds 8a-8z (mortality, % )
Plutella
xylostellas
Tetranychus
cinnabarinus
Aphis
craccivora
1
2
3
Compd.
R
R
R
200 100
50
200 100
50
200 100
50
μg/ μg/ μg/ μg/ μg/ μg/ μg/ μg/ μg/
mL mL mL mL mL mL mL mL mL
8a
8b
8c
8d
8e
8f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-OMe
-H
2-F
2-Cl
3-Cl
4-Cl
3,4-diMe
2,4-diF
100
100
100
100
100
60
30
50
70
40
0
60
0
0
0
0
0
0
0
0
—
—
—
—
—
—
—
65
0
0
60
71
71
0
30
—
—
0
0
60
—
0
—
—
0
—
—
—
—
—
—
—
—
—
—
0
—
—
—
100 100 100
80
50
8g
0
0
—
—
8h
—
—
0
—
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-MeC6H4
2,4-diCl
3-Me
4-Me
4-OMe
4-OCF3
-H
2-F
3-F
4-F
3-Cl
4-Cl
4-Br
3-NO2
2,4-diF
2,4-diCl
6-Cl-3-Me
4-F
100
100 100
100
100
100 100
100
100
100 100
100
100
30
—
0
0
0
60
80
—
—
0
—
—
—
—
80
0
60
45
86
0
—
45
—
—
30
60
15
45
—
71
60
80
95
65
90
95
70
0
95
0
90
95
90
0
—
—
20
—
—
40
100 100
100 100
100 100
60
100
0
95
100
100
0
0
100
100
86
100 100
100 71
100 100 100
100
100 100
45
60
71
45
90
80
0
—
0
90
—
80
80
80
—
—
—
0
—
50
90
—
0
50
65
—
—
—
—
—
—
100 100
100
90
86
71
86
—
45
95
65
40
50
70
—
—
8u
8v
—
86
80
100
8w
8x
8y
8z
90
100
30
0
70
0
100 100 100
86
10
0
30
—
—
—
—
—
4-MeC6H4
4-Cl
20
0
—
Imidacloprid
Fenpyroximate
Pyridalyl
100 100 100
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
100 100 100
—
—
—
100 100 100
“—” refers to “not tested”.

Table 2. Toxicities of compounds 8q, 8r, and 8w, and Pyridalyl against Plutella xylostella
regression equation
Y = 1.51 + 2.70x
Y = 1.22 + 3.43x
Y = 1.25 + 3.76x
Y = 2.22 + 2.24X
LC50a (μg/mL)
33.75
rb
Compd.
8q
8r
8w
Pyridalyl
0.9986
0.9978
0.9907
0.9981
19.61
9.78
17.40
a LC50 refers to median lethal concentration.
b r refers to correlative coefficient.
In summary, a series of pyrazole oxime derivatives bearing a 1,3,4-thiadiazole moiety have
been synthesized and evaluated for their acaricidal activity against T. cinnabarinus, and
insecticidal activities against A. craccivora and P. xylostella. Some of the derivatives displayed
good acaricidal and insecticidal properties. Among these compounds, compound 8m showed 80%
acaricidal activity against T. cinnabarinus at the concentration of 50 μg/mL, compound 8f
possessed 100% insecticidal activities against A. craccivora at the concentration of 50 μg/mL,
compounds 8r and 8w had 100%, and 100% insecticidal activities against P. xylostella at the
concentration of 50 μg/mL, respectively. Interestingly, compounds 8s and 8t had broad spectrum
biological activities, they exhibited satisfactory insecticidal activities against A. craccivora and P.
xylostella besides potential acaricidal activity against T. cinnabarinus. Further analogue synthesis
and structural optimization are well under way.
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 Natural Science Foundation of Jiangsu Province (No. BK20140425), the
Technology Project Fund of Nantong City (Nos. AS2014011, CP12013002).

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 the novel pyrazole oximes containing a
1,3,4-thiadiazole moiety are potential candidate structures for new pesticide.
O
N
N
N
N
R1
O
N
N
O
O
S
O
N
N
R2
O
O
R3
Fenpyroximate
8a-8z
R1 =Me, Et
R2 =Me, 4-MeC6H4
R3 =Me, F, Cl, Br, etc.
O
N
N
N
N
H
F3C
S
Thiazafluron