Synthesis and bioactivities of novel pyrazole oxime derivatives containing a 1,2,3-thiadiazole moiety

Article abstract of DOI:10.1016/j.bmcl.2016.07.068

A series of new pyrazole oxime compounds bearing a 1,2,3-thiadiazole ring were designed, synthesized, and evaluated for their insecticidal, acaricidal and antitumor activities. Bioassays demonstrated that some title compounds displayed satisfactory insecticidal and acaricidal properties. Especially, compounds 8d and 8h exhibited 90% insecticidal activities against Aphis craccivora at the concentration of 100?μg/mL. Interestingly, some of the target compounds possessed significant antitumor activities against four human cancer cell lines in vitro. Among them, compounds 8e (IC₅₀?=?7.19?μM), 8l (IC₅₀?=?6.56?μM), 8m (IC₅₀?=?8.12?μM), and 8r (IC₅₀?=?7.06?μM) had better inhibitory activities against HCT-116 cells than the control 5-fluorouracil (IC₅₀?=?29.50?μM). Additionally, compounds 8j, 8m, and 8r showed wonderful inhibitory activities against SGC-7901 cells with the IC₅₀values of 11.46, 9.41, and 8.64?μM, respectively, which were superior to that of the control 5-fluorouracil.

Full text of DOI:10.1016/j.bmcl.2016.07.068

Accepted Manuscript
Synthesis and bioactivities of novel pyrazole oxime derivatives containing a
1,2,3-thiadiazole moiety
Hong Dai, Shushan Ge, Gang Li, Jia Chen, Yujun Shi, Linyu Ye, Yong Ling
PII:
S0960-894X(16)30796-X
http://dx.doi.org/10.1016/j.bmcl.2016.07.068
BMCL 24112
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
7 May 2016
8 July 2016
28 July 2016
Please cite this article as: Dai, H., Ge, S., Li, G., Chen, J., Shi, Y., Ye, L., Ling, Y., Synthesis and bioactivities of
novel pyrazole oxime derivatives containing a 1,2,3-thiadiazole moiety, Bioorganic & Medicinal Chemistry
Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.07.068
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Synthesis and bioactivities of novel pyrazole oxime derivatives
containing a 1,2,3-thiadiazole moiety
Hong Dai a,b, Shushan Ge b, Gang Li a, Jia Chen a, Yujun Shi a,*, Linyu Ye a, Yong Lingb,*
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 new pyrazole oxime compounds bearing a 1,2,3-thiadiazole ring were designed,
synthesized, and evaluated for their insecticidal, acaricidal and antitumor activities. Bioassays
demonstrated that some title compounds displayed satisfactory insecticidal and acaricidal
properties. Especially, compounds 8d and 8h exhibited 90% insecticidal activities against Aphis
craccivora at the concentration of 100 μg/mL. Interestingly, some of the target compounds
possessed significant antitumor activities against four human cancer cell lines in vitro. Among
them, compounds 8e (IC50 = 7.19 μM), 8l (IC50 = 6.56 μM), 8m (IC50 = 8.12 μM), and 8r (IC50 =
7.06 μM) had better inhibitory activities against HCT-116 cells than the control 5-fluorouracil
(IC50 = 29.50 μM). Additionally, compounds 8j, 8m, and 8r showed wonderful inhibitory
activities against SGC-7901 cells with the IC50 values of 11.46, 9.41, and 8.64 μM, respectively,
which were superior to that of the control 5-fluorouracil.
Keywords: Pyrazole oxime, 1,2,3-Thiadiazole, Synthesis, Bioactivity
In the past few decades, heterocycles plays a vital role in the field of agriculture and medicine.
Pyrazole is a classical nitrogen-containing heterocycle which extensively exists in natural products

and non-natural products.1,2 Most of these pyrazole derived compounds have been investigated to
possess various bioactivities such as insecticidal,3 acaricidal,4,5 antibacterial,6,7 and anticancer
activities.8,9 Pyrazole oxime derivatives are important parts of pyrazole compounds with diverse
bioactivities like insecticidal,10 fungicidal,11 and anti-tobacco mosaic virus (TMV) activity.12 For
instance, Fenpyroximate (Figure 1), a potent acaricide carrying a pyrazole oxime in the structure,
is widely used in crop protection.13,14 Furthermore, in 2005 Park et al. also found some
Fenpyroximate analogues displayed interesting antitumor activities.15 This endowed a great
impetus to the study of biologically active pyrazole oxime compounds.
On the other hand, as an important five-member heterocycle, 1,2,3-thiadiazole derivatives have
also attracted considerable attention due to their versatile bioactivities including fungicidal,16
insecticidal,17 and antivirus activities.18 Recently, Fan et al. reported several series of
1,2,3-thiadiazole derivatives bearing other heterocyclic ring like triazole, and so on, and some of
these compounds exhibited good anti-TMV activities.19,20 More recently, Xu et al. synthesized a
series of new 1,2,3-thiadiazoles that displaying perfect antivirus activity against TMV.21
Additionally, many 1,2,3-thiadiazole containing derivatives are found to exhibit potent
antiamoebic,22 and antitumor property.23 Therefore, 1,2,3-thiadiazole-based compounds became a
focus of chemical and pharmaceutical research.
Inspired by these facts, we envisioned that introduction of a substituted 1,2,3-thiadiazole ring
into pyrazole oxime scaffold might produce some compounds possessing a wide spectrum
bioactivities. In the present study, we describe the synthesis of a number of novel pyrazole oxime
derivatives bearing a 1,2,3-thiadiazole moiety. Moreover, all the title compounds have been
investigated for their biological activities containing insecticidal, acaricidal, and antitumor

activities.
S
N
N
N
N
O
R1
N
O
O
R2
N
N
O
R1 =Me, Et, n-Pr
R2 =Me, F, Cl, Br, I, etc.
O
N
O
S
N
N
N
N
O
R1
N
Fenpyroximate
Cl
R1 =Me, Et, n-Pr
Target Compounds
Figure 1. Design of target compounds.
The synthetic route of the target compounds 8a-8t and 10a-10c was depicted in Scheme 1. The
key intermediate 4-alkyl-5-chloromethyl-1,2,3-thiadiazole (4) was synthesized from compound 1.
The condensation of intermediate 1 with methyl hydrazinocarboxylate afford compound 2.24
Intermediate 2 reacted with thionyl chloride to give compound 3.25 Intermediate 3 was treated by
two steps including reduction and chlorination to obtain the crucial intermediate
4-alkyl-5-chloromethyl-1,2,3-thiadiazole (4). Pyrazole oximes (7) and (9) were prepared from
o
compound 5. Intermediate 5 was condensed with sodium substituted phenol at 105 C to afford
5-aryloxy substituted pyrazole carbaldehyde (6),26 which then reacted with hydroxylamine
hydrochloride under basic condition to produce 5-aryloxy pyrazole oximes (7) smoothly. Similarly,
compound 5 was transformed into 5-chloropyrazole oxime (9) by the treatment with
hydroxylamine hydrochloride. Finally, compound
7
or
9
was admixed with

4-alkyl-5-chloromethyl-1,2,3-thiadiazole (4) in CH3CN using potassium carbonate as alkali to
form corresponding pyrazole oximes containing a 1,2,3-thiadiazole moiety successfully.27 The title
1
compounds have all been confirmed by H NMR, 13C NMR, and elemental analyses (detailed
information see Supplementary data).
O
O
R1
Me
N
N
NH
O
O
a
b
N
O
O
R
R1
O
O
R
S
R
R1
R1
O
O
3
1
R =Me, Et
2
1
Me, Et, n-Pr
R =
N
c
N
Cl
S
O
4
OH
H3C
H3C
H3C
H
H
N
e
d
N
R2
N
R2
N
Cl
O
N
N
O
N
CH3
CH3
CH3
7
6
5
R1
N
S
N
O
H3C
f
N
R2
8a-8t
N
O
N
CH3
8p: R1 =Et, R2 =4-OCF3
8k: R1 =Me, R2 =4-t-bu
8l: R1 =Me, R2 =2,3-diF
8m: R1 =Me, R2 =3,5-diF
8n: R1 =Et, R2 =2-Cl
8a: R1 =Me, R2 =2-Cl
8b: R1 =Me, R2 =3-F
8c: R1 =Me, R2 =3-CF3
8d: R1 =Me, R2 =4-F
8e: R1 =Me, R2 =4-Br
8f: R1 =Me, R2 =4-I
8q: R1 =n-Pr, R2 =2-Cl
8r: R1 =n-Pr, R2 =4-F
8s: R1 =n-Pr, R2 =4-Cl
8g: R1 =Me, R2 =3-Me
8h: R1 =Me, R2 =4-Me
8i: R1 =Me, R2 =2-OCF3
8o: R1 =Et, R2 =4-Me
8j: R1 =Me, R2 =4-OCF3
8t: R1 =n-Pr, R2 =2-Me
R1
N
N
S
O
OH
O
H3C
N
H3C
H
H3C
N
g
h
N
N
N
Cl
N
Cl
N
Cl
N
CH3
CH3
CH3
10a-10c
9
5
10c: R1 =n-Pr
10b: R1 =Et
10a: R1 =Me
Scheme 1. Synthesis of compounds 8a-8t, 10a-10c. Reagents and conditions: (a) NH2NHCOOCH3,
CH3CH2OH, rt, 10 h; (b) SOCl2, CH2Cl2, 0 oC to rt, 24 h; (c) (i) NaBH4, I2, CH3OH, 0 oC to rt, 3 h; (ii) SOCl2,
reflux, 30 min; (d) sodium substituted phenol, DMSO, 105 oC, 8-18 h; (e) NH2OH·HCl, KOH, CH3OH, reflux,
6-17 h; (f) compound 4, K2CO3, CH3CN, reflux, 7-20 h; (g) NH2OH·HCl, KOH, CH3CH2OH, reflux, 8 h; (h)

compound 4, K2CO3, CH3CN, reflux, 10-13 h.
The synthesized compounds 8a-8t and 10a-10c were evaluated for insecticidal activities against
Plutella xylostella and Aphis craccivora, and acaricidal activity against Tetranychus cinnabarinus
using known procedures,28-30 and Pyridalyl, Imidacloprid and Fenpyroximate were used as the
positive controls, respectively. As shown in Table 1, some of the target compounds exhibited
excellent insecticidal activities against Plutella xylostella at a concentration of 200 μg/mL. For
instance, the mortalities of compounds 8a, 8d, 8e, 8h, 8k, 8l, 8m, and 10a against P. xylostella
were all 100%, which were similar to that of the control Pyridalyl. Some of them displayed good
insecticidal properties against P. xylostella when the dosage was reduced to 100 μg/mL,
compounds 8e and 8f had 80% and 62% inhibition rates, respectively. Compounds 8e and 8f were
still active against P. xylostella even when the dosage was lowered to 50 μg/mL with inhibitory
values of 43% and 60%, respectively. Based on the structure-insecticidal activity data, we found
that when R1 is Et or n-Pr, all of the target compounds showed no insecticidal activity against P.
xylostella at 200 μg/mL. When R1 is Me, some designed compounds had better insecticidal
activity against P. xylostella than did the corresponding ethyl and n-propyl derivatives. For
example, compounds 8a, 8n, 8q, 10a, 10b, and 10c possessed 100%, 0%, 0%, 100%, 0%, and 0%
insecticidal activity against P. xylostella at the concentration of 200 μg/mL, respectively. In
addition, we can also see that when R1 is Me, the substituent at 2-, 4-, 2,3- or 3,5-position of
phenyl ring was halogen (8a, 8d, and 8e) or the substituent at 4-position of phenyl ring was alkyl
(8h and 8k), it was advantageous to increase the insecticidal activity at 200 μg/mL. Meanwhile,
some designed compounds displayed good insecticidal properties against A. craccivora besides
satisfactory insecticidal activity against P. xylostella. For example, compounds 8b, 8d, 8f, 8g, 8h,
8j, 8k, 8m, and 10a had 98%, 99%, 95%, 90%, 100%, 100%, 95%, 90%, and 100% insecticidal

activity against A. craccivora at the concentration of 200 μg/mL, respectively, which were equally
to that of the control Imidacloprid. Moreover, compounds 8b, 8d, 8h, 8j, 8k, and 10a showed
significant insecticidal activity against A. craccivora at the concentrations of 100 μg/mL and 50
μg/mL. At the concentration of 100 μg/mL, 8d and 8h possessed 90% and 90% inhibitory rates,
respectively, which were similar to that of Imidacloprid. From the data presented in Table 1, we
can find that structure-insecticidal activity relationship of some derivatives against A. craccivora
was similar to structure-insecticidal activity relationship against P. xylostella. When R1 is Me,
some designed compounds displayed relatively higher insecticidal activity against A. craccivora
than did the corresponding ethyl and n-propyl derivatives, and 3-, 4-, or 3,5-position of phenyl
ring bearing halogen (8b, 8d, 8f, and 8m), alkyl (8g, 8h, and 8k) or trifluoromethoxy (8j) was
more favorable to the insecticidal activity against A. craccivora at 100 μg/mL and 50 μg/mL than
other substituents. Meanwhile, Table 1 also indicated that some target compounds possessed good
acaricidal activities against T. cinnabarinus at 200 μg/mL. For instance, the mortalities of
compounds 8b, 8f, and 8j against T. cinnabarinus were 80%, 90%, and 80%, respectively, which
were similar to that of the control Fenpyroximate. Additionally, compounds 8b and 8f were still
active against T. cinnabarinus when the concentration was lowered to 100 μg/mL with inhibitory
rates of 50% and 60%, respectively. The data listed in Table 1 showed that 4-iodo substituted
compound 8f had potent insecticidal properties against P. xylostella and A. craccivora beyond
moderate acaricidal activities against T. cinnabarinus at the concentrations of 200 μg/mL and 100
μg/mL.
The cytotoxicity of target compounds 8a-8t and 10a-10c against human pancreatic carcinoma
cells (Panc-1), human hepatoma cells (Huh-7), human colon cancer cells (HCT-116) and human

gastric cancer cells (SGC-7901) were tested in vitro by MTT method31 using sorafenib, cisplatin,
and 5-fluorouracil as the positive controls, respectively. The IC50 values were summarized in Table
2. As can be seen, compounds 8e and 8l exhibited optimal activity with IC50 values of 12.79, 12.22,
11.84, and 10.17 μM in Panc-1 and Huh-7 cells, respectively, which were comparable to those of
the controls sorafenib (11.50 μM) and cisplatin (12.70 μM). The cytotoxicity of most compounds
against HCT-116 cells was similar or superior to that of the control 5-fluorouracil. Among them,
compounds 8e, 8l, 8m, and 8r (IC50 = 7.19, 6.56, 8.12, and 7.06 μM, respectively) showed
stronger antiproliferative effects than 5-fluorouracil (IC50 = 29.50 μM). Table 2 also displayed that
some derivatives expressed important antitumor activity against SGC-7901 cell lines. Especially,
the IC50 values of 8c, 8e, 8g, 8h, 8j, 8m, 8n, 8p, 8q, 8r, 8s, and 8t were 12.39, 15.15, 12.75, 12.80,
11.46, 9.41, 15.79, 13.59, 17.62, 8.64, 18.55, and 16.26 μM, respectively, which were better than
that of 5-fluorouracil (56.12 μM). The data presented in Table 2 exhibited that 4-bromo substituted
compound 8e and 2,3-difluoro substituted analogue 8l possessed more potent inhibitory activity
against all tested cancer cells. All the above results suggested that appreciable biological activities
can be achieved through introducing the 1,2,3-thiadiazole group into pyrazole oxime heterocyclic
system. Meanwhile, this study also offers a significant basis for the design of novel molecules
with wide spectrum bioactivities.
In summary, a variety of new pyrazole oxime compounds carrying a 1,2,3-thiadiazole moiety
were designed and synthesized. Bioassays revealed that some of the designed compounds
displayed good insecticidal properties against P. xylostella and A. craccivora besides potential
acaricidal activities against T. cinnabarinus. Moreover, some title compounds exhibited
satisfactory antitumor activities against four cancer cells. Particularly, compounds 8e, 8l, 8m, and

8r expressed excellent inhibitory activities against HCT-116 cells with IC50 values of 7.19, 6.56,
8.12, and 7.06 μM, respectively, which were better than that of 5-fluorouracil (29.50 μM), and
compounds 8j, 8m, and 8r showed much higher anticancer activities against SGC-7901 cells than
the control 5-fluorouracil. Further studies on these compounds are in progress in our laboratory.
Table 1. Insecticidal and acaricidal activities of compounds 8a-8t and 10a-10c(mortality, %)
P. xylostella
A. craccivora
T. cinnabarinus
Compd.
200
100
50
200
100
50
200
100
50
μg/mL μg/mL μg/mL μg/mL μg/mL μg/mL μg/mL μg/mL μg/mL
100
71
0
0
—
—
15
98
—
80
—
52
0
80
—
50
—
0
8a
8b
45
100
100
64
84
100
66
50
100
100
100
0
0
0
0
0
0
0
100
0
0
—
0
80
62
0
0
0
0
0
—
—
43
60
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
100
—
—
62
99
20
95
90
100
22
100
95
19
90
0
0
0
0
0
0
0
100
0
0
55
90
—
70
70
90
—
85
80
—
75
—
—
—
—
—
—
—
85
—
—
—
100
—
31
60
—
41
38
58
—
59
50
—
45
—
—
—
—
—
—
—
61
—
—
—
100
—
0
0
0
90
0
0
0
80
0
0
0
0
0
0
0
0
0
0
0
—
—
—
60
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
100
—
—
—
0
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
100
0
0
—
—
—
—
—
—
—
0
—
—
100
—
—
8s
8t
10a
10b
10c
0
0
—
—
100
Pyridalyl
Imidacloprid
Fenpyroximate
100
—
—
—
100
—
“—” refers to “not tested”.
compounds
IC50, μM
Compd
Panc-1
>50
>50
HUH-7
>50
>50
HCT-116
42.53
>50
SGC-7901
8a
8b
8c
8d
8e
8f
8g
8h
8i
>50
>50
>50
>50
12.79
>50
>50
>50
>50
>50
>50
11.84
>50
>50
>50
>50
10.30
30.16
7.19
43.82
14.10
13.81
>50
12.39
>50
15.15
>50
12.75
12.80
>50
8j
11.46
>50
>50
12.82
8k
8l
>50
>50
>50
33.54
6.56
12.22
10.17
25.65

8m
8n
>50
>50
>50
>50
>50
>50
8.12
17.60
>50
9.41
15.79
19.80
8o
8p
>50
>50
>50
>50
>50
26.56
>50
>50
—
>50
>50
>50
>50
>50
>50
>50
>50
—
12.50
16.41
7.06
19.21
15.68
>50
>50
>50
29.50
—
—
13.59
17.62
8.64
18.55
16.26
>50
>50
>50
56.12
—
—
8q
8r
8s
8t
10a
10b
10c
5-Fluorouracil
Cisplatin
Sorafenib
—
11.50
12.70
—
“—” refers to “not tested”.
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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Graphical abstract
The present work reported that novel pyrazole oximes containing a 1,2,3-thiadiazole
moiety displayed good antitumor activity beyond satisfactory insecticidal and
acaricidal activities.
S
N
N
N
N
O
R1
N
O
R2
O
R1 =Me, Et, n-Pr
R2 =Me, F, Cl, Br, I, etc.
N
N
O
O
N
O
S
N
N
N
N
O
R1
Fenpyroximate
N
Cl
R1 =Me, Et, n-Pr