Synthesis and biological activities of 2,3-dihydro-1,3,4-oxadiazole compounds and its derivatives as potential activator of ryanodine receptors

Article abstract of DOI:10.1016/j.bmcl.2014.03.077

A series of novel 2,3-dihydro-1,3,4-oxadiazoles containing N-pyridylpyrazole carboxamides moieties were obtained by applying a new synthetic route. Their insecticidal tests against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of the compounds showed moderate to excellent activities at the testing concentrations. In particular, compound 6a showed 40% larvicidal activities against oriental armyworm at 1 mg/L, while 7a against diamondback was 100% at 0.01 mg/L. Calcium imaging results demonstrated that 6a, 6d and 7a stimulated a transient elevation in [Ca²⁺]_i in the absence of external calcium after the central neurons dye loading with fluo-3 AM, implying that these novel compounds were potential activators of the ligand-gated calcium channel on the endoplasmic reticulum.

Full text of DOI:10.1016/j.bmcl.2014.03.077

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2295–2299
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological activities of 2,3-dihydro-1,3,4-oxadiazole
compounds and its derivatives as potential activator of ryanodine
receptors
⇑
⇑
Yunyun Zhou, Baolei Wang, Fengjuan Di, Lixia Xiong, Na Yang, Yongqiang Li, Yuxin Li , Zhengming Li
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 2,3-dihydro-1,3,4-oxadiazoles containing N-pyridylpyrazole carboxamides moieties
were obtained by applying a new synthetic route. Their insecticidal tests against oriental armyworm
(Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of the compounds
showed moderate to excellent activities at the testing concentrations. In particular, compound 6a showed
40% larvicidal activities against oriental armyworm at 1 mg/L, while 7a against diamondback was 100% at
0.01 mg/L. Calcium imaging results demonstrated that 6a, 6d and 7a stimulated a transient elevation in
[Ca2+]i in the absence of external calcium after the central neurons dye loading with fluo-3 AM, implying
that these novel compounds were potential activators of the ligand-gated calcium channel on the
endoplasmic reticulum.
Received 8 February 2014
Revised 23 March 2014
Accepted 25 March 2014
Available online 3 April 2014
Keywords:
2,3-Dihydro-1,3,4-oxadiazoles
Insecticidal activity
Calcium channel
Ó 2014 Elsevier Ltd. All rights reserved.
Ryanodine receptor (RyR) is a distinct class of ligand-gated cal-
cium channels controlling the release of calcium from intracellular
stores.1 Anthranilic diamides were discovered by DuPont as a new
kind of pesticides targeting at the insect RyRs.2 The two diamides,
Chlorantraniliprole and Cyantraniliprole (Fig. 1) with excellent
insecticidal activity have been marketed,3 which are highly potent
activator of the insect RyRs.4 Due to the intrinsic selectivity for the
insect receptor and the low toxicity to mammals,5 this category of
insecticide has received considerable attention.
Since the discovery of Chlorantraniliprole, some structural
modification have been reported.6–10 We noticed that most optimi-
zations focused on the phenyl and N-pyridylpyrazole moieties, but
the modification of two amide moieties has not been fully re-
ported. In hope of enhancing their insecticidal activities, it is an
explorative study for us to modify the amido bridge in anthranilic
diamides.11,12
compounds which containing the oxadiazole ring have shown di-
verse biological activities, such as, anticancer,14 antibacterial,15
antifungal,16 etc., and our study found that these compounds have
good insecticidal activities.
Thus, a series of novel dimethyl-2,3-dihydro-1,3,4-oxadiazol-
inylaniline derivatives containing N-pyridylpyrazole group were
subsequently synthesized. Their insecticidal activities against or-
iental armyworms (Mythimna separata) and diamondback moth
(Plutella xylostella) were tested, which showed that some exhibited
excellent insecticidal activities. The structure–activity relationship
(SAR) was discussed as well. On the other hand, calcium imaging
technique was also adopted to investigate the effects on calcium
channels in the central neurons of Spodoptera exigua.
Compounds 1a–f were synthesized using 2-aminobenzoic acid
derivatives as starting materials. At first, 2-aminobenzoic acid
derivatives were converted to the acyl chloride by treatment with
thionyl chloride, then coupled with hydrazine hydrate (80%),
resulting in low yields. A different synthetic route via the interme-
diates of isatoic anhydride was applied and 1a–f were successfully
obtained with satisfactory yields and purity (Scheme 1).
The introduction of dihydroquinazolinone moiety13 displayed
good insecticidal activity and solubility (Fig. 1), and this results
encouraged us to synthesize other structures with such bridge-
modified structure. On the basis of the above consideration, a
replacement of NCH3 with NNH2 group in dihydroquinazolinone
moiety was designed through a bioisosterism approach. Unexpect-
edly, though the compound A was failed to obtain, a series of struc-
tures (B) containing new oxadiazoline ring was found. The
According to the literature,17,18 compounds 2 and 3 could be all
obtained in the presence of acetone as shown in Scheme 1 via step
iii. Compounds 3 were obtained under the same conditions, but at-
tempts to synthesize compounds 2 with the literature procedure
were failed. In the 1H NMR spectra of compound 3a, a broad signal
peak disappeared at 3.92–4.19 ppm compared with its starting
material 1a, demonstrating the condensation of NH2 in the –CON-
⇑
Corresponding authors. Tel.: +86 22 2350 3732; fax: +86 22 23505948 (Z.L.).
E-mail addresses: liyx128@nankai.edu.cn (Y. Li), nkzml@vip.163.com (Z. Li).
http://dx.doi.org/10.1016/j.bmcl.2014.03.077
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

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Y. Zhou et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2295–2299
Br
N
Br
N
HN
O
O
H
N
H
N
N
N
N
R
Cl
O
Cl
O
N
H
R`
N
Cl
N
Br
CH3
N
X
O
Chlorantraniliprole
A
N
N
O
R`
NH
Cl
O
R
N
Br
N
N
N
HN
O
Br
N
H
N
O
H
N
dihydroquinazolinone
N
Cl
N
O
NC
N
Cl
O
N
R
Cyantraniliprole
B
Figure 1. Design of target compounds.
O
NH2
N
R1
O
O
O
N
H
NH2
OH
NH2
R1
i
ii
iii
N
H
NH2
O
2
R1
R1
O
N
H
O
N
1a-f
N
R1
H
1a: R1=3-CH3, 5-Cl
1b: R1=5-Cl
3a: R1=3-CH3, 5-Cl
3b: R1=5-Cl
NH2
3a-f
1c: R1=4-Cl
3c: R1=4-Cl
1d: R1=3-CH3
3d: R1=3-CH3
1e: R1=3-CH3, 5-Br
1f : R1=3-CH3, 5-I
3e: R1=3-CH3, 5-Br
3f : R1=3-CH3, 5-I
Scheme 1. Reagents and conditions: (i) triphosgene, THF, room temperature; (ii) N2H4ÁH2O (80%), EtOH, room temperature; (iii) acetone, room temperature.
HNH2 with acetone. The structure of 3a was further proved by the
single crystal structure of its corresponding derivative 6a. It is
rationalized that the structure stated in former literature14 might
not be correct.
ring (Fig. 2). The average bond lengths and bond angles of the ring
systems (pyridine, pyrazole, benzene and oxadiazoline ring) are
within normal ranges.20–27 The pyridine ring is oblique with
pyrazole ring and benzene ring with dihedral angles (h) of 62.54°
and 66.18°, respectively. The benzene ring is nearly planar with
oxadiazoline ring with a small dihedral angle (h) of 6.65°. In the
molecular packing of 6a (Fig. 3), intermolecular C–HÁ Á ÁO and C–
HÁ Á ÁCl hydrogen bonds link the molecules, stacking them along
the c axis.
Table 1 shows the insecticidal activities data of the title com-
pounds 4a, 6a–n, 7a and Chlorantraniliprole against oriental army-
worm. The results indicated that some of the title compounds
exhibited good activities against oriental armyworm, the mortality
of 6a and 6c at 1 mg/L were 40%, 20%, respectively. And 7a showed
80% activity at 0.25 mg/L.
Surprisingly, when 3a reacted with methyl chloroformate, an
unprecedented structure 5a was obtained as the sole product in
high yield (Scheme 2). Referring to literature,19 a similar mecha-
nism was proposed for the formation of 5a (Scheme 3). In the pres-
ence of Et3N, the hydrazide underwent a deprotonation process,
the amide bond tautomerized, and the nucleophilic oxygen at-
tacked the carbon of imine to form the oxadiazolidine intermedi-
ate. Therefore 5a–l were successfully obtained by using
corresponding acylhydrazone and chlorocarbonate. Furthermore,
the oxadiazolidine intermediate could be acylated by pyridylpyraz-
ole carbonyl chloride to form product 4a.
Interestingly, product 6k (R3=CH3) could easily convert to 7a
quantitatively (Scheme 4), when the amount of Et3N was less than
1 equiv or during the regular chromatographic processing. Applica-
tion of 1.2 equiv of Et3N to the reaction mixture and addition of 1%
Et3N to the chromatography eluent were able to avoid this problem
and smoothly afforded 6k in high yield and purity. In addition, 6k
had much better solubility than 7a.
Activities varied significantly relating to the structures. For
instance, 6a–n with an amido bond showed an insecticidal activity
at low concentration, while 4a containing 1,3,4-oxadiazoline moi-
ety had no activity. The structural–activity relationship of substi-
tuted phenyl ring was summarized as follows: When R2 was
fixed as Br, R3 was fixed as CH3, the insecticidal activities of com-
pounds with different R1 indicated the sequence of 3-CH3, 5-Cl
(6a) > 3-CH3 (6i) ꢀ 3-CH3, 5-Br (6k) > 5-Cl (6e) ꢀ 4-Cl (6g) ꢀ 3-
CH3, 5-I (6m). The compounds without CH3 in benzene ring led
to a significant decrease in activity, compounds 6e–h showed no
activity at 100 mg/L, while no halogen on the benzene ring had rel-
atively small impact on the larvicidal activities, such as 6i and 6j
had about 50% activity at 10 mg/L. In addition, different halogen
substituted in benzene ring showed a clear trend in insecticidal
Compound 6a (deposition #CCDC 992835) was recrystallized
from ethyl acetate to give colorless crystal suitable for single
crystal X-ray diffraction with the following crystallographic
parameters: a = 12.644(3) Å, b = 14.171(3) Å, c = 14.501(3) Å,
a
= 90°, b = 109.50(3)°,
c
,
= 90°,
(000) = 1176, T = 293.15 K, 3.06° 6
l
= 1.938 mmÀ1, V = 2449.3(8) Å3,
Z = 4. Dc = 1.579 g cmÀ3
F
h 6 25.02°, R = 0.0440, wR = 0.1110. The crystal structure of 6a is
monoclinic and contains following four plane subunits: the ben-
zene ring, the pyridine ring, the pyrazole ring, and the oxadiazoline
activity -Cl > -Br > -I. For example, compound 6m had
a
significantly decrease in insecticidal activity at 200 mg/L. These

Y. Zhou et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2295–2299
2297
Cl
Br
N
N
N
O
N
N
O
i
NH2
N
NH
NH
N
Cl
O
O
4a
NH2
O
N
NH2
O
O
R3
O
R1
R1
R3
R2
N
N
N
N
O
3a-f
ii
iii
O
H
N
N
NH2
Cl
O
R1
N
R1
6a-n
5a-l
5a: R1=3-CH3, 5-Cl; R3=CH3
5g: R1=3-CH3; R3=CH3
5b: R1=3-CH3, 5-Cl; R3=CH2CH3
5c: R1=5-Cl; R3=CH3
5h: R1=3-CH3; R3=CH2CH3
5i: R1=3-CH3, 5-Br; R3=CH3
5d: R1=5-Cl; R3=CH2CH3
5e: R1=4-Cl; R3=CH3
5j: R1=3-CH3, 5-Br; R3=CH2CH3
5k: R1=3-CH3, 5-I; R3=CH3
5f: R1=4-Cl; R3=CH2CH3
5l: R1=3-CH3, 5-I; R3=CH2CH3
Scheme 2. Reagents and conditions: (i) Et3N, 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride, CH2Cl2, room temperature; (ii) Et3N, chlorocarbonate,
CH2Cl2, room temperature; (iii) Et3N, pyridylpyrazole carbonyl chloride, THF, room temperature.
O
R
N
NH
O
N
N
O
O
Et3N
O
R
+
Cl
O
NH2
CH2Cl2
NH2
R1
R1
-Cl
O
Et3N
Cl
O
R
Cl
N
N
N
O
N
N
O
R
O
N
O
O
NH2
NH2
NH2
R1
R1
R1
Scheme 3. The possible mechanism to afford 2,3-dihydro-1,3,4-oxadiazole.
O
O
O
Figure 2. A molecular structure of compound 6a.
N
N
HN
NH
O
O
Br
N
Br
N
O
O
H
H
N
H
3-position of pyrazole did not exhibit higher activities than bro-
mine as we expected. The compounds with different R3 also exhib-
ited little influence on larvicidal activities.
N
N
N
Cl
Cl
O
Br
Br
N
N
The larvicidal activities of 4a, 6a–n, 7a and Chlorantraniliprole
against diamondback moth were also evaluated and the activity
data were shown in Table 2. The results indicated that most of
the compounds showed excellent insecticidal activities at 1 mg/L.
In particular, at 0.01 mg/L the death rate of compound 6b, 6l and
7a against diamondback moth were 43%, 43% and 100%, respec-
tively. To our surprise, 6n showed 29% killing effect to diamond-
back at the concentration of 0.01 mg/L.
7a
6k
Scheme 4. The generation of compound 7a from 6k.
results indicated that 3-CH3 and 5-Cl groups were favorable on the
benzene ring to enhance the insecticidal activity compared to other
substituents.
However, compounds with different R2 showed minimal impact
on activities, with the sequence of -Br (6a) > -OCH2CF3 (6c) > -CF3
(6b). Compound 6c with the 2,2,2-trifluoroethoxy groups on the
Spodoptera exigua and oriental armyworms are major Lepidop-
tera pests in China. According to previous method,28 the calcium
imaging technique was used to determine whether these novel

2298
Y. Zhou et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2295–2299
Figure 3. Packing diagram of compound 6a.
Table 1
Insecticidal activities of compounds 4a, 6a–n, 7a and Chlorantraniliprole against oriental armyworms
Compounds
Larvicidal activity (%) at concn (mg/L)
No.
R1
R2
R3
200
6.7
100
100
100
100
50
100
50
25
10
5
2.5
1
0.25
4a
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
7a
3-CH3, 5-Cl
3-CH3, 5-Cl
3-CH3, 5-Cl
3-CH3, 5-Cl
3-CH3, 5-Cl
5-Cl
5-Cl
4-Cl
4-Cl
3-CH3
Br
Br
CF3
OCH2CF3
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
—
CH3
CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
40
100
60
100
60
40
20
25
26.7
10
100
100
100
100
65
45
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
40
40
60
3-CH3
3-CH3, 5-Br
3-CH3, 5-Br
3-CH3, 5-I
3-CH3, 5-I
3-CH3, 5-Br
CH2CH3
CH3
CH2CH3
CH3
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
100
Chlorantraniliprole
compounds are involved in the calcium concentration and the cor-
relation of [Ca2+]i (F/F0) with insecticidal activity. The effects on the
central neurons of S. exigua on the calcium homeostasis were stud-
ied after the neurons were loaded with fluo-3 AM.
compounds deliver calcium from endoplasmic reticulum to
cytoplasm.
Figure 5 exhibits change of [Ca2+]i versus recording time when
the neurons were treated with 500 mg/L of 6a and 7a. The peak
Figure 4 shows the change of [Ca2+
]
versus recording time
of [Ca2+
] decreased to 109.75 3.11% (n = 9) and 102.6 2.09%
i
i
when the neurons were treated with 6a, 6d and 7a. The peaks of
calcium concentration were elevated to be 108.74 3.5% (n = 9),
106.74 3.27% (n = 9), 110.56 3.38% (n = 9) of the initial value
when the cells were treated with 1000 mg/L of 6a, 6d and 7a,
respectively. Compared with the insecticidal activities data against
oriental armyworms, the recorded [Ca2+]i (F/F0) had a good positive
correlation with bioactivities. The results indicate that these novel
(n = 9) of the initial value after the neurons treated with 500 mg/
L 7a and 6a shorter than 20 s, respectively. The elevations of cal-
cium concentrations by 6a and 7a are in a concentration-depen-
dent manner.
In summary, a series of new oxadiazole benzamide analogs con-
taining 1,3,4-oxadiazoline group were synthesized. The structures
were characterized by 1H NMR and 13C NMR spectroscopy, single

Y. Zhou et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2295–2299
2299
Table 2
tests. The preliminary structure–activity relationship of the title
compounds indicated that the 3-CH3 and 5-Cl groups on the
benzene ring and 3-Br on pyrazole were preferred. The calcium
imaging experiment demonstrated that these novel title
compounds are potential activators of the ligand-gated calcium
channel on the endoplasmic reticulum.
Insecticidal activities of compounds 4a, 6a–n, 7a and Chlorantraniliprole against
diamondback moth
Compounds
Larvicidal activity (%) at concn (mg/L)
10
1
0.1
0.01
4a
0
6a
6b
6c
6d
100
100
100
100
0
100
100
100
100
30
90
43
57
43
14
Acknowledgments
The project was supported by the National Basic Research
Program of China (973 project # 2010CB126106), Natural Science
Foundation of China (No. 31370039), National Key Technologies
Research and Development Program (2011BAE06B05), Tianjin Nat-
ural Science Foundation, China (No. 11JCYBJC08600), Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin)
and Specialized Research Fund for the Doctorial Program of Higher
Education (SRFDP# 20110031110017).
6e
6f
0
6g
6h
100
86
43
43
6i
6j
6k
6l
6m
6n
7a
100
100
100
100
100
100
100
100
100
71
86
100
43
100
100
100
86
14
43
43
90
71
100
100
29
100
100
Supplementary data
Chlorantraniliprole
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
03.077.
120
118
116
114
112
110
108
106
104
102
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5.6
5.7
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Figure 5. Effects of 500 mg/L of 6a and 7a on [Ca2+
] in the central neurons of S.
i
exigua when extracellular Ca2+ was in absence (EGTA replace Ca2+). The central
neurons of S. exigua third larvae were dyed by loading with fluo-3 AM.
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crystal X-ray diffraction analysis and HRMS. The bioassays indi-
cated that some of the compounds showed good insecticidal activ-
ities based on the oriental armyworm and diamondback moth