Synthesis and biological evaluation of benzothiazol-based 1,3,4-oxadiazole derivatives as amyloid β-targeted compounds against Alzheimer’s disease

Article abstract of DOI:10.1007/s00706-017-1993-x

Abstract: A series of new benzothiazol-based 1,3,4-oxadiazole derivatives were synthesized and evaluated for their neuroprotective effects against Aβ_25–35-induced toxicity in SH-SY5Y cells. The bioassay results indicated that most of the tested compounds exhibited promising neuroprotective activity. In particular, compound 2-[[[5-[(4-bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole showed the most potent activity (95.7% of cell viability at 10?μM), better than the positive control EGCG (90.7% of cell viability at 10?μM). Furthermore, compounds 2-[[[5-[(2-bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole, 2-[[[5-[(4-bromo-2-fluorophenylmethylyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole, and 2-[[[5-[(4-methoxyphenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole displayed neuroprotective activity similar to EGCG (87.7, 89.1, and 87.7% of cell viability, respectively, at 10?μM). The preliminary SARs analysis indicated that benzene ring is the key factor for the neuroprotective activity and the bromo atom substituted at 4-position of the benzene ring favors the neuroprotective activity. In addition, the fluoro group in the benzene ring appears not beneficial for the neuroprotective activity. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-017-1993-x

Monatsh Chem
DOI 10.1007/s00706-017-1993-x
ORIGINAL PAPER
Synthesis and biological evaluation of benzothiazol-based 1,3,4-
oxadiazole derivatives as amyloid b-targeted compounds against
Alzheimer’s disease
Wen-wen Mei1,3 Sha-sha Ji2,3 Wei Xiao6 Xue-dong Wang3 Cheng-shi Jiang1,4
•
•
•
•
•
Wen-quan Ma5 Hai-yan Zhang2 Jing-xu Gong1 Yue-wei Guo1
•
•
•
Received: 17 January 2017 / Accepted: 9 May 2017
Ó Springer-Verlag Wien 2017
Abstract A series of new benzothiazol-based 1,3,4-oxa-
diazole derivatives were synthesized and evaluated for
their neuroprotective effects against Ab25–35-induced tox-
icity in SH-SY5Y cells. The bioassay results indicated that
most of the tested compounds exhibited promising neuro-
protective activity. In particular, compound 2-[[[5-[(4-
bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]-
benzothiazole showed the most potent activity (95.7% of
cell viability at 10 lM), better than the positive control
EGCG (90.7% of cell viability at 10 lM). Furthermore,
compounds 2-[[[5-[(2-bromophenylmethyl)thio]-1,3,4-oxa-
diazol-2-yl]methyl]thio]benzothiazole, 2-[[[5-[(4-bromo-2-
fluorophenylmethylyl)thio]-1,3,4-oxadiazol-2-yl]methyl]-
thio]benzothiazole,
and
2-[[[5-[(4-methoxyphenyl-
methyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothia-
zole displayed neuroprotective activity similar to EGCG
(87.7, 89.1, and 87.7% of cell viability, respectively, at
10 lM). The preliminary SARs analysis indicated that
benzene ring is the key factor for the neuroprotective
activity and the bromo atom substituted at 4-position of
the benzene ring favors the neuroprotective activity. In
addition, the fluoro group in the benzene ring appears not
beneficial for the neuroprotective activity.
Wen-wen Mei, Sha-sha Ji, and Wei Xiao contributed equally to this
work.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-1993-x) contains supplementary
material, which is available to authorized users.
Graphical abstract
C
& Hai-yan Zhang
hzhang@simm.ac.cn
B
H
H
N
NH2
NH
N
N
O
A
N
& Jing-xu Gong
jxgong@mail.shcnc.ac.cn
N
H
1
N
O
N
State Key Laboratory of Drug Research, Shanghai Institute of
N
S
Materia Medica, Chinese Academy of Sciences, 555 Zu
Chong Zi Road, Zhangjiang Hi-Tech Park, Shanghai 201203,
People’s Republic of China
S
S
R
2
CAS Key Laboratory of Receptor Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, People’s Republic of China
Keywords Structure–activity relationships Á
Heterocycles Á Drug research Á Neuroprotective effects
3
College of Pharmacy, Weifang Medical University,
Shandong, People’s Republic of China
4
School of Biological Science and Technology, University of
Jinan, Shandong, People’s Republic of China
Introduction
5
Weifang Biomedical Innovation and Entrepreneurship
Service Center, Shandong, People’s Republic of China
Alzheimer’s disease (AD), known as the most prevalent
type of dementia, is a progressive neurodegenerative dis-
ease which causes symptoms of memory loss and cognitive
6
Jiangsu Kanion Pharmaceutical Co. Ltd, Lianyungang,
Jiangsu, People’s Republic of China
123

W. Mei et al.
impairment, eventually lead to the loss of cognitive func-
tion [1]. AD, which affected 36 million people worldwide
in recent years, has placed a heavy burden on family and
decreased the quality of life in patients, but even worse,
the numbers of AD patients are estimated to increase up to
114 million by 2050 [2]. Therefore, scientific researchers
have put massive efforts to better understanding of the
pathogenesis of the disease as well as developing effective
therapeutic agents to be able to prevent or to cure AD
[3–6]. However, to date, no satisfactory treatment has been
proved to prevent or cure AD. For this reason, there is an
urgent need for developing new drugs being able to lim-
iting and stopping the process of AD.
of CXCR4, a chemokine receptor deeply involved in HIV
infection, rheumatoid arthritis, cancer development/pro-
gression, and metastasization [18]. Interestingly,
phidianidines were found to be selective inhibitors of
dopamine transporter (DAT) as well as partial agonist of the
l opioid receptor, these results enlightening us that they can
be utilized for developing new ligands or ligand analogs for
central nervous system (CNS) targets. Recently, a series of
phidianidine-based derivatives have been synthesized and
some derivatives exhibited promising neuroprotective
effects against amyloid-beta 25–35 (Ab25–35)-, hydrogen
peroxide (H2O2)-, or oxygen-glucose deprivation (OGD)-
induced neurotoxicity in SH-SY5Y cells [19]. These
results provoked our great interest in further exploring
neuroprotective activities of phidianidine-based compounds.
In this communication, the neuroprotective effects against
Ab25–35-induced toxicity in SH-SY5Y cells of new ben-
zothiazol-based 1,3,4-oxadiazole derivatives are reported.
Although AD pathogenesis is multifaceted and difficult
to pinpoint, genetic and pathological evidence strongly
supports that amyloid-beta (Ab) plays an early and vital -
role in AD [7]. An alternative hypothesis indicates that Ab
can cause cellular toxicity, which ultimately results in
neuronal dysfunction and death. Therefore, development of
active compounds to improve Ab-associated neurotoxicity
has been taken up as a promising therapeutic strategy
against AD [8].
Results and discussion
Chemistry
Marine nature products (MNPs) have drawn the attention
of both medicinal chemists and pharmacologists for several
decades, due to their chemical diversities and various bio-
logical activities as well. MNPs have played and continued
playing a vital role in the development of new drugs and
drug candidates [9–12]. Marine alkaloids exhibit various
kinds of pharmacological activities such as antitrypanoso-
mal, antibacterial, antimalarial, anti-infective activities, and
so on [13, 14]. Our group has long engaged in isolation,
synthesis, and biological evaluation of MNPs from the South
China Sea marine organisms for many years, and in the
course of these efforts, recently, two novel alkaloids, phid-
ianidines A (1a) and B (1b) (Fig. 1), have been isolated
from the opisthobranch mollusk Phidiana militaris. These
two alkaloids, featured by the first identified MNPs bearing
an uncommon 1,2,4-oxadiazole moiety, exhibited promising
antitumor activity against C6 and HeLa cells with IC50
values of 0.64 and 0.14 lM, respectively [15]. Phidianidines
have attracted many researchers’ interests due to their
unique structure and excellent bioactivity [16, 17]. In addi-
tion, phidianidine A was found to be a novel potential ligand
Analysis of the structural characteristic of phidianidines A
and B, as shown in Fig. 2, reveals that their structures
contained three partials, namely moiety A, B, and C. The
moiety A, the indole motif is an important pharmacophore
widely presented in numerous bioactive natural products or
drugs [20]. The moiety B, the 1,2,4-oxadiazole ring has
been incorporated in drug discovery programs as an
essential element of pharmacophore in contribution of
ligand binding [21, 22]. Our previous preliminary struc-
ture–activity relationships (SAR) study about the moiety C
suggested that the guanidine structure was not required for
neuroprotective activity [19], while the different substi-
tuted benzene rings which replaced the guanidine moiety
play a crucial role for their bioactivity.
Benzothiazole (BTA) scaffold, the main moiety of tra-
ditional amyloid-binding dyes-thioflavin-T (ThT) [23],
exhibited strong affinity for amyloid fibrils and was used as
promising imaging agents targeting to Ab plaques [24–26].
In addition, compounds contain BTA moiety are quite
capable of inhibiting Ab aggregation [27–29] as well as Ab
induced neurotoxicity [30, 31]. In another hand, oxadia-
zoles are a class of heterocyclic compounds with broad
spectrum of biological activities [32–36], specially the
1,3,4-oxadiazole derivatives displayed excellent affinity for
Ab aggregates [37] including excellent affinity for Ab
aggregates [38, 39]. All this evidences suggest that com-
bining 1,3,4-oxadiazole fragment with BTA moiety might
be a potential therapeutic strategy for AD. In this work,
H
H
N
NH2
NH
N
N
O
N
R
1a: phidianidine A, R=Br,
1b: phidianidine B, R=H
N
H
Fig. 1 Structures of phidianidines A and B
123

Synthesis and biological evaluation of benzothiazol-based 1,3,4-oxadiazole derivatives as…
N
S
S
C
B
N
O
H
N
BTA
N
H
N
NH2
NH
N
S
N
S
S
R
N
N
O
A
Target compounds 2
N
H
N
S
R
O
General Structure
Fig. 2 Structural modifications
1,3,4-oxadiazole was introduced to moiety B to replace
1,2,4-oxadiazole. Substituted benzylthio group or different
alkylthio groups were reserved as moiety C. Accordingly,
we designed a series of novel phidianidines analogs 2
bearing different terminal groups (Fig. 2).
intermediate 6 was formed via reactions of hydrazide 5
with carbon disulfide in the presence of KOH under
refluxing EtOH in 70% yield [41]. Finally, the intermediate
6 was converted into 2 in good yield by reacting with
different substituted benzyl bromide in the presence of
K2CO3 using CH3CN as solvent.
The synthetic route of compounds 2 is shown in
Scheme 1. First, commercially available 1,3-benzothia-
zole-2-thiol (3) was reacted with ethyl chloroacetate to
produce ester 4 in 95% yield [40]. Then, treatment of the
ester 4 with 80% hydrazine hydrate in refluxing EtOH gave
hydrazide 5 in 80% yield [41]. Furthermore, the key
Pharmacology
The influence of the compounds on cell viabilities of SH-
SY5Y with or without Ab25–35 exposure was measured.
Scheme 1
O
O
ClCH2CO2Et,
S
S
S
N2H4·H2O, EtOH
Et3N, EtOH
SH
S
OEt
S
N
NH NH2
N
N
N
5
3
4
N
O
N
BrCH2R, K2CO3,
CH3CN
N
S
N
CS2, KOH, EtOH
S
N
S
O
S
S
F
SH
R
6
2
Cl
Cl
F
F
Me
R=
F
2a
2b
2c
2f
2d
2e
Br
F
F3C
CF3
NO2
Br
Br
2h
2i
2l
2g
2j
2k
O
O
O
Br
O
SO2Me
OMe
Br
2m
2o
2n
2p
2r
2q
2s
2t
123

W. Mei et al.
Fig. 3 Effects of compounds
alone on cell viability of SH-
SY5Y cells without Ab25–35
exposure. The cell viability was
expressed as percentage of the
untreated control (100%).
Values are mean SEM of at
least three independent
150
100
50
experiments
0
con
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2l
2m
10 μM
The active neuroprotective compounds (10 lM) did not
cause notable changes in cell viability of SH-SY5Y cells,
when incubating with the cells for 24 h (Fig. 3). These
compounds exhibited significant neuroprotective effects
against Ab25–35-induced neurotoxicity in SH-SY5Y cells,
and the screening data are shown in Table 1. SH-SY5Y
cells exposed to 10 lM Ab25–35 for 24 h resulted in
decrease cell viability (63.2%) as compared with control.
As listed in the table, compounds 2a–2m (except for 2k)
markedly attenuated Ab25–35-induced cytotoxicity at the
concentration of 10 lM with cell viabilities ranged from
74.6 to 95.7%, while compounds 2n–2t showed no activity.
All the test compounds at 1 lM did not show beneficial
effects against Ab25–35-induced neurotoxicity. As a posi-
tive control, EGCG showed 72.3 and 90.7% of cell
viability at 1 and 10 lM, respectively. Compound 2h
bearing bromo group at the 4-position of the benzene ring
showed the strongest activity (95.7% of cell viability at
10 lM), better than the positive control EGCG. In addition,
the neuroprotective effects of 2-chlorine compound 2e
(87.7% of cell viability at 10 lM), 2-fluoro-4-bromo
compound 2i (89.1% of cell viability at 10 lM), and
4-methoxy compound 2m (87.7% of cell viability at
10 lM) were comparable with EGCG. Furthermore, a
significant change in cell viability of SH-SY5Y cells was
not observed when the cells were incubated with 10 lM of
active compounds for 24 h in Ab25–35-free condition
(Fig. 3). This result indicates that the neuroprotective
activity of compounds may not be attributed to the pro-
motion of cell proliferation.
A primary structure–activity relationship (SAR) study
showed that the R group in moiety C is essentially
important for the bioactivity. In fact, most synthesized
compounds bearing benzene rings as R groups exhibited
potent neuroprotective activity against Ab25–35-induced
neurotoxicity, while compounds with R group bearing
alkyl or ester showed no activity. Compared with com-
pound 2a, the introduction of fluoro groups in the benzene
ring (2c, 2d) decreased the neuroprotective activity.
Coincidentally, the unanimous conclusion was reached
from the comparison of 2-chloro compound 2e and
2-chloro-4-fluoro compound 2f as well as the comparison
of 4-bromo compound 2h and 2-fluoro-4-bromo compound
2i. Interestingly, trifluoromethyl substitution at C-4 posi-
tion in the benzene ring (2k) led to the loss of
neuroprotective activity, while 2-trifluoromethyl com-
pound 2j exhibited neuroprotective activity (78.2% of cell
viability at 10 lM), indicating that the CF3 group at C-2
position might be helpful for the neuroprotective activity.
However, the opposite result has been observed for the
4-bromo substituted compound 2h, which showed the
highest activity (95.7% of cell viability at 10 lM) among
all the tested compounds. Such result suggested that the
activity of the compounds should not only be influenced by
Table 1 Protective effects of compounds against Ab25–35-induced
neurotoxicity in SH-SY5Y cells
Compound
Cell viability/%
(10 lM)
Compound
Cell viability/%
(10 lM)
2a
2b
2c
2d
2e
2f
79.8
79.6
74.6
77.9
87.7
80.3
84.4
95.7
89.1
78.2
2k
2l
–
85.0
2m
2n
2o
87.7
–
–
2p
2q
2r
–
2g
2h
2i
–
–
2s
–
2j
2t
–
EGCG
90.7
The cell viability was expressed as percentage of the untreated control
(100%). Values are means of three independent experiments. The cell
viability under Ab25–35 exposure was 63.2 1.3%. EGCG was
employed as positive control
‘‘–’’, no protection
123

Synthesis and biological evaluation of benzothiazol-based 1,3,4-oxadiazole derivatives as…
the position of the substituted group (e.g., 4-CF3 vs.
2-CF3), but also by the group itself (e.g., 4-CF3 vs. 4-Br).
Compound 2n, bearing a bulky sulfoxide group at 4-posi-
tion in the benzene ring, was lack of neuroprotective
activity probably due to the strong steric hindrance. In
addition, the replacement of electron-withdrawing groups
(trifluoromethyl, sulfoxide, or halogen groups) with elec-
tron-releasing groups (such as methoxyl group) provided
the corresponding 2m, which still showed potent neuro-
protective activity (87.7% of cell viability at 10 lM),
indicating that electronic effect of the substitution in
4-position might not be a key factor in their neuroprotec-
tive activity against Ab25–35-induced neurotoxicity.
CHCl3 signal (d(H) = 7.26 ppm) as an internal standard
for 1H NMR and CDCl3 signal (d(C) = 77.0 ppm) for 13
NMR; d in ppm, J in Hz. ESI–MS: Q-TOF Micro LC/MS–
MS mass spectrometer. EI-MS: Finnigan-MAT-95 mass
spectrometer.
C
Methyl 2-(benzo[d]thiazol-2-ylthio)acetate (4)
To a solution of 3.34 g 1,3-benzothiazol-2-ylthiol 3
(20.00 mmol), triethylamine (25.00 mmol) in EtOH was
added 5 cm3 ethyl chloroacetate (25.00 mmol). The reac-
tion mixture was refluxed in 20 cm3 EtOH for 3 h. After
removal of EtOH under reduced pressure, the resulting
mixture was recrystallized with EtOH to obtain white
crystals (3.80 g, 75.10%). The spectra of acetate 4 were
similar to the Ref. [39].
Conclusion
2-(Benzo[d]thiazol-2-ylthio)acetohydrazide (5)
Compound 4 (3.80 g, 15.02 mmol) and 2.4 cm3 80%
hydrazine hydrate (40.00 mmol) in 30 cm3 EtOH were
refluxed for 14 h. After removal of solvent under reduced
pressure, the resulting mixture was recrystallized with
EtOH to obtain white crystals (3.30 g, 84.83%). The
spectra of hydrazide 5 were similar to Ref. [41].
In the present work, a series of novel benzothiazol-based
1,3,4-oxadiazole derivatives were designed and synthe-
sized, and their neuroprotective effects against Ab25–35
-
induced neurotoxicity in SH-SY5Y cells were evaluated.
Based on the preliminary SAR analysis, most of the target
compounds containing benzothiazol-based 1,3,4-oxadia-
zole skeleton showed potential neuroprotective activities.
In particular, compound 2h exhibited the neuroprotective
activity superior to the positive control EGCG. While the
neuroprotective activity of compound 2e, 2i, and 2m was
comparable with EGCG. The preliminary SAR study
indicated that benzene ring played a pivotal role in neu-
roprotective activity and the position of substitution was
important for activity. Bromo substitution at 4-position
improved the neuroprotective activity. In addition, groups
contain fluoro on the benzene ring which was not con-
ducive to the activity. The pharmacological data obtained
here may be useful for the design of novel neuroprotective
compounds with the skeleton of benzothiazol-based 1,3,4-
oxadiazole derivatives. Further studies to improve the
neuroprotective effect and in vivo bioassay of this class of
compounds are in progress.
5-[(Benzo[d]thiazol-2-ylthio)methyl]-1,3,4-oxadiazole-2-
thiol (6)
A mixture of 3.30 g hydrazide 5 (12.74 mmol), 1.70 g KOH
(30.00 mmol), and 2 cm3 CS2 (30 mmol) was refluxed in
20 cm3 EtOH for 18 h. After completion of the reaction, the
reaction solution was concentrated under reduced pressure,
and 30 cm3 ethyl acetate was added and neutralized to slight
acidity (pH *6) by HCl. Then, the resulting mixture was
extracted with ethyl acetate and purified by silica-gel chro-
matography (EtOAc/hexanes, 1:4) to yield the product as an
pale yellow powder (2.6 g, 72.87%). The spectra of thiol 7
were similar to the Ref. [42].
General procedure for preparation of compounds 2
A mixture of 84 mg thiol 6 (0.30 mmol), 0.42 g K2CO3
(3.00 mmol), and bromide (0.60 mmol) was stirred for 4 h
in CH3CN at room temperature. The reaction solution was
concentrated under reduced pressure, and was extracted
with CH2Cl2. The organic layer was concentrated and was
purified by silica gel column chromatography to afford
benzothiazol-based 1,3,4-oxadiazole derivatives 2a–2t,
respectively.
Experimental
The starting materials and reagents, purchased from
commercial suppliers, were used without further purifi-
cation. All solvents used for the reactions were dried prior
to use according to standard procedures. All primary
reagents were commercially available. Anal. TLC: pre-
coated G60 F-254 silica gel plates (SiO2; Yan Tai Zi Fu
Chemical Group Co.). Column chromatography (CC):
silica gel (SiO2, 200–300 mesh; Qing Dao Hai Yang
Chemical Group Co.), solvents were of analytical grade.
NMR spectra: Bruker Avance spectrometer (400 MHz for
1H and 100 or 150 MHz for 13C), using the residual
2-[[5-(Phenylmethylthio)-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2a, C17H13N3OS3)
Yield 44.0%; white solid; m.p.: 96–100 °C; Rf = 0.44
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.96–7.89 (m, 1H, Ar–H), 7.80 (d,
J = 8.0 Hz, 1H, Ar–H), 7.52–7.43 (m, 1H, Ar–H),
7.43–7.25 (m, 6H, Ar–H), 4.82 (s, 2H, –CH2–), 4.44 (s, 2H,
123

W. Mei et al.
–CH2–) ppm; 13C NMR (101 MHz, CDCl3): d = 165.1
(C), 164.0 (C), 163.2 (C), 152.7 (C), 135.7 (C), 135.3 (C),
129.1 (CH), 128.8 (CH), 128.1(CH), 126.3 (CH), 124.8
(CH), 122.0 (CH), 121.2 (CH), 36.7(CH2), 26.2 (CH2)
ppm; HREI-TOF: m/z calcd. for C17H13N3OS3 (M?)
371.0221, found 371.0220.
2-[[5-[(2-Chlorophenyl)methylthio]-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2e, C17H12ClN3OS3)
Yield 64.2%; white solid; m.p.: 66–75 °C; Rf = 0.34
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.89 (d, J = 8.0 Hz, 1H, Ar–H), 7.75 (d,
J = 7.6 Hz, 1H, Ar–H), 7.51 (dd, J = 7.5, 1.7 Hz, 1H, Ar–
H), 7.46–7.39 (m, 1H, Ar–H), 7.38–7.27 (m, 2H, Ar–H),
7.20 (td, J = 7.7, 1.8 Hz, 1H, Ar–H), 7.14 (td, J = 7.5,
1.3 Hz, 1H, Ar–H), 4.79 (s, 2H, –CH2–), 4.51 (s, 2H,
–CH2–) ppm; 13C NMR (101 MHz, CDCl3): d = 165.0
(C), 164.1 (C), 163.2 (C), 152.6 (C), 135.6 (C), 134.27 (C),
133.5 (C), 131.4 (CH), 129.7 (CH), 129.6 (CH), 127.0
(CH), 126.3 (CH), 124.8 (CH), 121.9 (CH), 121.2 (CH),
34.5 (CH2), 26.2 (CH2) ppm; HREI-TOF: m/z calcd. for
C17H12ClN3OS3 (M?) 404.9831, found 404.9815.
2-[[5-[(3-Methylphenyl)methylthio]-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2b, C18H15N3OS3)
Yield 83.1%; yellow solid; m.p.: 58–68 °C; Rf = 0.42
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.95–7.90 (m, 1H, Ar–H), 7.80–7.76 (m, 1H,
Ar–H), 7.50–7.42 (m, 1H, Ar–H), 7.38–7.30 (m, 1H, Ar–
H), 7.24–7.14 (m, 3H, Ar–H), 7.13–7.07 (m, 1H, Ar–H),
4.81 (s, 2H, –CH2–), 4.40 (s, 2H, –CH2–), 2.34 (s, 3H,
–CH3) ppm; 13C NMR (101 MHz, CDCl3): d = 165.2 (C),
163.9 (C), 163.2 (C), 152.7 (C), 138.6 (C), 135.6 (C), 135.2
(C), 129.8 (CH), 128.9 (CH), 128.7 (CH), 126.3 (CH),
126.2 (CH), 124.8 (CH), 122.0 (CH), 121.2 (CH), 36.75
(CH2), 26.2 (CH2), 21.4 (CH3) ppm; HREI-TOF: m/z calcd.
for C18H15N3OS3 (M?) 385.0377, found 385.0370.
2-[[5-[(2-Chloro-4-fluorophenyl)methylthio]-1,3,4-oxadia-
zol-2-yl]methylthio]benzothiazole (2f, C17H11ClFN3OS3)
Yield 92.4%; yellow solid; m.p.: 66–71 °C; Rf = 0.43
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.91 (d, J = 8.1, 1H, Ar–H), 7.79 (d,
J = 8.0, 1H, Ar–H), 7.55 (dd, J = 8.6, 6.0 Hz, 1H, Ar–H),
7.48–7.42 (m, 1H, Ar–H), 7.35 (td, J = 7.7, 1.2 Hz, 1H,
Ar–H), 7.14 (dd, J = 8.4, 2.6 Hz, 1H, Ar–H), 6.90 (td,
J = 8.3, 2.6 Hz, 1H, Ar–H), 4.82 (s, 2H, –CH2–), 4.50 (s,
2H, –CH2–) ppm; 13C NMR (126 MHz, CDCl3):
d = 164.5 (C), 163.8 (C), 162.7 (C), 161.8 (d,
J = 249.5 Hz, C), 152.2 (C), 135.2 (C), 134.7 (d,
J = 10.4 Hz, C), 132.1 (d, J = 8.9 Hz, C), 129.2 (d,
J = 3.5 Hz, CH), 125.9 (CH), 124.4 (CH), 121.5 (CH),
120.8 (CH), 116.8 (d, J = 25.0 Hz, CH), 113.8 (d,
J = 21.0 Hz, CH), 33.4 (CH2), 25.7 (CH2) ppm; HREI-
TOF: m/z calcd. for C17H11ClFN3OS3 (M?) 422.9737,
found 422.9717.
2-[[5-[(3-Fluorophenyl)methylthio]-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2c, C17H12FN3OS3)
Yield 94.3%; yellow solid; m.p.: 91–96 °C; Rf = 0.38 (pet-
roleum ether:acetone 3:1); H NMR (400 MHz, CDCl3):
1
d = 7.92 (d, J = 8.1 Hz, 1H, Ar–H), 7.80 (d, J = 8.0 Hz,
1H, Ar–H), 7.51–7.43 (m, 1H, Ar–H), 7.41–7.32 (m, 3H, Ar–
H), 7.04–6.95 (m, 2H, Ar–H), 4.82 (s, 2H, –CH2–), 4.40 (s,
2H, –CH2–) ppm; 13C NMR (151 MHz, CDCl3): d = 164.9
(C), 164.1 (C), 163.1 (C), 162.5 (d, J = 246.0 Hz, C), 152.7
(C), 135.7 (C), 131.3 (d, J = 3.3 Hz, C), 130.9 (d,
J = 8.3 Hz, CH), 126.3 (CH), 124.8 (CH), 122.0 (CH),
121.21 (CH), 115.7 (d, J = 21.0 Hz, CH), 35.9 (CH2), 26.2
(CH2) ppm; HREI-TOF: m/z calcd. for C17H12FN3OS3 (M?)
389.0127, found 389.0125.
2-[[5-[(3-Bromophenyl)methylthio]-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2g, C17H12BrN3OS3)
Yield 61.5%; yellow oil; Rf = 0.35 (petroleum ether:ace-
tone 3:1); 1H NMR (400 MHz, CDCl3): d = 7.91 (d,
J = 8.1 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H, Ar–H), 7.56 (s,
1H, Ar–H), 7.51–7.38 (m, 2H), Ar–H, 7.38–7.30 (m, 2H,
ArH, Ar–H), 7.16 (t, J = 7.8 Hz, 1H, Ar–H), 4.81 (s, 2H, –
CH2–), 4.37 (s, 2H, –CH2–) ppm; 13C NMR (151 MHz,
CDCl3): d = 164.6 (C), 164.2 (C), 163.1 (C), 152.7 (C),
137.8 (C), 135.7 (C), 132.0 (CH), 131.2 (CH), 130.3 (CH),
127.8 (CH), 126.3 (CH), 124.8 (CH), 122.7 (C), 122.0
(CH), 121.2 (CH), 35.9 (CH2), 26.2 (CH2) ppm; HREI-
TOF: m/z calcd. for C17H12BrN3OS3 (M?) 448.9326, found
448.9317.
2-[[5-[(3,4-Difluorophenyl)methylthio]-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2d, C17H11F2N3OS3)
Yield 57.3%; white solid; m.p.: 85–92 °C; Rf = 0.36
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.91 (d, J = 8.1 Hz, 1H, Ar–H), 7.80 (d,
J = 8.0 Hz, 1H, Ar–H), 7.51–7.43 (m, 1H, Ar–H),
7.40–7.33 (m, 1H, Ar–H), 7.28–7.21 (m, 1H, Ar–H),
7.16–7.01 (m, 2H, Ar–H), 4.82 (s, 2H, –CH2–), 4.37 (s, 2H,
–CH2–) ppm; 13C NMR (151 MHz, CDCl3): d = 164.5
(C), 164.2 (C), 163.1 (C), 152.7 (C), 151.0 (t, J = 13.0 Hz,
C), 149.3 (t, J = 13.0 Hz, C), 135.7 (C), 132.6 (t,
J = 4.5 Hz, C), 126.3 (CH), 125.3 (dd, J = 6.4, 3.7 Hz,
CH), 124.9 (CH), 122.0 (CH), 121.2 (CH), 118.2 (d,
J = 17.9 Hz, CH), 117.5 (d, J = 17.5 Hz, CH), 35.6
(CH2), 26.2 (CH2) ppm; HREI-TOF: m/z calcd. for C17-
H11F2N3OS3 (M?) 407.0032, found 407.0028.
2-[[5-[(4-Bromophenyl)methylthio]-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2h, C17H12BrN3OS3)
Yield 85%; white solid, m.p.: 96–100 °C; Rf = 0.35 (pet-
1
roleum ether:acetone 3:1); H NMR (400 MHz, CDCl3):
123

Synthesis and biological evaluation of benzothiazol-based 1,3,4-oxadiazole derivatives as…
d = 7.94–7.88 (m, 1H, Ar–H), 7.79 (dd, J = 8.0, 0.6 Hz,
1H, Ar–H), 7.50–7.39 (m, 3H, Ar–H), 7.38–7.33 (m, 1H,
Ar–H), 7.30–7.23 (m, 2H, Ar–H), 4.81 (s, 2H, –CH2), 4.36
(s, 2H, –CH2) ppm; 13C NMR (101 MHz, CDCl3):
d = 164.7 (C), 164.1 (C), 163.1 (C), 152.7 (C), 135.6 (C),
134.6 (C), 131.0 (CH), 130.8 (CH), 126.4 (CH), 124.9
(CH), 122.2 (C), 122.0 (CH), 121.2 (CH), 36.0 (CH2), 26.2
(CH2) ppm; HREI-TOF: m/z calcd. for C17H12BrN3OS3
(M?) 448.9326, found 448.9331.
CF3), 122.0 (CH), 121.2 (CH), 35.9 (CH2), 26.2 (CH2)
ppm; HREI-TOF: m/z calcd. for C18H12F3N3OS3 (M?)
439.0095, found 439.0096.
2-[[5-[(4-Nitrophenyl)methylthio]-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2l, C17H12N4O3S3)
Yield 71.3%; white solid; m.p.: 98–102 °C; Rf = 0.20
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.94–7.88 (m, 1H), 7.82–7.76 (m, 1H, Ar–H),
7.51–7.38 (m, 3H, Ar–H), 7.38–7.33 (m, 1H, Ar–H),
7.30–7.24 (m, 2H, Ar–H), 4.81 (s, 2H, –CH2–), 4.36 (s, 2H,
–CH2–) ppm; 13C NMR (101 MHz, CDCl3): d = 164.5
(C), 164.1 (C), 163.0 (C), 152.6 (C), 147.5 (C), 143.2 (C),
135.6 (C), 130.0 (CH), 126.4 (CH), 124.9 (CH), 123.9
(CH), 121.9 (CH), 121.35 (CH), 35.5 (CH2), 26.1 (CH2)
ppm; HREI-TOF: m/z calcd. for C17H12N4O3S3 (M?)
416.0072, found 416.0068.
2-[[5-[(4-Bromo-3-fluorophenyl)methylthio]-1,3,4-oxadia-
zol-2-yl]methylthio]benzothiazole (2i, C17H11BrFN3OS3)
Yield 78.3%; yellow solid; m.p.: 82–85 °C; Rf = 0.40
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.90 (d, J = 8.1 Hz, 1H, Ar–H), 7.78 (d,
J = 8.0 Hz, 1H, Ar–H), 7.50–7.42 (m, 1H, Ar–H),
7.39–7.31 (m, 2H, Ar–H), 7.25–7.15 (m, 2H, Ar–H), 4.80
(s, 2H, –CH2–), 4.38 (s, 2H, –CH2–) ppm; 13C NMR
(151 MHz, CDCl3): d = 164.6 (C), 164.3 (C), 163.1 (C),
160.6 (d, J = 252.0 Hz, C), 152.7 (C), 135.6 (C), 132.3 (d,
J = 3.8 Hz, CH), 127.6 (d, J = 3.7 Hz, CH), 126.3 (CH),
124.84 (CH), 122.6 (d, J = 9.5 Hz) (C), 122.4 (d,
J = 15.0 Hz, C), 122.0(CH), 121.2 (CH), 119.3 (d,
J = 64.0 Hz, CH), 29.5 (d, J = 2.8 Hz, CH2), 26.2 (CH2)
ppm; HREI-TOF: m/z calcd. for C17H11BrFN3OS3 (M?)
466.9232, found 466.9221.
2-[[5-[(4-Methoxyphenyl)methylthio]-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2m, C18H15N3O2S3)
Yield 63.2%; yellow solid; m.p.: 58–67 °C; Rf = 0.34
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.92 (dd, J = 8.2, 0.5 Hz, 1H, Ar–H), 7.79
(dd, J = 8.0, 0.6 Hz, 1H, Ar–H), 7.51–7.42 (m, 1H, Ar–H),
7.39–7.25 (m, 3H, Ar–H), 6.87–6.79 (m, 2H, Ar–H), 4.81
(s, 2H, –CH2–), 4.39 (s, 2H, –CH2–), 3.79 (s, 3H, –CH3)
ppm; 13C NMR (101 MHz, CDCl3): d = 165.2 (C), 163.8
(C), 163.2 (C), 159.4 (C), 152.7 (C), 135.6 (C), 130.3 (CH),
127.2 (C), 126.3 (CH), 124.8 (CH), 121.9 (CH), 121.2
(CH), 114.1 (CH), 55.3 (CH3), 36.4 (CH2), 26.2 (CH2)
ppm; HREI-TOF: m/z calcd. for C18H15N3O2S3 (M?) 401.
0326, found 401.0318.
2-[[5-[[2-(Trifluoromethyl)phenyl]methylthio]-1,3,4-oxa-
diazol-2-yl]methylthio]benzothiazole (2j, C18H12F3N3OS3)
Yield 83.5%; white solid; m.p.: 95–98 °C; Rf = 0.30
(petroleum ether:acetone 3:1); 1H NMR (400 MHz):
d = 7.91 (d, J = 8.1 Hz, 1H, Ar–H), 7.79 (d, J = 7.9 Hz,
1H, Ar–H), 7.69 (dd, J = 18.9, 7.6 Hz, 2H, Ar–H), 7.52-
7.31 (m, 4H, Ar–H), 4.83 (s, 2H, –CH2–), 4.64 (s, 2H, –
CH2–) ppm; 13C NMR (151 MHz): d = 165.1 (C), 164.3
(C), 163.1 (C), 152.7 (C), 135.6 (C), 134.3 (C), 132.4 (CH),
132.0 (CH), 128.7 (q, J = 30.0 Hz, C), 128.4 (CH), 126.4
(q, J = 5.5 Hz, CH), 126.3 (CH), 124.8 (CH), 124.2 (d,
J = 273.0 Hz, CF3), 122.0 (CH), 121.2 (CH), 33.2 (CH2),
26.2 (CH2) ppm; HREI-TOF: m/z calcd. for C18H12F3N3-
OS3 (M?) 439.0095, found 439.0096.
2-[[5-[(4-Methylsulfonylphenyl)methylthio]-1,3,4-oxadia-
zol-2-yl]methylthio]benzothiazole (2n, C18H15N3O3S4)
Yield 89.0%; white solid; m.p.: 120–123 °C; Rf = 0.44
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.94–7.83 (m, 3H, Ar–H), 7.82–7.75 (m, 1H,
Ar–H), 7.60 (d, J = 8.4 Hz, 2H, Ar–H), 7.49–7.41 (m, 1H,
Ar–H), 7.38–7.31 (m, 1H, Ar–H), 4.80 (s, 2H, –CH2–),
4.45 (s, 2H, –CH2–), 3.02 (s, 3H, –CH3) ppm; 13C NMR
(151 MHz, CDCl3): d = 164.4 (C), 164.2 (C), 163.1 (C),
152.7 (C), 142.2 (C), 140.1 (C), 135.6 (C), 130.1 (CH),
127.8 (CH), 126.4 (CH), 124.9 (CH), 121.9 (CH), 121.3
(CH), 44.5 (CH3), 35.7 (CH2), 26.2 (CH2) ppm; HREI-
TOF: m/z calcd. for C18H15N3O3S4 (M?) 448.9996, found
448.9993.
2-[[5-[[4-(Trifluoromethyl)phenyl]methylthio]-1,3,4-oxa-
diazol-2-yl]methylthio]benzothiazole (2k, C18H12F3N3OS3)
Yield 83.5%; yellow solid; m.p.: 90–96 °C; Rf = 0.31
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.91 (d, J = 8.1 Hz, 1H, Ar–H), 7.80 (d,
J = 8.0 Hz, 1H, Ar–H), 7.54 (q, J = 8.4 Hz, 4H, Ar–H),
7.47 (t, J = 7.7 Hz, 1H, Ar–H), 7.36 (t, J = 7.6 Hz, 1H,
2-[[5-(Butylthio)-1,3,4-oxadiazol-2-yl]methylthio]benzo-
thiazole (2o, C14H15N3OS3)
Ar–H), 4.82 (s, 2H, –CH2–), 4.46 (s, 2H, –CH2–) ppm; 13
C
Yield 78.1%; yellow solid; m.p.: 45–52 °C; Rf = 0.42
(petroleum ether:acetone 3:1); 1H NMR (400 MHz,
CDCl3): d = 7.90 (d, J = 8.1 Hz, 1H, Ar–H), 7.76 (d,
J = 8.0 Hz, 1H, Ar–H), 7.48–7.39 (m, 1H, Ar–H),
NMR (151 MHz, CDCl3): d = 164.5 (C), 164.3 (C), 163.1
(C), 152.7 (C), 139.7 (C), 135.6 (C), 130.3 (q,
J = 33.0 Hz, C), 129.4 (CH), 126.3 (CH), 125.7 (q,
J = 33.0 Hz, CH), 124.9 (CH), 123.9 (d, J = 270.0 Hz,
123

W. Mei et al.
7.35–7.25 (m, 1H, ArH), 4.80 (s, 2H, –CH2–), 3.18 (t,
J = 8.0 Hz, 2H, –CH2–), 1.78–1.65 (m, 2H, –CH2–),
1.47–1.34 (m, 2H, –CH2–), 0.90 (t, J = 7.4 Hz, 3H, –CH3)
ppm; 13C NMR (151 MHz, CDCl3): d = 165.8 (C), 163.7
(C), 163.2 (C), 152.7 (C), 135.6 (C), 126.3 (CH), 124.8
(CH), 121.9 (CH), 121.2 (CH), 32.2 (CH2), 31.2 (CH2),
26.3 (CH2), 21.7 (CH2), 13.5 (CH3) ppm; HREI-TOF: m/z
calcd. for C14H15N3OS3 (M?) 337.0377, found 337.0377.
J = 8.1 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H, Ar–H),
7.49–7.42 (m, 1H, Ar–H), 7.38–7.30 (m, 1H, Ar–H), 4.82
(s, 2H, –CH2–), 4.22 (q, J = 7.1 Hz, 2H, –CH2–), 4.03 (s,
2H, –CH2–), 1.27 (t, J = 7.1 Hz, 3H, –CH3) ppm; 13C
NMR (126 MHz, CDCl3): d = 166.8 (CO), 163.8 (C),
163.8 (C), 162.6 (C), 152.2 (C), 135.2 (C), 125.9 (CH),
124.4 (CH), 121.5 (CH), 120.8 (CH), 62.0 (CH2), 33.8
(CH2), 25.7 (CH2), 13.6 (CH3) ppm; HREI-TOF: m/z calcd.
for C14H13N3O3S3 (M?) 367.0119, found 367.0128.
2-[[5-(2-Bromopropylthio)-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2p, C13H12BrN3OS3)
Yield 66.3%; yellow oil; Rf = 0.30 (petroleum ether:ace-
tone 3:1); 1H NMR (400 MHz, CDCl3): d = 7.92 (d,
J = 8.0 Hz, 1H, Ar–H), 7.79 (d, J = 8.0 Hz, 1H, Ar–H),
7.46 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H, Ar–H), 7.35 (ddd,
J = 8.4, 7.3, 1.1 Hz, 1H, Ar–H), 4.82 (s, 2H, –CH2–), 3.49
(t, J = 6.2 Hz, 2H, –CH2–), 3.35 (t, J = 6.9 Hz, 2H, –
CH2–), 2.37–2.28 (m, 2H, –CH2–) ppm; 13C NMR
(126 MHz, CDCl3): d = 164.6 (C), 163.6 (C), 162.7 (C),
152.2 (C), 135.2 (C), 125.9 (CH), 124.4 (CH), 121.5 (CH),
120.8, (CH), 31.1 (CH2), 30.9 (CH2), 30.2 (CH2), 25.8
(CH2) ppm; HREI-TOF: m/z calcd. for C13H12BrN3OS3
(M?) 400.9326, found 400.9334.
2-[[5-(4-Pentenylthio)-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2t, C15H15N3O3S3)
Yield 80.2%; yellow oil; Rf = 0.40 (petroleum
ether:acetone 3:1); 1H NMR (400 MHz, CDCl3):
d = 7.96–7.87 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H, Ar–H),
7.49–7.40 (m, 1H, Ar–H), 7.37–7.29 (m, 1H, Ar–H),
5.82–5.66 (m, 1H, –CH=), 5.12–4.92 (m, 2H, –C=CH2),
4.80 (s, 2H, –CH2–), 3.18 (t, J = 7.3 Hz, 2H, –CH2–),
2.15 (q, J = 7.1 Hz, 2H, –CH2–), 1.85 (qui, J = 7.3 Hz,
2H, –CH2–) ppm; 13C NMR (101 MHz, CDCl3):
d = 165.6 (C), 163.7 (C), 163.2 (C), 152.7 (C), 136.8
(CH), 135.6 (C), 126.3 (CH), 124.8 (CH), 121.9 (CH),
121.2 (CH), 115.9 (=CH2), 32.3 (CH2), 31.7 (CH2), 28.2
(CH2), 26.2 (CH2) ppm; HREI-TOF: m/z calcd. for C15-
H15N3O3S3 (M?) 349.0377, found 349.0380.
2-[[5-(3-Bromobutylthio)-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2q, C14H14BrN3OS3)
Yield 69.0%; yellow oil; Rf = 0.31 (petroleum ether:ace-
tone 3:1); 1H NMR (400 MHz, CDCl3): d = 7.95–7.89 (m,
1H, Ar–H), 7.82-7.76 (m, 1H, Ar–H), 7.51–7.41 (m, 1H,
Ar–H), 7.39–7.31 (m, 1H, Ar–H), 4.82 (s, 2H, –CH2–),
3.39 (t, J = 6.3, 2H, –CH2–), 3.22 (t, J = 6.9 Hz, 2H, –
CH2–), 2.06–1.86 (m, 4H, –CH2CH2–) ppm; 13C NMR
(126 MHz, CDCl3): d = 164.9 (C), 163.5 (C), 162.7 (C),
152.3 (C), 135.2 (C), 125.9 (CH), 124.4 (CH), 121.5 (CH),
120.8 (CH), 32.1 (CH2), 31.1 (CH2), 30.8 (CH2), 27.4
(CH2), 25.8 (CH2) ppm; HREI-TOF: m/z calcd. for C14-
H14BrN3OS3 (M?) 414.9482, found 414.9482.
Neuroprotection activity against Ab25–35-induced
neurotoxicity in SH-SY5Y cells
SH-SY5Y cells were high passages from American Type
Culture Collection (ATCC) and maintained at 37°C in a
humidifiedatmosphere containing5% CO2. Cellswereseeded
intomultiwell platesatadensity of2–2.59105 cellspercm3 in
MEM/F12 medium (Gibco), supplemented with 10% heat-
inactivated bovine calf serum, 100 U/cm3 penicillin, and 100
lg/cm3 streptomycin. Experiments were carried out 24 h after
cells were seeded. Stock solution of Ab25–35 (Sigma, 1 mM)
was prepared in phosphate buffer saline (PBS) with 4%
dimethylsulfoxide (DMSO) and stored at -20°C, and diluted
to0.1 mM withPBSbeforeapplication tocultures. All the test
compounds were dissolved in DMSO to 10 mM as a stock
solution, stored at -20°C, and diluted with MEM/F12 med-
ium before usage. After pretreatment with the compounds for
2 h, 10 lM Ab25–35 were added to SH-SY5Y cell cultures for
24 h. Assays for cell viability were performed 24 h after
cultured in fresh medium.
2-[[5-(Methoxycarbonylmethylthio)-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2r, C13H11N3OS3)
Yield 85.0%; yellow oil; Rf = 0.19 (petroleum ether:ace-
tone 3:1); 1H NMR (400 MHz, CDCl3): d = 7.91 (d,
J = 8.1 Hz, 1H, Ar–H), 7.78 (d, J = 8.0 Hz, 1H, Ar–H),
7.49–7.41 (m, 1H, Ar–H), 7.38–7.31 (m, 1H, Ar–H), 4.82
(s, 2H, –CH2–), 4.04 (s, 2H, –CH2–), 3.76 (s, 3H, –CH3)
ppm; 13C NMR (126 MHz, CDCl3): d = 167.3 (CO),
163.9 (C), 163.7 (C), 162.6 (C), 152.2 (C), 135.2 (C), 125.9
(CH), 124.4 (CH), 121.5 (CH), 120.8 (CH), 52.8 (CH3),
33.6 (CH2), 25.7 (CH2) ppm; HREI-TOF: m/z calcd. for
C14H14BrN3O3S3 (M?) 352.9963, found 352.9950.
Acknowledgements This research work was financially supported by
the Natural Science Foundation of China (Nos. 81520108028,
21672230, 41506187, 81302692, 41476063, 4167060562, and
8160131016), NSFC-Shandong Joint Fund for Marine Science
Research Centers (Grant No. U1406402), SCTSM Project (Nos.
14431901100, 15431901000), and the SKLDR Projects
(SIMM1501ZZ-03).
2-[[5-(Ethoxycarbonylmethylthio)-1,3,4-oxadiazol-2-
yl]methylthio]benzothiazole (2s, C14H13N3O3S3)
Yield 81.7%; yellow oil; Rf = 0.20 (petroleum ether:ace-
tone 3:1); 1H NMR (400 MHz, CDCl3): d = 7.91 (d,
123

Synthesis and biological evaluation of benzothiazol-based 1,3,4-oxadiazole derivatives as…
21. Chaluvaraju KC, Niranjan MS, Kiran S (2011) Int J Pharm Pharm
Sci 3:9
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