Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety

Article abstract of DOI:10.1016/j.bmcl.2014.09.086

A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC₅₀ value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC₅₀ values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC₅₀ values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.

Full text of DOI:10.1016/j.bmcl.2014.09.086

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antitumor activities of novel hybrid molecules
containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base
moiety
⇑
Kai Zhang, Peng Wang, Li-Na Xuan, Xiao-Yun Fu, Fen Jing, Sha Li, Yu-Ming Liu, Bao-Quan Chen
Department of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, 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 hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base
moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-
Received 1 April 2014
Revised 5 September 2014
Accepted 29 September 2014
Available online xxxx
7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that
most of the tested compounds showed potent antitumor activities, and some compounds exhibited
stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these
compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC50 value
Keywords:
of 2.84
with IC50 values of 4.56 and 4.25
liferative activity against A549 cells, with IC50 values of 4.11 and 4.13
l
M. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells,
M, respectively. Compounds 8a and 8n exhibited significant antipro-
M, respectively. The pharmaco-
1
1
,3,4-Oxadiazole
,3,4-Thiadiazole
l
l
Schiff base
logical results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for
modulating antiproliferative activities against various tumor cell lines.
Ó 2014 Elsevier Ltd. All rights reserved.
Antitumor agents
Cancer is considered to be second most common cause of
deaths after cardiovascular diseases in the world. Despite
significant progress has been achieved in anticancer therapy, the
discovery and development of effective anticancer drugs remain
liposolubility, and the mesoionic nature of 1,3,4-thiadiazole makes
this class of compounds to show good tissue permeability.
Similarly, 1,3,4-oxadiazole is a versatile lead molecule for
designing potential bioactive agent. Compounds containing 1,3,4-
oxadiazole nucleus have been reported to exhibit diverse biological
1
one of the most intractable worldwide health problems. During
3
1–34
35,36
37,38
recent years, some small molecules containing various azoles were
synthesized as potential anticancer agents, and have become the
subject of considerable growing interest for treatment of
activities such as anticancer,
antioxidant,
anti-inflammatory
antibacterial,
1
3,14
39,40
17,18
antifungal,
anticonvulsant,
and pro-
4
1,42
toporphyrinogen oxidase inhibitory properties.
Moreover,
2
–4
cancer.
1,3,4-oxadiazole heterocycles are very good bioisosteres of amides
and esters, which contribute substantially to increasing pharmaco-
logical activity by participating in hydrogen bonding interactions
with the receptors. Importantly, the combination of different
heterocyclic backbone with thiadiazole or oxadiazole nucleus
may show synergistic effect, and thus has drawn widespread
As an important class of heterocyclic compounds, 1,3,4-thiadiaz-
oles are associated with many types of biological properties,
5
,6
7,8
9,10
including antioxidant, antibacterial, antidepressant,
antidi-
and antiinflamma-
In particular, many of differently substituted
,3,4-thiadiazole derivatives, including Schiff base derivatives,
are of significant interested because they possess anticancer
1
1,12
13,14
15,16
abetic,
tory effects.
antifungal,
anticonvulsant
1
7,18
8
,21,33,36,43,44
1
attention.
Considering the biological significance of 1,3,4-thiadiazole,
1,3,4-oxadiazole and Schiff base moiety, we herein designed and
synthesized a series of novel hybrid molecules containing 1,3,
4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety
(Fig. 1). Meanwhile, their in vitro antitumor activities were evalu-
ated against SMMC-7721, MCF-7 and A549 cells with the ultimate
aim of developing novel potent antitumor agents.
1
9–25
activities.
For this type of derivatives, a different mechanism
of action is assigned, depending on the type of modification of the
2
6–28
1
,3,4-thiadiazole ring.
The action connected with the apoptotic
mechanisms and angiogenesis, which is a crucial step in the tumor-
2
9,30
igenesis, seems to be very promising in anticancer therapy.
Moreover, the sulfur atom of 1,3,4-thiadiazole imparts improved
In this study, fourteen derivatives 8a–8n were synthesized and
reported for the first time.
⇑
Corresponding author. Tel.: +86 22 60214259; fax: +86 22 60214252.
E-mail address: chenbaoquan66@126.com (B.-Q. Chen).
http://dx.doi.org/10.1016/j.bmcl.2014.09.086
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
0
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2
K. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
HO
Table 1
N
N
N
N
In vitro antiproliferative activities of compounds 8a–8n against a panel of human
O
S
S
N
C
H
tumor cell lines
R
Compound
IC50 a
(lM)
Figure 1. Structure of target compounds.
SMMC-7721
MCF-7
A549
8
8
8c
8
8e
8
8
8h
8i
8
8
8
8
a
b
7.10
13.14
31.82
2.84
9.76
15.62
18.08
7.55
9.14
8.32
9.36
11.60
8.75
21.98
4.56
7.95
4.11
20.12
18.10
30.12
7.15
20.02
7.85
24.30
22.04
8.82
As depicted in Scheme 1, the key intermediate 3 was prepared
by condensing 2-amino-5-mercapto-1,3,4-thiadiazole with salicyl-
aldehyde in ethanol using concentrated sulfuric acid as catalyst
d
4
5
6.78
under reflux condition. Aryl acid hydrazides 6a–6n were synthe-
sized by the reaction of 85% hydrazine hydrate and compounds 5a–
f
g
17.97
15.50
4.55
37.08
4.34
10.01
7.60
15.74
16.92
5.62
5
n which derived from substituted benzoic acids 4a–4n, in ethanol
under reflux condition. Treatment of compounds 6a–6n with
chloroacetic acid in presence of phosphorus oxychloride under
reflux condition give 2-chloromethyl-5-aryl-1,3,4-oxadiazole
j
k
l
20.28
6.55
36.89
4.13
4
6
7
a–7n. Finally, the target compounds 8a–8n were successfully
obtained via the reaction of intermediates 7a–7n and compound
in acetone in the presence of K CO using PEG-400 as catalyst
under reflux condition for 2–5 h. All the synthesized compounds
a–8n were purified by recrystallization using appropriate solvent.
m
13.89
4.25
14.26
8n
5
-FUb
8.13
3
2
3
a
The concentration that causes a 50% cell proliferation inhibition.
Used as a positive control.
b
8
1
The structures of target compounds were characterized by IR,
H
NMR, ESI-MS techniques and elemental analysis (see Supplemen-
tary data).
The antiproliferative activities of the newly synthesized com-
pounds 8a–8n were tested against SMMC-7721 (human liver can-
cer cell), MCF-7 (human breast cancer cell) and A549 (human lung
cancer cell) cell lines using CCK-8 [2-(2-methoxy-4-nitrophenyl)-
of the sort and position of substituents on antitumor activity
against SMMC-7721 cells did not show apparent regularity. Espe-
cially noteworthy is compound 8d bearing 4-chloro substituent,
showed the best inhibitory effect against SMMC-7721 cells, with
IC50 values of 2.84 lM. In MCF-7 cells, with the exception of
3
-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monoso-
dium salt] assay, which was used as a substitute for MTT assay
see Supplementary data). Inhibition of cell proliferation by these
compounds 8b, 8c, 8h, 8j and 8m containing 4-fluoro, 4-chloro,
3-methyl, 3-methoxy and 3-nitro substituents, respectively, which
displayed moderate antitumor activities, the other compounds
exhibited very good antiproliferative effects with IC50 values range
(
active compounds at various concentrations were measured, and
their IC50 (the concentration that causes a 50% cell proliferation
inhibition) values were calculated and summarized in Table 1.
from 4.25 to 9.76 lM, and most of compounds 8a–8n inhibited
the proliferation better than 5-fluorouracil. As compared with
compound 8a, the majority of compounds 8a–8n displayed the
enhanced antitumor activities. Among these compounds, 4-meth-
oxy and 4-nitro substituted derivatives, compounds 8k and 8n
displayed highly effective antitumor activities against MCF-7 cells,
5
-Fluorouracil (5-FU) was used as a positive control.
As shown in Table 1, all newly synthesized compounds 8a–8n
all exhibited antiproliferation against SMMC-7721 cells with dif-
ferent degrees, and some compounds showed better activities than
positive control 5-fluorouracil. The substituent group of phenyl
ring on the 1,3,4-oxadiazole plays important roles in the potency
of biologically active compounds. As compared with compound
with IC50 values of 4.56 and 4.25 lM, respectively. This observation
is poorly understood. Therefore, these results indicated that the
electronic effect of substituents for the antiproliferative activity
against MCF-7 cell lines is complex and unexplained at present.
In A549 cells, compound 8a displayed significant antiproliferative
8
a with no substituent at the phenyl ring, the majority of com-
pounds 8a–8n resulted in a decrease in activity. But, the influence
OH
HO
N
N
N
N
a
CHO
+
HS
c
S
N
C
H
HS
b
S
NH
2
3
1
2
COOH
COOEt
CONHNH2
R
R
R
4
a-n
5a-n
6a-n
8
a: R=H
8
b: R=4-F
N
N
e
d
8c: R=2-Cl
2
CH Cl
8
d: R=4-Cl
O
R
8e: R=2-Br
8
8
8
8
f: R=4-Br
7
a-n
g: R=2-CH
h: R=3-CH
i: R=4-CH
3
3
3
HO
8j: R=3-OCH
N
N
N
N
3
3
8
k: R=4-OCH
8
l: R=3,4,5-Tri-OCH
O
S
S
N
C
3
R
H
8m: R=3-NO
2
8
n: R=4-NO2
8
a-n
Scheme 1. Synthesis of the target compounds 8a–8n. Reagents and conditions: (a) ethanol, concd H
NH NH O (85%), ethanol, reflux, 8–12 h; (d) chloroacetic acid, POCl
ÁH
2
SO
4
, reflux, 0.5 h; (b) ethanol, concd H
CO , PEG-400, reflux, 2–5 h.
2 4
SO , reflux, 8–12 h; (c)
2
2
2
3
, reflux, 6 h; (e) compound 3, acetone, K
2
3
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K. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
activity, with IC50 value of 4.11
also showed significant antitumor activity, with IC50 value of
.13 M, the other compounds all highly decreased the antiprolif-
l
M. Except compound 8n, which
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