Synthesis of novel antiproliferative 1,2,3-triazole hybrids using the molecular hybridisation approach

Article abstract of DOI:10.3184/174751916X14761050193688

A series of nine novel 1,2,3-triazole-chalcone derivatives were designed using the molecular hybridisation approach and synthesised by click chemistry. Most of the synthesised compounds exhibited moderate to good antiproliferative activity against oesophagus, gastric and neuroendocrine cancer cell lines, but a compound containing a p-bromo group in the A ring and a [(4,5-dihydrothiazol-2-yl)thio]methyl group attached at the 4-position of a p-[3-(1,2,3-triazol-1-yl)propyloxy] group in the B ring showed the highest activity with an IC50 value of 8.16 μM against neuroendocrine cancer cells. The structure activity relationships of all nine compounds were discussed.

Full text of DOI:10.3184/174751916X14761050193688

674 RESEARCH PAPER
VOL. 40 NOVEMBER, 674–677
JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis of novel antiproliferative 1,2,3-triazole hybrids using the molecular
hybridisation approach
Dong-Jun Fu, Jian Song, Ruo-Han Zhao, Ying-Chao Liu, Yan-Bing Zhang*, and Hong-Min Liu
Collaborative Innovation Center of New Drug Research and Safety Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001,
P.R. China
A series of nine novel 1,2,3-triazole-chalcone derivatives were designed using the molecular hybridisation approach and synthesised by
click chemistry. Most of the synthesised compounds exhibited moderate to good antiproliferative activity against oesophagus, gastric
and neuroendocrine cancer cell lines, but a compound containing a p-bromo group in the A ring and a [(4,5-dihydrothiazol-2-yl)thio]methyl
group attached at the 4-position of a p-[3-(1,2,3-triazol-1-yl)propyloxy] group in the B ring showed the highest activity with an IC50 value
of 8.16 μM against neuroendocrine cancer cells. The structure activity relationships of all nine compounds were discussed.
Keywords: 1,2,3-triazole, chalcone, molecular hybridisation, antiproliferative
Heterocyclic scaffolds play important roles in drug design
and organic reactions. 1,2,3-Triazoles have received attention
in medicinal chemistry and organic chemistry due to their
excellent biological activities and easy synthesis via click
reactions.1,2 In recent years, 1,2,3-triazoles have gained
special attention as antiproliferative agents because several
biologically active compounds contain that group such as the
spirooxindole-derived morpholine-fused-1,2,3-triazole 1,3 and
the 1,2,3-triazole linked chalcone 2 (Fig. 1).4
Chalcones, which are important constituents of natural
products, are abundant in edible plants where they are known
to be the precursors of flavonoids and isoflavonoids.5 There is
growing interest in the pharmacological potential of chalcones,
which constitute an important group of natural and synthetic
products that have been screened for their wide range of
pharmacological activities as antibacterial,6,7 antitumour,8,9
anti-inflammatory,10,11 antifungal and antioxidant agents.12,13
Our group has recently reported four variously substituted
chalcone derivatives as antiproliferative agents (Fig. 2). In one
series a pyridine ring featured as ring B with ring A containing
a 4-amino side chain containing a 1,2,3-triazole ring and a
terminal substituted phenyl group (3).14 A recurring feature
of three other series was a trimethoxylated B ring, with a side
chain containing either a thiocarbamate (4),15 an imidazole
group (5),16 or a cyclic amino group (6)17 at the 4-position of
ring A.
Molecular hybridisation is a strategy of rational design
of new ligands or prototypes based on the recognition of
pharmacophoric subunits in the molecular structure of two
or more known bioactive derivatives.18 The above interesting
findings and our continuous quest to synthesise antiproliferative
1,2,3-triazole analogues, led us to carry out the molecular
hybridisation of a biologically active chalcone and a bioactive
1,2,3-triazole to integrate them in one molecular platform to
generate a new hybrid architecture with the aim of exploring the
impact of such modification on the anticancer agents.
Results and discussion
As shown in Fig. 3, a molecular hybridisation strategy based on
the structures of a bioactive highly substituted chalcone and a
bioactive 1,2,3-triazole compound 2 yielded a scaffold which
has four parts: (i) a 1,2,3-triazole as a central core, (ii) a di-
substituted chalcone attached thereto via (iii) a medium-chain
alkoxyl group for lipophilicity, and (iv) an attachment at the
4-position of the 1,2,3-triazole of a thiomethyl group to which is
attached various N-heterocycles.
The synthetic routes are shown in Scheme
1 and
Scheme 2. Commercially available thiols were treated with
propargyl bromide to provide I (Scheme 1). Target derivatives
were synthesised by a click reaction in the presence of
CuSO4·5H2O and sodium ascorbate (Scheme 2). The structures
of the synthesised compounds were characterised using spectral
methods, and all spectral data corroborated the assumed
structures.
All the synthesised derivatives were evaluated for their
cytotoxic activity in vitro against three cancer cell lines,
MGC-803 (human gastric cancer cell line), SK-N-SH (human
OH
O
O
O
O
N
N
N
l
C
N
O
N
N
O
O
N
2
1
Fig. 1 The structures of 1,2,3-triazole analogues as antiproliferative agents.
O
O
O
S
F
C
3
N
S
O
O
N
N
N
N
H
N
O
N
4
3
O
O
O
O
O
O
N
O
N
O
O
6
N
5
Fig. 2 Reported chalcones as antiproliferative agents.
* Correspondent. E-mail: zhangyb@zzu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2016 675
O
O
O
OH
B
Triazole backbone with
drug-like properties
O
O
OH
O
Molecular
Hybridisation
R2
O
N
N
OH
O
S
R1
N
O
Antitumor
pharmacophore
fragment
Liphophilicity
control
Cl
Azole
units
O
O
O
N
N
N
Antitumor agents
Fig. 3 Illustration of the design strategy for target compounds.
(i) Propargyl bromide,
K2CO3, acetone, r.t.
S
R1
R1
SH
I
S
N
S
N
S
S
I-2
I-1
S
N
N
N
S
N
N
N
S
I-4
I-3
Scheme 1
O
O
N3
O
(i) CuSO4.5H2O,VcNa,
THF-H2O, rt.
R2
R2
+
S
N
R1
N
O
N
R1
III
II
I
S
N
N
N
N
=
R1
=
R1
=
=
R1
R1
N
S
N
S
N
S
N
III-1 R2 = 4-F
III-2 R2 = 4-Cl
III-3 R2 = 4-Br
III-9 R2 = 4-Cl
III-4 R2 = 4-F
III-5 R2 = 4-Cl
III-6 R2 = 4-Br
III-7 R2 = 4-F
III-8 R2 = 4-Cl
Scheme 2
Table 1 The antiproliferative activity against oesophagus (EC109), human
neuroendocrine (SK-N-SH) and gastric (MGC-803) cancer cell lines of
the synthesised 1,2,3-triazole-chalcone derivatives III-1–9 (Scheme 2)
neuroendocrine cancer cell line), and EC-109 (human
oesophagus cancer cell line) using the MTT assay method and
compared with the well-known anticancer drug 5-fluorouracil.19
The antiproliferative activity results of compounds III-1–9
are shown in Table 1. All compounds exhibited moderate
antiproliferative activity against at least one of the three selected
cancer cell lines. Among them, compound III-3 showed the
highest antiproliferative activity with an IC50 value of 8.16 μM,
better than 5-FU, against SK-N-SH cells (Table 1).
We found that the nature of the substituent on the benzene
ring of chalcone has a remarkable effect on their antiproliferative
activity. Of the tested compounds against the EC-109 cell line,
compound III-3 with the bromine atom on the A ring of the
chalcone showed more potent antiproliferative activity (30.35 μM)
than the corresponding fluoro- and chloro-compounds III-1
and III-2. For the MGC-803 cell line, compound III-6 with the
chlorine atom on the benzene ring of chalcone showed higher
activity (15.43 μM) than all other derivatives.
IC50 (μM)a
Compound
EC-109
>100
SK-N-SH
13.59 0.72
>100
MGC-803
24.38 0.63
68.72 1.88
18.56 0.61
49.07 1.69
48.61 0.62
15.43 0.94
36.43 1.57
23.27 1.59
37.94 0.68
7.14 0.28
III-1
III-2
III-3
III-4
III-5
III-6
III-7
III-8
III-9
5-FUb
>100
30.35 0.84
58.39 0.68
>100
8.16 0.49
12.28 1.22
14.45 1.25
14.44 1.68
12.53 0.26
26.13 0.68
10.45 0.84
9.85 0.76
29.17 0.59
86.24 1.68
37.80 1.79
34.65 0.72
10.30 0.32
aAntiproliferative activity was assayed by exposure for 48 h to the tested substances and
expressed as the concentration required to inhibit tumour cell proliferation by 50% (IC50).
The data are presented as the means with standard deviation from the dose–response
curves of three independent experiments. b5-FU = 5-fluorouracil.
To determine whether the azole rings might affect the activity,
compounds containing 4,5-dihydrothiazole-2-thiol (III-1–3),

676 JOURNAL OF CHEMICAL RESEARCH 2016
Preparation of compounds (III-1–9); general procedure
benzo[d]thiazole-2-thiol (III-4–6), 1,3,4-thiadiazole-2-thiol
(III-7–8) and 1-methyl-1H-tetrazole-5-thiol (III-9) were
synthesised and their antiproliferative activities are shown
in Table 1. Replacing the 1,3,4-thiadiazole-2-thiol scaffold
of compound III-7 (12.53 μM) with 1-methyl-1H-tetrazole-
5-thiol (III-9, 10.45 μM) led to a small increment of activity
against SK-N-SH cancer cells, whereas, changing the benzo[d]
thiazole-2-thiol (III-5, 48.61 μM) to a 1,3,4-thiadiazole-2-thiol
(III-8, 23.27 μM) or a 1-methyl-1H-tetrazole-5-thiol (III-9,
37.94 μM) led to an improvement of activity against MGC-
803 cells, indicating the significance of the azole rings in their
antiproliferative activity.
Compound I (1.05 mmol), compound II (1 mmol), CuSO4·5H2O
(0.2 mmol) and sodium ascorbate (0.1 mmol) were dissolved in THF/
H2O (5 mL/5 mL) and stirred at room temperature. The reaction was
monitored by TLC until the reaction was finished. Upon completion,
the reaction mixture was concentrated under vacuum, the residue was
dissolved in EtOAc and washed with water and brine, and then dried
over anhydrous Na2SO4 and concentrated under vacuum to afford
compounds III-1–9 which were purified by column chromatography
(petroleum ether:EtOAc = 6:1).
(E)-3-{4-[3-(4-{[(4,5-dihydrothiazol-2-yl)thio]methyl}-1H-1,2,3-
triazol-1-yl)propoxy]phenyl}-1-(4-fluorophenyl)prop-2-en-1-one
(III-1): Yellow solid; yield 85%; m.p. 129–131 °C; 1H NMR (400
MHz, CDCl3) δ 8.05 (dd, J = 8.8, 5.5 Hz, 2H), 7.79 (d, J = 15.6 Hz,
1H), 7.61 (d, J = 8.7 Hz, 2H), 7.54 (s, 1H), 7.40 (d, J = 15.6 Hz, 1H),
7.18 (t, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.57 (t, J = 6.7 Hz,
2H), 4.41 (s, 2H), 4.14 (t, J = 8.0 Hz, 2H), 4.00 (t, J = 5.7 Hz, 2H), 3.36
(t, J = 8.0 Hz, 2H), 2.54–2.31 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 188.8, 166.8, 164.8, 164.3, 160.5, 144.6, 134.8, 131.1, 130.3, 127.9,
123.2, 119.5, 115.6, 114.9, 64.2, 64.1, 47.0, 35.8, 29.8, 27.1; HRMS
(ESI) calcd for C24H23FN4NaO2S2 [M + Na]+: 505.1148, found:
505.1144.
In summary, a series of chalcone-1,2,3-triazole derivatives
1
were synthesised, and their structures characterised by H
NMR, 13C NMR, and HRMS. Their in vitro antiproliferative
activities were then tested, using a MTT assay, against three
selected cancer cell lines (SK-N-SH, EC-109 and MGC-803) and
compared with the well-known anticancer drug 5-fluorouracil.
Most of the synthesised compounds exhibited moderate to
good activity against all the cancer cell lines selected. In
particular, the promising compound III-3 showed the highest
antiproliferative activity with an IC50 value of 8.16 μM against
SK-N-SH cancer cells.
(E)-1-(4-chlorophenyl)-3-{4-[3-(4-{[(4,5-dihydrothiazol-2-yl)
thio]methyl}-1H-1,2,3-triazol-1-yl)propoxy]phenyl}prop-2-en-
1-one (III-2): Yellow solid; yield 62%; m.p. 129–131 °C; H NMR
1
Experimental
(400 MHz, CDCl3) δ 7.96 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 15.6 Hz,
1H), 7.60 (d, J = 8.6 Hz, 2H), 7.54 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H),
7.38 (d, J = 15.6 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 4.57 (t, J = 6.7 Hz,
2H), 4.41 (s, 2H), 4.14 (t, J = 8.0 Hz, 2H), 4.00 (t, J = 5.7 Hz, 2H), 3.36
(t, J = 8.0 Hz, 2H), 2.54–2.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
189.1, 164.8, 160.6, 145.0, 144.4, 139.0, 136.7, 130.4, 129.9, 128.9, 127.9,
123.2, 119.4, 114.9, 64.2, 64.1, 47.0, 35.8, 29.7, 27.1; HRMS (ESI) calcd
for C24H23ClN4NaO2S2 [M + Na]+: 521.0842; found: 521.0849.
All reagents and solvents used were of analytical grade and were
purchased from commercial sources. Thin-layer chromatography
(TLC) was carried out on glass plates coated with silica gel and
visualised by UV light (254 nm). Melting points were determined on
a Beijing Keyi XT4A apparatus and are uncorrected. NMR spectra
were obtained on a Bruker DPX 400 MHz spectrometer (1H NMR at
400 MHz, 13C NMR at 100 MHz) in CDCl3 or DMSO-d6 using TMS
as internal standard. Chemical shifts are given in ppm and coupling
constants are given in Hz. Mass spectra (MS) were recorded on a
Bruker 3000 mass spectrometer by electrospray ionisation (ESI).
(E)-1-(4-bromophenyl)-3-{4-[3-(4-{[(4,5-dihydrothiazol-2-yl)
thio]methyl}-1H-1,2,3-triazol-1-yl)propoxy]phenyl}prop-2-en-
1
1-one (III-3): Yellow solid; yield 87%; m.p. 138–140 °C; H NMR
(400 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 15.6 Hz,
1H), 7.62 (dd, J = 16.4, 8.6 Hz, 4H), 7.53 (s, 1H), 7.37 (d, J = 15.6 Hz,
1H), 6.91 (d, J = 8.7 Hz, 2H), 4.57 (t, J = 6.7 Hz, 2H), 4.41 (s, 2H), 4.14
(t, J = 8.0 Hz, 2H), 4.00 (t, J = 5.7 Hz, 2H), 3.36 (t, J = 8.0 Hz, 2H),
2.54–2.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 189.3, 164.8, 160.6,
145.0, 144.4, 137.1, 131.9, 130.4, 130.0, 127.9, 123.2, 119.4, 114.9, 64.2,
64.1, 47.0, 35.8, 29.8, 27.1; HRMS (ESI) calcd for C24H23BrN4NaO2S2
[M + Na]+: 565.0347; found: 565.0343.
(E)-3-[4-(3-{4-[(benzo[d]thiazol-2-ylthio)methyl]-1H-1,2,3-
triazol-1-yl}propoxy)phenyl]-1-(4-fluorophenyl)prop-2-en-1-
one (III-4): Yellow solid; yield 80%; m.p. 140–142 °C; 1H NMR
(400 MHz, CDCl3) δ 8.06 (dd, J = 8.7, 5.5 Hz, 2H), 7.90–7.68 (m,
3H), 7.64 (s, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.36 (ddd, J = 30.8, 13.3,
7.7 Hz, 3H), 7.18 (t, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.68 (s,
2H), 4.55 (t, J = 6.7 Hz, 2H), 3.96 (t, J = 5.7 Hz, 2H), 2.50–2.27 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 188.8, 166.8, 165.9, 164.3, 160.5,
153.0, 144.7, 135.5, 134.8, 131.1, 130.3, 127.9, 126.1, 124.4, 123.4, 121.4,
121.2, 119.5, 115.8, 114.8, 64.2, 47.0, 29.7, 27.7; HRMS (ESI) calcd for
C28H23FN4NaO2S2 [M + Na]+: 553.1148; found: 553.1144.
(E)-3-[4-(3-{4-[(benzo[d]thiazol-2-ylthio)methyl]-1H-1,2,3-
triazol-1-yl}propoxy)phenyl]-1-(4-chlorophenyl)prop-2-en-1-one
(III-5): White solid; yield 84%; m.p. 156–158 °C; 1H NMR (400
MHz, CDCl3) δ 7.94 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.1 Hz, 1H),
7.73 (t, J = 11.8 Hz, 2H), 7.61 (s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.46 (d,
J = 8.5 Hz, 2H), 7.42–7.25 (m, 3H), 6.82 (d, J = 8.7 Hz, 2H), 4.66 (s,
2H), 4.53 (t, J = 6.7 Hz, 2H), 3.94 (t, J = 5.7 Hz, 2H), 2.51–2.28 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 189.1, 165.9, 160.5, 153.0, 145.0,
144.2, 139.0, 136.7, 135.5, 130.4, 129.9, 128.9, 127.8, 126.1, 124.4,
123.4, 121.4, 121.2, 119.4, 114.8, 64.2, 47.0, 29.7, 27.7; HRMS (ESI)
calcd for C28H23ClN4NaO2S2 [M + Na]+: 569.0842; found: 569.0849.
(E)-3-[4-(3-{4-[(benzo[d]thiazol-2-ylthio)methyl]-1H-1,2,3-
triazol-1-yl}propoxy)phenyl]-1-(4-bromophenyl)prop-2-en-1-
Synthesis of 2-(prop-2-yn-1-ylthio) derivatives (I-1–4); general
procedure
To a stirred solution of mercaptan (3 mmol) in acetone (15 mL),
propargyl bromide (3 mmol) and K2CO3 (3 mmol) were added carefully
and the reaction mixture was refluxed for 5 h. Upon completion, the
reaction mixture was concentrated under vacuum, the residue was
dissolved in EtOAc (30 mL) and washed with water and brine, dried over
anhydrous Na2SO4 and concentrated under vacuum to afford compounds
I-1–4, which were used in the next reaction without further purification.
2-(Prop-2-yn-1-ylthio)-4,5-dihydrothiazole (I-1): Colourless oil;
yield 74%; 1H NMR (400 MHz, DMSO-d6) δ 4.16 (t, J = 8.0 Hz, 2H),
3.94 (d, J = 2.6 Hz, 2H), 3.48 (t, J = 8.0 Hz, 2H), 3.21 (t, J = 2.6 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ 161.8, 79.5, 74.1, 63.9, 35.5,
20.1; HRMS (ESI) calcd for C6H8NS2 [M + H]+: 158.0095; found:
158.0098.
2-(Prop-2-yn-1-ylthio)benzo[d]thiazole (I-2): Yellow solid; yield
47%; m.p. 50–52 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.75–7.62 (m,
2H), 7.41–7.30 (m, 2H), 4.23 (d, J = 2.6 Hz, 2H), 3.31 (t, J = 2.6 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ 162.7, 151.4, 141.2, 124.7,
124.5, 118.5, 110.3, 79.2, 74.6, 20.3; HRMS (ESI) calcd for C10H8NS2
[M + H]+: 206.0010; found: 206.0098.
2-(Prop-2-yn-1-ylthio)-1,3,4-thiadiazole (I-3): Colourless oil; yield
1
78%; H NMR (400 MHz, DMSO-d6) δ 9.59 (dd, J = 3.5, 1.6 Hz,
1H), 4.23 (dd, J = 2.2, 1.6 Hz, 2H), 3.25 (ddd, J = 7.9, 4.9, 2.6 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ 164.0, 154.5, 79.0, 74.8, 22.2;
HRMS (ESI) calcd for C5H5N2S2 [M + H]+: 156.9899; found: 156.9894.
1-Methyl-5-(prop-2-yn-1-ylthio)-1H-tetrazole (I-4): White solid;
1
yield 83%; m.p. 61–62 °C; H NMR (400 MHz, DMSO-d6) δ 4.12
(d, J = 2.6 Hz, 2H), 3.99 (s, 3H), 3.26 (t, J = 2.6 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 152.3, 78.9, 74.9, 33.8, 21.6; HRMS (ESI)
calcd for C5H7N4S [M + H]+: 155.0393; found: 155.0391.

JOURNAL OF CHEMICAL RESEARCH 2016 677
one (III-6): Yellow solid; yield 70%; m.p. 159–162 °C; 1H NMR
(400 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 2H), 7.85–7.71 (m, 3H), 7.64
(d, J = 7.7 Hz, 3H), 7.53 (d, J = 8.6 Hz, 2H), 7.35 (ddd, J = 19.4, 15.3,
7.5 Hz, 3H), 6.84 (d, J = 8.6 Hz, 2H), 4.68 (s, 2H), 4.55 (t, J = 6.7 Hz,
2H), 3.96 (t, J = 5.7 Hz, 2H), 2.52–2.29 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 189.3, 165.9, 160.5, 153.0, 145.1, 137.2, 135.5, 131.9, 130.4,
130.0, 127.8, 127.7, 126.1, 124.4, 123.4, 122.6, 121.4, 121.2, 119.3,
114.8, 64.2, 47.0, 29.7, 27.7; HRMS (ESI) calcd for C28H23BrN4NaO2S2
[M + Na]+: 613.0347; found: 613.0343.
highest DMSO concentration of the medium (0.1%) did not have any
substantial effect on the determined cellular functions.
Acknowledgement
This work was supported by the National Natural Sciences
Foundations of China (No. 81430085, 81273393).
Electronic Supplementary Information
Additional data and spectra are available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
(E)-3-{4-[3-(4-{[(1,3,4-thiadiazol-2-yl)thio]methyl}-1H-1,2,3-
triazol-1-yl)propoxy]phenyl}-1-(4-fluorophenyl)prop-2-en-1-one
(III-7): Yellow solid; yield 75%; m.p. 139–141 °C; 1H NMR (400
MHz, CDCl3) δ 8.97 (s, 1H), 8.16–7.93 (m, 2H), 7.78 (d, J = 15.6 Hz,
1H), 7.72 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 15.6 Hz, 1H),
7.17 (t, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.67 (s, 2H), 4.55 (t,
J = 6.8 Hz, 2H), 3.98 (t, J = 5.7 Hz, 2H), 2.55–2.25 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 188.8, 166.8, 164.3, 160.5, 151.8, 144.7, 143.3,
134.8, 130.3, 127.9, 123.8, 119.5, 115.8, 115.6, 114.9, 64.2, 47.1, 29.8,
28.2; HRMS (ESI) calcd for C23H20FN5NaO2S2 [M + Na]+: 504.0946;
found: 504.0940.
(E)-3-{4-[3-(4-{[(1,3,4-thiadiazol-2-yl)thio]methyl}-1H-1,2,3-
triazol-1-yl)propoxy]phenyl)-1-(4-chlorophenyl)prop-2-en-1-
one (III-8): Yellow solid; yield 80%; m.p. 171–173 °C; 1H NMR
(400 MHz, CDCl3) δ 9.00 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.81 (d,
J = 15.6 Hz, 1H), 7.74 (s, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.50 (d,
J = 8.5 Hz, 2H), 7.40 (d, J = 15.6 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 4.70
(s, 2H), 4.57 (t, J = 6.8 Hz, 2H), 4.01 (t, J = 5.7 Hz, 2H), 2.53–2.32 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 189.2, 165.1, 160.6, 151.8, 145.0,
143.4, 139.0, 136.7, 130.4, 129.9, 128.9, 127.9, 123.8, 119.4, 114.9, 64.2,
47.1, 29.8, 28.2; HRMS (ESI) calcd for C23H20ClN5NaO2S2 [M + Na]+:
520.0649; found: 520.0645.
(E)-1-(4-chlorophenyl)-3-{4-[3-(4-{[(1-methyl-1H-tetrazol-5-yl)
thio]methyl}-1H-1,2,3-triazol-1-yl)propoxy]phenyl}prop-2-en-1-one
(III-9): White solid; yield 84%; m.p. 135–137 °C; 1H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 13.9 Hz, 2H), 7.62 (d,
J = 8.7 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 15.6 Hz, 1H),
6.92 (d, J = 8.7 Hz, 2H), 4.64 (s, 2H), 4.57 (t, J = 6.9 Hz, 2H), 4.01 (t,
J = 5.7 Hz, 2H), 3.88 (s, 3H), 2.51–2.33 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 189.1, 160.6, 153.7, 145.0, 142.8, 139.0, 136.7, 130.4, 129.9,
128.9, 127.9, 124.0, 119.5, 114.9, 64.2, 47.1, 33.4, 29.7, 27.4; HRMS (ESI)
calcd for C23H22ClN7NaO2S [M + Na]+: 518.1146; found: 518.1142.
Received 11 August 2016; accepted 29 August 2016
Paper 1604253 doi: 10.3184/174751916X14761050193688
Published online: 24 October 2016
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Antiproliferative activity assays
All cancer cell lines were maintained in minimal essential medium
supplemented with 10% foetal bovine serum (FBS) and 1% penicillin-
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