Synthesis and antitumor evaluation of novel fused heterocyclic 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives

Article abstract of DOI:10.1007/s00044-019-02409-2

In this study, twenty three 3,6-disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives were synthesized and their antiproliferative activities in vitro were studied against SMMC-7721, HeLa, A549, and L929 by the CCK-8 assay. The bioassay results demonstrated that all tested compounds 8(a–w) exhibited antiproliferation with different degrees, and some compounds showed better effects than reference drug 5-fluorouracil. Among these screened compounds, compounds 8a, 8d, and 8l displayed significant antitumor activities in inhibiting SMMC-7721cell proliferation with IC₅₀ values of 1.64, 1.74, and 1.61 μM, respectively. Compounds 8d and 8l were manifested highly effective biological activity versus HeLa cells with IC₅₀ values of 2.23 and 2.84 μM, respectively. Compound 8l was found to have the highest antitumor potency against A549 cells with IC₅₀ value of 2.67 μM. Furthermore, all compounds exhibited weaker cytotoxic effects than 5-fluorouracil on normal cell lines L929.

Full text of DOI:10.1007/s00044-019-02409-2

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02409-2
ORIGINAL RESEARCH
Synthesis and antitumor evaluation of novel fused heterocyclic
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives
Xiao-Jia Liu1 Hai-Ying Liu1 Hai-Xin Wang1 Yan-Ping Shi1 Rui Tang1 Shuai Zhang1 Bao-Quan Chen1
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Received: 8 April 2019 / Accepted: 19 July 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
In this study, twenty three 3,6-disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives were synthesized and their
antiproliferative activities in vitro were studied against SMMC-7721, HeLa, A549, and L929 by the CCK-8 assay. The
bioassay results demonstrated that all tested compounds 8(a–w) exhibited antiproliferation with different degrees, and some
compounds showed better effects than reference drug 5-fluorouracil. Among these screened compounds, compounds 8a, 8d,
and 8l displayed significant antitumor activities in inhibiting SMMC-7721cell proliferation with IC50 values of 1.64, 1.74,
and 1.61 µM, respectively. Compounds 8d and 8l were manifested highly effective biological activity versus HeLa cells with
IC50 values of 2.23 and 2.84 µM, respectively. Compound 8l was found to have the highest antitumor potency against A549
cells with IC50 value of 2.67 µM. Furthermore, all compounds exhibited weaker cytotoxic effects than 5-fluorouracil on
normal cell lines L929.
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Keywords Triazolo-thiadiazole Disulfides Antitumor activity
Introduction
antioxidant (Menteşe et al. 2013; Padmaja et al. 2015),
antimicrobial (Ceylan 2016; Li et al. 2016), antidepressant
(Chelamalla et al. 2017; Khan et al. 2016), antifungal
(Miniyar et al. 2017; Er et al. 2017), anticonvulsant (Kah-
veci et al. 2014; Harish et al. 2014), and anti-inflammatory
activities (Liu et al. 2016; Banerjee et al. 2016). In parti-
cular, a great number of 1,2,4-triazole and 1,3,4-thiadiazole
derivatives have been proved to show potent antitumor
activities (Meti et al. 2016; Zhao et al. 2016; Bhatt et al.
2018; Vudhgiri et al. 2017). Moreover, The fused 1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazole moieties were found to
have various biological properties, such as antioxidant
(Chidananda et al. 2012), antimicrobial (Almajan et al.
2010; Cui et al. 2017), anticonvulsant (Deng et al. 2012),
and anti-inflammatory (Chidananda et al. 2012; Akhter
et al. 2014). Particularly, this class of compounds have
received considerable attention in the last few decades,
owing to their effective anticancer importance (Chowrasia
et al. 2017; Xu et al. 2017; Rostom et al. 2017; Husain et al.
2013). Moreoever, disulfide derivatives are also known to
display a wide spectrum of biological activities including
anti-Alzheimer’s (Roldán-Peňa et al. 2017), antibacterial
(Sheppard et al. 2018; Turos et al. 2008), anti-HIV-1
(Cesarini et al. 2008), antioxidant (Roldán-Peňa et al.
2017), and herbicidal properties (Li et al. 2013; Shang et al.
2012). Especially, the antitumor potential of disulfide
Cancer has become one of the most terrible diseases around
the world because of its low cure and high mortality.
Therefore, the design and development of new drugs for
cancer therapeutics is an important and challenging task for
medicinal chemists worldwide (Anand et al. 2008; Alegaon
et al. 2017; Chowrasia et al. 2017).
The heterocyclic compounds bearing 1,2,4-triazole or
1,3,4-thiadiazole moieties are of special interest to medic-
inal chemists because of their exceptional chemical and
versatile biological properties including potential
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-019-02409-2) contains supplementary
material, which is available to authorized users.
* Yan-Ping Shi
yanpingshi@126.com
* Bao-Quan Chen
chenbaoquan66@126.com
1
School of Chemistry and Chemical Engineering, Tianjin Key
Laboratory of Organic Solar Cells And Photochemical
Conversion, Tianjin University of Technology, Tianjin 300384,
China

Medicinal Chemistry Research
N
N
8e bearing 4-methoxyl substituent at the phenyl ring while
R1 is n-butyl group, showed moderate antitumor activity
with IC50 value of 14.42 µM, the other compounds exhib-
ited good antiproliferative effects with IC50 values ranging
from 1.61 to 9.45 µM. Meanwhile, the majority of the tested
compounds showed better activities than positive control 5-
fluorouracil. In particular, compounds 8a, 8d, and 8l dis-
played significant antitumor activities against SMMC-7721
cells with IC50 values of 1.64, 1.74, and 1.61 µM, respec-
tively. As compared with compound 8a (IC50 = 1.64 µM),
which has no substituent at the phenyl ring while R1 is n-
butyl group, compounds 8(b–h) all showed weaker activ-
ities against SMMC-7721 cells. In HeLa cells, compounds
8c, 8e, 8j, 8m, and 8u showed moderate antiproliferative
activity with IC50 values of 12.67, 21.29, 14.25, 24.30, and
21.49 µM, respectively. The other compounds all showed
good antiproliferative effects with IC50 values ranging from
2.23 to 9.71 µM, and displayed higher activities than posi-
tive control 5-fluorouracil. Among them, compounds 8d
and 8l exhibited highly effective biological activity against
HeLa cells with IC50 values of 2.23 and 2.84 µM, respec-
tively. In A549 cells, except compounds 8g, 8q, and 8w,
showed moderate antiproliferative activity with IC50 values
of 25.26, 14.85 and 17.07 µM, respectively. The other
compounds all exhibited good antitumor effects with IC50
values ranging from 2.67 to 9.07 µM, and most of the tested
compounds showed better activities than positive control 5-
N
S
R2
N
S
S
R1
Fig. 1 The structure of target compounds 8(a–w)
derivatives attracts the great interest of medicinal chemists
in recent years (Branowska et al. 2018; Hong et al. 2015;
Rubino et al. 2017; Vale et al. 2017) (Fig. 1).
In view of the abovementioned findings, in order to
screen out novel antitumor agents bearing disulfide core
with high efficiency and low toxicity, hybrid compounds
possessing disulfide and 1,2,4-triazolo[3,4-b]-1,3,4-thiadia-
zole moieties will be formed, and some cells growth inhi-
bitory effects will be examined in our research.
Results and discussion
Synthesis
As exhibited in Scheme 1, twenty three novel 1,2,4-triazole
[3,4-b]-1,3,4-thiadiazole derivatives 8(a–w) were synthe-
sized and reported for the frist time. The preparation of S-
alkyl-thioisothiourea hydrochloride 2 was carried out by the
reported literature method (Sirakawa et al. 1970). The 3-
substitutedphenyl-1,2,4-triazole-[3,4-b]-1,3,4-thiadiazole-6-
thiol 7 were obtained according to the reported procedure
(Eweiss and Bahajaj 1987). Finally, the target compounds 8
(a–w) were successfully gained by the reaction of inter-
mediates 2 and compounds 7 in the presence of NaHCO3 in
ethanol and water at room temperature. All newly synthe-
sized compounds 8(a–w) were purified by silica gel column
chromatography and their structures were confirmed by IR,
1H NMR, 13C NMR, and HR-ESI-MS.
fluorouracil. As compared with compound 8i (IC50
=
7.35 µM), which has no substituent at the phenyl ring while
R1 is 2-butyl group, compounds 8(j–p) all displayed better
activities against A549 cells. Among them, compound 8l
possessing 4-methyl substituent at the phenyl while R1 is 2-
butyl group, exhibited the best inhibitory effect against
A549 cells with IC50 value of 2.67 µM. Furthermore, all
compounds exhibited weaker cytotoxic effects than 5-
fluorouracil on normal cell lines L929.
Conclusion
Pharmacology evaluation
The present study comprises the synthesis of some novel
3,6-disubstituted
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles
Evaluation of the antiproliferative activities in vitro for 3,6-
disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles 8(a–w)
was carried out by utilizing the CCK-8 assay against
SMMC-7721, HeLa, A549, and L929 cell lines. The inhi-
bitory activities IC50 (μM) were expressed in Table 1.
All synthesized compounds 8(a–w) showed different
degrees of antitumor activities, and some compounds
showed better effects than positive control 5-fluorouracil
against various cancer cell. The substituent groups R1 and
R2 played important roles in the potency of biologically
active compounds. In SMMC-7721 cells, except compound
and screening for their antiproliferative activities against
SMMC-7721, HeLa, A549, and L929 cell lines via the
CCK-8 assay. The preliminary investigation revealed that
the tested compounds have potency of inhibition for three
tumor cell lines, and the effects of substituents on anticancer
efficacy have been observed. Interestingly, some com-
pounds showed stronger antitumor effects than reference
drug 5-fluorouracil, and several screened compounds, such
as 8a, 8d, and 8l, displayed promising biological activities.
Furthermore, all tested compounds exhibited weaker cyto-
toxic effects than 5-fluorouracil on the normal cell lines

Medicinal Chemistry Research
S
NH
a
S
R1SH
+
HCl
R1
S
NH2
H2N
NH2
2
1
COOCH3
COONHNH2
b
c
R2
R2
3
5
4
O
N
N
H
N
S
SH
N
H
N
d
R2
R2
S-K+
NH2
6
N
N
N
N
N
S
N
S
e
f
R2
R2
N
N
SH
S
S
R1
8(a-w)
7
R2 (R1 = n-C4H9): H (8a), 4-Cl (8b), 4-F (8c), 4-CH3 (8d), 4-OCH3 (8e), 4-OH (8f), 4-C(CH3)3
8g 8h 8i 8j 8k 8l 8m
),
(
), 3,4,5-(OCH3)3
(
); R2 (R1 = 2-C4H9): H ( ), 4-Cl ( ), 4-F ( ), 4-CH3 ), 4-OCH3
(
(
4-OH (8n), 4-C(CH3)3 (8o), 3,4,5-(OCH3)3 (8p); R2 (R1 = i-C4H9): H (8q), 4-Cl (8r), 4-F (8s),
8t 8u 8v 8w
4-CH3 ), 4-OCH3
(
(
), 4-OH ( ), 4-C(CH3)3
(
)
Scheme 1 Synthesis of target compounds 8(a–w). Reaction conditions
and reagents: Conc. HCl, H2O2 (30%), 0–5 °C, 8–10 h;
4–6 h; d NH2NH2·H2O (85%), EtOH, reflux, 5–8 h; e KOH, CS2,
MeOH, reflux, 10–15 h; f compound 2, EtOH, NaHCO3/H2O, rt, 4–6 h
a
b
NH2NH2·H2O (85%), EtOH, reflux, 5–8 h; c KOH, CS2, EtOH, 0–5 °C,
L929. Therefore, the pharmacological results could be
helpful for improving the potency and selectivity of this
class of compounds.
General method for the synthesis of 3,6-
disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles
8(a–w)
S-Alkyl-thioisothiourea hydrochloride 2 (2.2 mmol) and 3-
substitutedphenyl-1,2,4-triazole-[3,4-b]-1, 3,4-thiadiazole-6-
thiol 7 (2.0 mmol) were dissolved in water (5 mL) and ethanol
(15 mL). Then, a solution of saturated NaHCO3 (20 mL) was
added dropwise with stirring for 4 h at room temperature.
Solid crude products were obtained by filtration. The inso-
luble solid was collected and purified by silica gel column
chromatography with petroleum ether/ethyl acetate (8:1,
volume ratio) as eluent to afford the desired products.
Material and methods
Synthesis
Unless otherwise noted, all solvents and reagents were used
as received without further purification. Melting points were
determined by an X-6 microscope melting point apparatus
and are uncorrected. Infrared spectra were obtained in KBr
pellets on a Nicolet Avatar 370 spectrometer. NMR spectra
were recorded on a Bruker Avance III 400 MHz spectro-
meter (1H, 400 MHz; 13C, 100 MHz) using DMSO-d6 as
solvent and tetramethylsilane as internal standard. Chemical
shifts are given in ppm downfield from tetramethylsilane
and the coupling constants (J) are in hertz (Hz). The high-
resolution mass spectra were taken with a Waters Xevo
G2 spectrometer. The reaction progress of some inter-
mediates, such as compounds 5, 6, and 7, was monitored by
thin layer chromatography.
3-Phenyl-6-(n-butyldisulfanyl)-1,2,4-triazole-[3,4-b]-1,3,4-
thiadiazole (8a)
White solid, Yield 76.5%, m.p.: 92.3–93.7 °C; IR (KBr) cm−1:
2930, 1613, 1452, 1381, 1230, 685, 504; 1H NMR (DMSO-
d6, 400 MHz) δ (ppm): 8.18 (d, J = 7.2 Hz, 2H, Ar-H),
7.55–7.62 (m, 3H, Ar-H), 3.09 (t, J = 7.2 Hz, 2H, CH2),
1.67–11.74 (m, 2H, CH2), 1.33–1.43 (m, 2H, CH2), 0.89 (t,
J = 7.2 Hz, 3H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ

Medicinal Chemistry Research
Table 1 Inhibition (IC50) of
SMMC-7721, HeLa, A549, and
L929 cells proliferation by
compounds 8(a–w)
Compound
IC50 (μM)
SMMC-7721
HeLa
A549
L929
8a
8b
8c
1.64 0.11
5.46 0.26
5.38 0.29
1.74 0.09
14.42 1.25
2.63 0.11
2.29 0.13
4.56 0.39
3.22 0.12
6.19 0.25
2.49 0.09
1.61 0.10
5.20 0.36
2.64 0.13
6.23 0.47
3.30 0.14
5.58 0.31
9.45 0.78
2.80 0.12
3.50 0.15
6.74 0.37
5.91 0.36
2.11 0.09
5.62 0.28
8.15 0.92
9.71 0.45
12.67 0.66
2.23 0.13
21.29 1.35
3.88 0.22
3.82 0.29
8.45 0.48
7.33 0.34
14.25 1.01
7.76 0.23
2.84 0.19
24.30 1.59
3.34 0.22
5.73 0.33
9.01 0.45
9.67 0.63
9.58 0.56
3.41 0.27
9.20 0.88
21.49 1.24
3.42 0.21
7.09 0.34
17.21 0.27
6.52 0.21
3.84 0.09
5.56 0.19
4.18 0.22
7.61 0.38
8.63 0.35
25.26 1.57
4.47 0.23
7.35 0.29
5.89 0.23
7.06 0.42
2.67 0.17
6.27 0.35
3.08 0.16
7.02 0.37
3.14 0.16
14.85 1.03
7.64 0.48
8.07 0.42
8.03 0.38
6.20 0.38
9.07 0.77
17.07 1.25
8.13 0.34
3.85 0.27
7.75 0.31
14.13 0.89
3.15 0.12
19.09 1.29
6.68 0.28
8.13 0.41
5.10 0.26
4.31 0.21
6.85 0.37
3.71 0.23
3.16 0.18
22.32 1.87
4.62 0.33
9.34 0.63
15.64 1.01
16.39 1.11
15.43 0.89
6.94 0.34
6.43 0.49
12.49 0.70
9.93 0.65
7.62 0.43
2.98 0.15
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
8u
8v
8w
5–FU
(ppm): 173.84, 154.47, 145.33, 130.76, 129.55 (2C),
126.23 (2C), 125.72, 39.18, 30.91, 21.34, 13.87; HR-ESI-
MS m/z: calcd for C13H14N4S3 [M + H]+ 323.0465, found
323.0459.
(DMSO-d6, 400 MHz) δ (ppm): 8.22 (dd, J = 8.8 Hz, 2H,
Ar-H), 7.46 (dd, J = 8.8 Hz, 2H, Ar-H), 3.09 (t, J = 7.2 Hz,
2H, CH2), 1.66–1.74 (m, 2H, CH2), 1.36–1.45 (m, 2H,
CH2), 0.89 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (DMSO-d6,
100 MHz) δ (ppm): 164.78, 162.31, 154.48, 144.58, 128.67
(2C) (JC-F = 8.7 Hz), 122.35 (JC-F = 2.9 Hz), 116.67 (2C)
(JC-F = 22.0 Hz), 39.16, 30.89, 21.33, 13.87; HR-ESI-MS
m/z: calcd for C13H13N4S3F [M + H]+ 341.0386, found
341.0365.
3-(4-Cholorophenyl)-6-(n-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8b)
White solid, Yield 65.2%, m.p.: 95.6–96.7 °C; IR (KBr) cm−1:
1
2930, 1610, 1449, 1381, 1230, 684, 505; H NMR (DMSO-
d6, 400 MHz) δ (ppm): 8.19 (d, J = 8.8 Hz, 2H, Ar-H), 7.68
(d, J = 8.8 Hz, 2H, Ar-H), 3.09 (t, J = 7.2 Hz, 2H, CH2),
1.66–1.74 (m, 2H, CH2), 1.37–1.43 (m, 2H, CH2), 0.89 (t, J =
7.2 Hz, 3H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ (ppm):
174.32, 155.11, 143.08, 135.01, 129.06 (2C), 127.75 (2C),
125.06, 39.18, 30.90, 21.34, 13.87; HR-ESI-MS m/z: calcd for
C13H13N4S3Cl [M + H]+ 357.0072, found 357.0069.
3-(4-Methylphenyl)-6-(n-butyldisulfanyl)-1,2,4-triazole-[3,4-
b]-1,3,4-thiadiazole (8d)
White solid, Yield 78.5%, m.p.: 83.9–84.2 °C; IR (KBr) cm−1:
2931, 1612, 1451, 1380, 1233, 682, 503; 1H NMR (DMSO-
d6, 400 MHz) δ (ppm): 7.86 (d, J = 8.0 Hz, 2H, Ar-H), 7.36
(d, J = 8.0 Hz, 2H, Ar-H), 2.97 (t, J = 7.2 Hz, 2H, CH2),
2.37 (s, 3H, Ar-CH3), 1.64–1.74 (m, 2H, CH2), 1.33–1.41
(m, 2H, CH2), 0.87 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(DMSO-d6, 100 MHz) δ (ppm): 160.36, 156.23, 140.85,
131.04, 130.14 (2C), 129.75, 126.52 (2C), 38.62, 30.57,
21.49, 21.28, 13.92; HR-ESI-MS m/z: calcd for C14H16N4S3
[M + H]+ 337.0635, found 337.0615.
3-(4-Fluorophenyl)-6-(n-butyldisulfanyl)-1,2,4-triazole-[3,4-
b]-1,3,4-thiadiazole (8c)
Yellow solid, Yield 60.7%, m.p.: 64.7–65.3 °C; IR (KBr)
1
cm−1: 2932, 1613, 1450, 1382, 1230, 685, 503; H NMR

Medicinal Chemistry Research
3-(4-Methoxyphenyl)-6-(n-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8e)
30.91, 21.32, 13.87; HR-ESI-MS m/z: calcd for
C16H20N4O3S3 [M + H]+ 413.0797, found 413.0776.
White solid, Yield 66.8%, m.p.: 90.3–91.6 °C; IR (KBr)
3-Phenyl-6-(2-butyldisulfanyl)-1,2,4-triazole-[3,4-b]-1,3,4-
thiadiazole (8i)
1
cm−1: 2933, 1613, 1451, 1379, 1230, 681, 505; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 8.10 (d, J = 8.8 Hz, 2H, Ar-
H), 7.15 (d, J = 8.8 Hz, 2H, Ar-H), 3.84 (s, 3H, OCH3),
3.09 (t, J = 7.2 Hz, 2H, CH2), 1.66–1.73 (m, 2H, CH2),
White solid, Yield 62.7%, m.p. 89.3–90.1 °C; IR (KBr) cm−1:
2930, 1612, 1451, 1380, 1231, 684, 504; H NMR (DMSO-
1
1.37–1.43 (m, 2H, CH2), 0.89 (t, J = 7.2 Hz, 3H, CH3); 13
C
d6, 400 MHz) δ (ppm): 8.17 (d, J = 7.2 Hz, 2H, Ar-H),
7.55–7.63 (m, 3H, Ar-H), 3.26–3.31 (m, 1H, CH), 1.62–1.75
(m, 2H, CH2), 1.37 (d, J = 6.4 Hz, 3H, CH3), 0.99 (t, J =
7.2 Hz, 3H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ (ppm):
174.14, 154.47, 145.36, 130.83, 129.60 (2C), 126.29 (2C),
125.70, 49.91, 28.83, 20.06, 11.64; HR-ESI-MS m/z: calcd for
C13H14N4S3 [M + Na]+ 345.0297, found 345.0278.
NMR (DMSO-d6, 100 MHz) δ (ppm): 173.48, 161.17,
154.02, 145.09, 127.88 (2C), 118.23, 114.95 (2C), 55.81,
39.20, 30.90, 21.33, 13.86; HR-ESI-MS m/z: calcd for
C14H16N4OS3 [M + H]+ 353.0577, found 353.0565.
3-(4-Hydroxyphenyl)-6-(n-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8f)
3-(4-Chlorophenyl)-6-(2-butyldisulfanyl)-1,2,4-triazole-[3,4-
b]-1,3,4-thiadiazole (8j)
White solid, Yield 82.5%, m.p.: 108.5–109.4 °C; IR (KBr)
1
cm−1: 2931, 1614, 1455, 1384, 1231, 682, 505; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 10.07 (s, H, OH), 8.01 (d,
J = 8.8 Hz, 2H, Ar-H), 6.96 (d, J = 8.8 Hz, 2H, Ar-H), 3.09
(t, J = 7.2 Hz, 2H, CH2), 1.66–1.72 (m, 2H, CH2),
White solid, Yield 82.5%, m.p.: 90.7–92.3 °C; IR (KBr) cm−1:
1
2931, 1612, 1450, 1381, 1229, 684, 503; H NMR (DMSO-
d6, 400 MHz) δ (ppm): 8.18 (d, J = 8.8 Hz, 2H, Ar-H), 7.68
(d, J = 8.8 Hz, 2H, Ar-H), 3.26–3.31 (m, 1H, CH), 1.58–1.78
(m, 2H, CH2), 1.36 (d, J = 6.4 Hz, 3H, CH3), 0.99 (t, J =
7.2 Hz, 3H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ (ppm):
174.50, 154.57, 144.39, 135.43, 129.70 (2C), 127.84 (2C),
124.52, 49.93, 28.85, 20.06, 11.65; HR-ESI-MS m/z: calcd for
C13H13N4S3Cl [M + H]+ 357.0083, found 357.0069.
1.38–1.43 (m, 2H, CH2), 0.89 (t, J = 7.2 Hz, 3H, CH3); 13
C
NMR (DMSO-d6, 100 MHz) δ (ppm): 174.28, 159.67,
153.90, 145.34, 127.99 (2C), 116.89, 116.29 (2C), 39.18,
30.88, 21.32, 13.87; HR-ESI-MS m/z: calcd for
C13H14N4OS3 [M + H]+ 339.0422, found 339.0408.
3-(4-Tert-butylphenyl)-6-(n-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8g)
3-(4-Fluorophenyl)-6-(2-butyldisulfanyl)-1,2,4-triazole-[3,4-
b]-1,3,4-thiadiazole (8k)
White solid, Yield 79.6%, m.p.: 92.7–93.4 °C; IR (KBr)
1
cm−1: 2935, 1613, 1451, 1380, 1230, 682, 504; H NMR
Yellow solid, Yield 68.6%, m.p. 62.5–63.1 °C; IR (KBr)
1
(DMSO-d6, 400 MHz) δ (ppm): 8.10 (d, J = 8.4 Hz, 2H, Ar-
H), 7.61 (d, J = 8.4 Hz, 2H, Ar-H), 3.09 (t, J = 7.2 Hz, 2H,
CH2), 1.63–1.73 (m, 2H, CH2), 1.36–1.45 (m, 2H, CH2),
1.32 (s, 9H, CH3), 0.88 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(DMSO-d6, 100 MHz) δ (ppm): 174.65, 154.41, 153.37,
145.15, 126.31 (2C), 126.10 (2C), 123.22, 39.17, 35.09,
31.37 (3C), 30.90, 21.32, 13.87; HR-ESI-MS m/z: calcd for
C17H22N4S3 [M + H]+ 379.1097, found 379.1085.
cm−1: 2932, 1611, 1453, 1381, 1230, 684, 504; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 8.22 (dd, J = 8.8 Hz, 2H, Ar-
H), 7.46 (t, J = 8.8 Hz, 2H, Ar-H), 3.24–3.30 (m, 1H, CH),
1.60–1.75 (m, 2H, CH2), 1.36 (d, J = 6.8 Hz, 3H, CH3),
0.97–1.01 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (DMSO-d6,
100 MHz) δ (ppm): 164.79, 162.32, 154.40, 144.57, 128.70
(2C) (JC-F = 8.7 Hz), 122.35 (JC-F = 3.1 Hz), 116.66 (2C) (JC-F
= 22.0 Hz), 49.92, 28.84, 20.07, 11.65; HR-ESI-MS m/z: calcd
for C13H13N4S3F [M + H]+ 341.0382, found 341.0365.
3-(3,4,5-Trimethoxyphenyl)-6-(n-butyldisulfanyl)-1,2,4-
triazole-[3,4-b]-1,3,4-thiadiazole (8h)
3-(4-Methylphenyl)-6-(2-butyldisulfanyl)-1,2,4-triazole-[3,4-
b]-1,3,4-thiadiazole (8l)
White solid, Yield 65.2%, m.p.: 106.6–107.3 °C; IR (KBr)
1
cm−1: 2931, 1613, 1452, 1380, 1233, 685, 504; H NMR
White solid, Yield 58.3%, m.p.: 85.7–86.2 °C; IR (KBr) cm−1:
2932, 1610, 1450, 1383, 1231, 683, 503; 1H NMR (DMSO-
d6, 400 MHz) δ (ppm): 7.86 (d, J = 8.0 Hz, 2H, Ar-H), 7.35
(d, J = 8.0 Hz, 2H, Ar-H), 3.08–3.14 (m, 1H, CH), 2.36 (s,
3H, Ar-CH3), 1.51–1.75 (m, 2H, CH2), 1.31 (d, J = 6.8 Hz,
3H, CH3), 0.93 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(DMSO-d6, 100 MHz) δ (ppm): 160.08, 156.24, 140.46,
(DMSO-d6, 400 MHz) δ (ppm): 7.48 (s, 2H, Ar-H), 3.87 (s,
6H, CH3O), 3.75 (s, 3H, CH3O), 3.09 (t, J = 7.2 Hz, 2H,
CH2), 1.62–1.72 (m, 2H, CH2), 1.33–1.45 (m, 2H, CH2),
0.89 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (DMSO-d6,
100 MHz) δ (ppm): 167.41, 153.76 (2C), 139.78, 131.96,
129.12, 121.06, 103.90 (2C), 60.67, 56.54 (2C), 39.07,

Medicinal Chemistry Research
131.91, 130.04 (2C), 129.53, 126.40 (2C), 48.43, 28.44,
21.39, 20.11, 11.50; HR-ESI-MS m/z: calcd for C14H16N4S3
[M + H]+ 337.0631, found 337.0615.
CH), 1.60–1.78 (m, 2H, CH2), 1.37 (d, J = 6.4 Hz, 3H,
CH3), 0.99 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (DMSO-d6,
100 MHz) δ (ppm): 173.87, 153.76 (2C), 145.16, 139.83,
129.11, 121.02, 103.96 (2C), 60.67, 56.56 (2C), 49.64,
28.83, 20.04, 11.61; HR-ESI-MS m/z: calcd for
C16H20N4O3S3 [M + H]+ 413.0797, found 413.0776.
3-(4-Methoxyphenyl)-6-(2-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8m)
White solid, Yield 88.2%, m.p.: 87.8–88.6 °C; IR (KBr)
3-Phenyl-6-(i-butyldisulfanyl)-1,2,4-triazole-[3,4-b]-1,3,4-
thiadiazole (8q)
1
cm−1: 2930, 1616, 1450, 1381, 1235, 683, 505; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 8.11 (d, J = 8.8 Hz, 2H, Ar-
H), 7.15 (d, J = 8.8 Hz, 2H, Ar-H), 3.84 (s, 3H, OCH3),
3.25–3.32 (m, 1H, CH), 1.58–1.76 (m, 2H, CH2), 1.35 (d,
J = 6.8 Hz, 3H, CH3), 0.99 (t, J = 7.6 Hz, 3H, CH3); 13C
NMR (DMSO-d6, 100 MHz) δ (ppm): 174.63, 161.10,
154.08, 145.02, 127.87 (2C), 118.42, 114.96 (2C), 55.82,
49.90, 28.84, 20.07, 11.65; HR-ESI-MS m/z: calcd for
C14H16N4OS3 [M + H]+ 353.0590, found 353.0565.
White solid, Yield 81.4%, m.p. 105.1–106.3 °C; IR (KBr)
1
cm−1: 2931, 1610, 1451, 1380, 1232, 683, 504; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 8.8 (d, J = 7.2 Hz, 2H, Ar-
H), 7.55–7.62 (m, 3H, Ar-H), 3.01 (d, J = 6.8 Hz, 2H,
CH2), 1.93–2.03 (m, 1H, CH), 1.01 (d, J = 6.4 Hz, 6H,
CH3); 13C NMR (DMSO-d6, 100 MHz) δ (ppm): 174.44,
154.62, 145.15, 130.65, 129.52 (2C), 126.20 (2C), 125.88,
48.38, 28.24, 21.66 (2C); HR-ESI-MS m/z: calcd for
C13H14N4S3 [M + H]+ 323.0480, found 323.0459.
3-(4-Hydroxyphenyl)-6-(2-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8n)
3-(4-Chlorophenyl)-6-(i-butyldisulfanyl)-1,2,4-triazole-[3,4-
b]-1,3,4-thiadiazole (8r)
White solid, Yield 78.4%, m.p.: 103.4–104.2 °C; IR (KBr)
1
cm−1: 2932, 1611, 1450, 1382, 1231, 683, 504; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 10.08 (s, H, OH), 8.01 (d,
J = 8.4 Hz, 2H, Ar-H), 6.96 (d, J = 8.4 Hz, 2H, Ar-H),
3.25–3.30 (m, 1H, CH), 1.61–1.76 (m, 2H, CH2), 1.36 (d,
J = 6.4 Hz, 3H, CH3), 0.99 (t, J = 7.2 Hz, 3H, CH3); 13C
NMR (DMSO-d6, 100 MHz) δ (ppm): 173.36, 159.87,
153.55, 145.63, 128.10 (2C), 116.55, 116.34 (2C), 49.89,
28.83, 20.07, 11.66; HR-ESI-MS m/z: calcd for
C13H14N4OS3 [M + H]+ 339.0426, found 339.0408.
White solid, Yield 79.8%, m.p. 101.1–102.3 °C; IR (KBr)
1
cm−1: 2930, 1612, 1450, 1381, 1230, 685, 503; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 8.18 (d, J = 8.8 Hz, 2H, Ar-
H), 7.68 (d, J = 8.8 Hz, 2H, Ar-H), 3.01 (d, J = 6.8 Hz, 2H,
CH2), 1.94–2.01 (m, 1H, CH), 1.01 (d, J = 6.8 Hz, 6H,
CH3); 13C NMR (DMSO-d6, 100 MHz) δ (ppm): 174.29,
154.78, 144.45, 135.45, 129.76 (2C), 127.9 (2C), 124.54,
48.37, 28.23, 21.65 (2C); HR-ESI-MS m/z: calcd for
C13H13N4S3Cl [M + H]+ 357.0077, found 357.0069.
3-(4-Tert-butylphenyl)-6-(2-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8o)
3-(4-Fluorophenyl)-6-(i-butyldisulfanyl)-1,2,4-triazole-[3,4-
b]-1,3,4-thiadiazole (8s)
White solid, Yield 78.6%, m.p.: 83.4–84.1 °C; IR (KBr)
1
cm−1: 2932, 1615, 1452, 1382, 1233, 684, 503; H NMR
Yellow solid, Yield 67.5%, m.p. 78.3–79.2 °C; IR (KBr)
1
(DMSO-d6, 400 MHz) δ (ppm): 8.08 (d, J = 8.4 Hz, 2H, Ar-
H), 7.62 (d, J = 8.4 Hz, 2H, Ar-H), 3.25–3.30 (m, 1H, CH),
1.60–1.76 (m, 2H, CH2), 1.36 (d, J = 7.2 Hz, 3H, CH3),
1.33 (s, 9H, CH3), 0.98 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(DMSO-d6, 100 MHz) δ (ppm): 173.81, 154.09, 153.55,
145.39, 126.32 (2C), 126.15 (2C), 122.95, 49.89, 35.09
(3C), 31.34, 28.84, 20.06, 11.65; HR-ESI-MS m/z: calcd
for C17H22N4S3 [M + H]+ 379.1099, found 379.1085.
cm−1: 2930, 1609, 1451, 1381, 1229, 684, 504; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 8.22 (dd, J = 8.8 Hz, 2H,
Ar-H), 7.45 (dd, J = 8.8 Hz, 2H, Ar-H), 3.01 (d, J = 6.8 Hz,
2H, CH2), 1.91–2.02 (m, 1H, CH), 1.01 (d, J = 6.8 Hz, 6H,
CH3); 13C NMR (DMSO-d6, 100 MHz) δ (ppm): 164.83,
162.35, 154.64, 144.14, 128.78 (2C) (JC-F = 8.8 Hz),
122.17 (JC-F = 2.8 Hz), 116.66 (2C) (JC-F = 22.1 Hz), 48.37,
28.23, 21.67 (2C); HR-ESI-MS m/z: calcd for C13H13N4S3F
[M + H]+ 341.0378, found 341.0365.
3-(3,4,5-Trimethoxyphenyl)-6-(2-butyldisulfanyl)-1,2,4-
triazole-[3,4-b]-1,3,4-thiadiazole (8p)
3-(4-Methylphenyl)-6-(i-butyldisulfanyl)-1,2,4-triazole-[3,4-
b]-1,3,4-thiadiazole (8t)
White solid, Yield 70.3%, m.p. 114.6–115.3 °C; IR (KBr)
1
cm−1: 2931, 1613, 1451, 1385, 1233, 685, 504; H NMR
White solid, Yield 63.2%, m.p.: 90.4–91.2 °C; IR (KBr)
1
(DMSO-d6, 400 MHz) δ (ppm): 7.48 (s, 2H, Ar-H), 3.88 (s,
6H, CH3O), 3.75 (s, 3H, CH3O), 3.28 (t, J = 7.2 Hz, 1H,
cm−1: 2931, 1614, 1451, 1382, 1231, 680, 504; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 7.86 (d, J = 8.0 Hz, 2H, Ar-

Medicinal Chemistry Research
H), 7.36 (d, J = 8.0 Hz, 2H, Ar-H), 2.87 (d, J = 6.8 Hz, 2H,
CH2), 2.37 (s, 3H, Ar-CH3), 1.97–2.06 (m, 1H, CH), 0.97
(d, J = 6.8 Hz, 6H, CH3); 13C NMR (DMSO-d6, 100 MHz)
δ (ppm): 160.30, 156.26, 140.84, 131.95, 130.12 (2C),
129.11, 126.47 (2C), 48.18, 27.73, 21.82, 21.44 (2C); HR-
ESI-MS m/z: calcd for C14H16N4S3 [M + H]+ 337.063,
found 337.0615.
experiment. The inhibition (IC50) of the selected cells pro-
liferation by target compounds 8(a–w) and reference drug
was measured by our previous method as described in the
literature (Xuan et al. 2015).
Acknowledgements We are grateful to the Tianjin Municipal Natural
Science Foundation (18JCYBJC94900) and Training Project of
Innovation Team of Colleges and Universities in Tianjin (TD13-5020)
for financial support.
3-(4-Methoxyphenyl)-6-(i-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8u)
Compliance with ethical standards
White solid, Yield 83.6%, m.p.: 85.6–86.3 °C; IR (KBr) cm−1:
2932, 1612, 1453, 1383, 1233, 680, 504; H NMR (DMSO-
Conflict of interest The authors declare that they have no conflict of
interest.
1
d6, 400 MHz) δ (ppm): 8.12 (d, J = 8.8 Hz, 2H,Ar-H), 7.15 (d,
J = 8.8 Hz, 2H, Ar-H), 3.84 (s, 3H, OCH3), 3.01 (d, J =
6.8 Hz, 2H, CH2), 1.94–2.01 (m, 1H, CH), 1.01 (d, J = 6.8 Hz,
6H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ (ppm): 173.15,
161.07, 154.32, 144.72, 127.88 (2C), 118.50, 114.96 (2C),
55.82, 48.36, 28.22, 21.67 (2C); HR-ESI-MS m/z: calcd for
C14H16N4OS3 [M + H]+ 353.0596, found 353.0565.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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3-(4-Hydroxyphenyl)-6-(i-butyldisulfanyl)-1,2,4-triazole-
[3,4-b]-1,3,4-thiadiazole (8v)
White solid, Yield 70.5%, m.p.: 105.7–106.3 °C; IR (KBr)
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[3,4-b]-1,3,4-thiadiazole (8w)
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1
cm−1: 2931, 1614, 1450, 1383, 1231, 683, 505; H NMR
(DMSO-d6, 400 MHz) δ (ppm): 8.10 (d, J = 8.4 Hz, 2H, Ar-
H), 7.61 (d, J = 8.4 Hz, 2H, Ar-H), 3.01 (d, J = 6.8 Hz, 2H,
CH2), 1.93–2.03 (m, 1H, CH), 1.32 (s, 9H, CH3), 1.02 (d, J
= 6.4 Hz, 6H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ
(ppm): 174.14, 154.47, 153.42, 145.12, 126.31 (2C),
126.12 (2C), 123.14, 48.37, 35.10, 31.37 (3C), 28.23, 21.66
(2C); HR-ESI-MS m/z: calcd for C17H22N4S3 [M + H]+
379.1085, found 379.1085.
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