Synthesis and in vitro antiproliferative evaluation of novel hybrids from 1,3,4-Thiadiazole and benzisoselenazolone

Article abstract of DOI:10.1248/cpb.c15-00014

Novel hybrids from 1,3,4-thiadiazole and benzisoselenazolone were designed, synthesized and evaluated for their in vitro antiproliferative activities by CCK-8 assay against three types of human cancer cell lines, SMMC-7721, MCF-7 and A549 cells. The preli

Full text of DOI:10.1248/cpb.c15-00014

Vol. 63, No. 6
Chem. Pharm. Bull. 63, 431–437 (2015)
431
Regular Article
Synthesis and in Vitro Antiproliferative Evaluation of Novel Hybrids
from 1,3,4-Thiadiazole and Benzisoselenazolone
Fen Jing, Xiaoyun Fu, Sha Li, Baolin Li, Jijun Zhao, Xuefeng Wang, Yuming Liu, and
Baoquan Chen*
School of Chemistry and Chemical Engineering, Tianjin University of Technology; Tianjin 300384, China.
Received January 5, 2015; accepted March 19, 2015
Novel hybrids from 1,3,4-thiadiazole and benzisoselenazolone were designed, synthesized and evalu-
ated for their in vitro antiproliferative activities by CCK-8 assay against three types of human cancer cell
lines, SMMC-7721, MCF-7 and A549 cells. The preliminary bioassay results demonstrated that all tested
compounds 4a–p showed potent antiproliferative activities, and some compounds exhibited better effects
than positive control ethaselen and 5-fluorouracil (5-FU) against various cancer cell lines. Furthermore,
compound 4g showed significant antiproliferative activities against SMMC-7721 cells with an IC50 value of
2.08µM. Compounds 4b and 4m displayed highly effective biological activities against MCF-7 cells with an
IC50 values of 2.03 and 2.06µM, respectively. Compound 4i exhibited the best inhibitory effect against A549
cells with an IC50 value of 1.03µM.
Key words synthesis; 1,3,4-thiadiazole; benzisoselenazolone; ebselen; ethaselen; antiproliferative activity
Cancer is considered to be second most common cause of on the 1,3,4-thiadiazole ring. The preliminary bioassay results
deaths after cardiovascular diseases in the world. Despite sig- demonstrated that most of compounds showed potent anti-
nificant progress has been achieved in anticancer therapy, the proliferative activities against various cancer cell lines, and
management of malignancies in humans still constitutes one some compounds revealed stronger antiproliferative effect
of the most intractable worldwide health problems.1) Therefore, than positive control ebselen and ethaselen.36,37) In order to ob-
it is important to identify effective drugs and new targets for tain compounds with better antiproliferative activities. We re-
the treatment of cancer. Thioredoxin (Trx), thioredoxin reduc- port herein the synthesis of some new hybrids from 1,3,4-thia-
tase (TrxR) and nicotinamide adenine dinucleotide phosphate diazole and benzisoselenazolone. Meanwhile, their in vitro
(NADPH) comprise a thioredoxin system that is involved in antiproliferative activities were evaluated against SMMC-7721
many aspects of tumor physiology such as proliferation, apo- (human liver cancer cell), MCF-7 (human breast cancer cell)
ptosis and metastasis, and has become a novel attractive target and A549 (human lung cancer cell) cells with the ultimate aim
for development of new cancer therapeutics.2–7) Recently, of developing novel potent antitumor agents.
reports of selenium-containing heterocyclic compounds have
gradually increased because of their pharmaceutical appli-
cations, and have become hot spots in the studies of tumor
Results and Discussion
Chemistry As depicted in Chart 1, sixteen hybrids from
prevention and therapy.8–10) Among them, functionalized 1,3,4-thiadiazole and benzisoselenazolone were synthesized
benzisoselenazolone moieties are present in many pharma- and reported for the first time. The preparation of 4-chlo-
cologically active substances. The prominent examples are romethylbenzoyl chloride 2a–p was carried out by reported
ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one, Fig. 1] and literature method.34) The reaction of commercially available
ethaselen [1,2-(bis-1,2-benzisoselenazol-3(2H)-one) ethane, 2-amino-5-mercapto-1,3,4-thiadiazole with compounds 2a–p
Fig. 1], which possess potent antioxidant, anti-inflammatory, in the presence of NaOH in water and ethanol at room tem-
anticancer and cholinesterase inhibitory activities.4,11–14) Par- perature yielded the desired intermediates 3a–p in 76–89%
ticularly, as a novel organoselenium compound targeting yields. 2-Chloroselenobenzoyl chloride was prepared accord-
thioredoxin reductase (TrxR), ethaselen has been reported to ing to reported literature method.4) Finally, the target com-
exhibit broad spectrum of antitumor effects with slight toxic- pounds 4a–p were successfully obtained via the condensation
ity, and has now entered Phase I clinical trials in China.4–6)
of intermediates 3a–p and 2-chloroselenobenzoyl chloride
1,3,4-Thiadiazole is a privileged scaffold incorporated in the presence of triethylamine in dry acetonitrile at room
in many compounds presenting a wide range of pharmaco- temperature. All newly synthesized compounds 4a–p were
logical activities, such as antioxidant,15,16) antibacterial,17,18) purified by silica gel column chromatography and their struc-
antidepressant,19,20) antidiabetic,21,22) antifungal,23,24) anticon-
vulsant,25,26) antiinflammatory,27,28) antileishmanial29) and
acetylcholinesterase inhibitory properties.30) In particular,
1,3,4-thiadiazole derivatives are of significant interested be-
cause of their anticancer activities.31–35)
Recently, we have reported the synthesis of 1,3,4-thia-
diazole derivatives bearing benzisoselenazolone moiety, which
contained substituted benzoylmethylthio and phenyl groups
Fig. l. Structures of Ebselen (1) and Ethaselen (2)
*To whom correspondence should be addressed. e-mail: chenbaoquan66@126.com
© 2015 The Pharmaceutical Society of Japan

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Vol. 63, No. 6 (2015)
Reaction conditions and reagents: a) 4-Chloromethylbenzoyl chloride, Et3N, CH2Cl2, rt, 4–6h; b) 2-Amino-5-mercapto-1,3,4-thiadiazole, NaOH, H2O, EtOH, rt, 7–8h,
76–89%; c) 2-Chloroselenobenzoyl chloride, Et3N, dry CH3CN, rt, 8–10h, 45–58%.
Chart 1. Synthesis of Target Compounds 4a–p
Table 1. The IC50 Values of Compounds 4a–p against Three Human
Cancer Cell Lines
As shown in Table 1, this class of compounds revealed
stronger antiproliferative effect than previous reported com-
pounds on the whole.36,37) Most of the newly synthesized com-
a)
IC50 (µM)
Compd.
pounds 4a–p exhibited very good antiproliferative activities
against SMMC-7721 cells. Especially noteworthy is compound
4g bearing 4-methoxy substituent at the phenyl ring, showed
significant antiproliferative activity with IC50 value of 2.08µM.
Except compounds 4l and 4p possessing 4-chloro and trifluo-
romethyl substituents, which displayed moderate antiprolifera-
tive activities, the other compounds displayed higher activities
than positive control ethaselen with IC50 values ranging from
2.08 to 9.21µM. The substituent groups of phenyl ring on the
1,3,4-thiadiazole play important roles in the potency of bio-
logically active compounds. As compared with compound 4a
which has no substituent at the phenyl ring, some compounds
showed enhanced antiproliferative effects. But, the electronic
effects of substituents on antiproliferative activity against
SMMC-7721 cells did not show apparent regularity. In MCF-7
cells, with the exception of compounds 4d, 4l and 4n contain-
ing 4-methyl, 4-chloro and 2-nitro substituents, which exhib-
ited moderate antiproliferative activity, the other compounds
displayed very good antiproliferative effects with IC50 values
ranging from 2.03 to 4.16µM. Meanwhile all compounds 4a–p
showed much better potency than positive control ethase-
len, and the majority of them exbibited better activities than
5-fluorouracil. As compared with compound 4a, the majority
SMMC-7721
MCF-7
A549
b)
Ethaselen
10.68 0.52
5.62 0.28
4.75 0.12
3.93 0.21
4.49 0.14
9.21 0.11
6.15 0.19
6.04 0.09
2.08 0.08
3.39 0.25
4.19 0.06
2.64 0.18
3.42 0.27
20.15 1.78
3.14 0.09
5.24 0.25
3.98 0.15
23.12 1.99
40.52 2.88
14.26 0.66
6.04 0.42
2.03 0.04
4.16 0.26
16.58 1.27
3.38 0.12
2.87 0.08
2.88 0.17
3.89 0.24
3.38 0.14
2.33 0.07
2.64 0.16
15.17 1.39
2.06 0.04
11.35 1.03
3.69 0.08
2.86 0.05
3.26 0.05
8.13 0.34
10.54 0.56
5.79 0.29
4.74 0.24
6.73 0.33
2.58 0.09
1.58 0.03
3.41 0.13
2.33 0.03
1.03 0.02
3.94 0.20
4.49 0.16
7.26 0.44
1.60 0.07
4.99 0.22
1.78 0.06
3.37 0.10
b)
5-FU
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
a) Each experiment was independently performed three times and expressed as
means standard deviation (S.D.). b) Used as positive control.
1
tures were characterized by IR, H-NMR, electrospray ioniza- of substituent groups resulted in a increase in the potency of
tion (ESI)-MS and elemental analysis.
compounds. Among them, 2-methyl and 4-bromo substituted
Biological Evaluation The antiproliferative activities derivatives, compounds 4b and 4m displayed highly effective
of the newly synthesized compounds 4a–p were tested biological activities against MCF-7 cells with IC50 values of
against SMMC-7721, MCF-7 and A549 cell lines using 2.03 and 2.06µM, respectively. In A549 cells, all compounds
CCK-8[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4- 4a–p showed higher activities than positive control 5-fluo-
disulfophenyl)-2H-tetrazolium monosodium salt] assay, which rouracil. Whereas, most of them, including compound 4a,
was used as a substitute for 3-(4,5-dimethylthiazol)-2-yl-2,5- displayed lower antiproliferative activities than ethaselen.
diphenyltetrazolium bromide (MTT) assay. Inhibition of cell With the exception of compound 4a, the other compounds
proliferation by these active compounds at various concentra- showed very good antiproliferative activities, and compound
tions were measured, and their IC50 (the concentration that 4i bearing 4-fluoro group, exhibited the best inhibitory effect
causes a 50% cell proliferation inhibition) values were calcu- with IC50 value of 1.03µM. Meanwhile, compounds 4b–p car-
lated and summarized in Table 1. Ethaselen and 5-fluorouracil ring various substituents all displayed increased activities in
were used as positive control.
comparison to compound 4a. These results suggest that the

Vol. 63, No. 6 (2015)
Chem. Pharm. Bull.
433
presence of substituent groups at the phenyl ring is favorable 7.28 (d, J=7.1Hz, 1H, Ar-H), 7.22 (t, J=7.2Hz, 1H, Ar-H),
for improving the potency of compounds against A549 cells. 7.17 (t, J=7.2Hz, 1H, Ar-H), 4.38 (s, 2H, CH2), 2.23 (s, 3H,
Therefore, it is necessary that the further investigation is car- CH3); ESI-MS m/z: 357.5 [M+H]+.
ried out through structural transformation.
2-Amino-5-[4-(3-methylphenylcarbamoyl)-benzylthio]-1,3,4-
thiadiazole (3c) White crystals; mp 215.8–217.8°C; Yield
1
85%; IR (KBr) cm–1: 1614, 1401, 1133, 991, 617, 418; H-NMR
Conclusion
In summary, a series of novel hybrids from 1,3,4-thiadiazole (DMSO-d6, 400MHz) δ (ppm): 10.15 (s, 1H, Ar-NH), 7.88–
and benzisoselenazolone were designed, synthesized and eval- 7.90 (d, J=8.2Hz, 2H, Ar-H), 7.61 (s, 1H, Ar-H), 7.55–7.57
uated for their in vitro antiproliferative activities against three (d, J=8.2Hz, 1H, Ar-H), 7.48–7.50 (d, J=8.2Hz, 2H, Ar-H),
types of human cancer cell lines. Some of the compounds 7.31 (s, 2H, NH2), 7.23 (t, J=7.7Hz, 1H, Ar-H), 6.91–6.93 (d,
inhibited the proliferation better than positive control ethase- J=7.7Hz, 1H, Ar-H), 4.38 (s, 2H, CH2), 2.31 (s, 3H, CH3);
len and 5-fluorouracil. In particular, compound 4g showed ESI-MS m/z: 357.5 [M+H]+.
significant antiproliferative activities against SMMC-7721cells
2-Amino-5-[4-(4-methylphenylcarbamoyl)-benzylthio]-1,3,4-
with IC50 value of 2.08µM. Compounds 4b and 4m displayed thiadiazole (3d) White crystals; mp 244.2–246.8°C; Yield
1
highly effective biological activities against MCF-7 cells with 84%; IR (KBr) cm–1: 1641, 1402, 1133, 994, 617, 419; H-NMR
IC50 values of 2.03 and 2.06µM, respectively. Compound 4i (DMSO-d6, 400MHz) δ (ppm): 10.15 (s, 1H, Ar-NH), 7.88–
exhibited the best inhibitory effect against A549 cells with 7.90 (d, J=8.2Hz, 2H, Ar-H), 7.63–7.66 (d, J=8.4Hz, 2H,
IC50 value of 1.03µM. Therefore, the results will be significant Ar-H), 7.48–7.50 (d, J=8.2Hz, 2H, Ar-H), 7.31 (s, 2H, NH2),
in the development of potent antiproliferative agents.
7.14–7.16 (d, J=8.4Hz, 2H, Ar-H), 4.38 (s, 2H, CH2), 2.28 (s,
3H, CH3); ESI-MS m/z: 357.5 [M+H]+.
2-Amino-5-[4-(2-methoxyphenylcarbamoyl)-benzylthio]-
Experimental
Chemistry Melting points were determined by a X-6 1,3,4-thiadiazole (3e) White crystals; mp 192.1–193.0°C;
microscope melting point apparatus and are uncorrected. IR Yield 87%; IR (KBr) cm–1: 1640, 1401, 1132, 994, 617, 419;
spectra were recorded in KBr pellets on a Nicolet Avatar 1H-NMR (DMSO-d6, 400MHz) δ (ppm): 9.42 (s, 1H, Ar-NH),
370 spectrometer. NMR spectra were performed on a Bruker 7.90–7.92 (d, J=8.3Hz, 2H, Ar-H), 7.76 (dd, J=1.5, 7.9Hz, 1H,
Avance III 400MHz spectrometer using DMSO-d6 as solvent Ar-H), 7.48–7.50 (d, J=8.3Hz, 2H, Ar-H), 7.31 (s, 2H, NH2),
and tetramethylsilane as internal standard. Chemical shifts 7.19 (dt, J=1.5, 8.2Hz, 1H, Ar-H), 7.10 (dd, J=1.2, 8.2Hz, 1H,
are showed in δ values (ppm) and the coupling constants are Ar-H), 6.97 (dt, J=1.2, 7.7Hz, 1H, Ar-H), 4.38 (s, 2H, CH2),
expressed in J values (Hz). Mass spectra were taken with a 3.84 (s, 3H, CH3); ESI-MS m/z: 373.5 [M+H]+.
Waters Xevo G2 QTof (ESI) mass spectrometer. Elemental
2-Amino-5-[4-(3-methoxyphenylcarbamoyl)-benzylthio]-
analyses (CHN) were performed on a Flash EA1112 instru- 1,3,4-thiadiazole (3f) White crystals; mp 189.0–190.8°C;
ment. Silica gel (200–300 mesh) for column chromatography Yield 85%; IR (KBr) cm–1: 1637, 1401, 1134, 995, 617, 419;
and silica GF254 for TLC were produced by Qing dao Marine 1H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.20 (s, 1H,
Chemical Company (China). Unless otherwise noted, all sol- Ar-NH), 7.88–7.90 (d, J=8.3Hz, 2H, Ar-H), 7.48–7.51 (d,
vents and reagents were obtained from commercial suppliers J=8.3Hz, 2H, Ar-H), 7.47 (t, J=2.1Hz, 1H, Ar-H), 7.36 (dd,
and used without further purification.
J=1.0, 8.1Hz, 1H, Ar-H), 7.31 (s, 2H, NH2), 7.25 (t, J=8.1Hz,
General Procedure for the Synthesis of 3a–p A solution 1H, Ar-H), 6.68 (dd, J=2.1, 8.1Hz, 1H, Ar-H), 4.38 (s, 2H,
of sodium hydroxide (6mmol) in water (10mL) was added to CH2), 3.75 (s, 3H, CH3); ESI-MS m/z: 373.5 [M+H]+.
a mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (6mmol),
2-Amino-5-[4-(4-methoxyphenylcarbamoyl)-benzylthio]-
appropriate 4-chloromethyl-N-(substituted-phenyl)-benzamide 1,3,4-thiadiazole (3g) White crystals; mp 246.5–248.5°C;
(2a–p, 5mmol) and ethanol (15mL). The mixture was stirred Yield 89%; IR (KBr) cm–1: 1641, 1401, 1107, 821, 617, 419;
for 7–8h at room temperature (the end of reaction was moni- 1H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.11 (s, 1H,
tored by TLC), After completion, the mixture was poured into Ar-NH), 7.88–7.90 (d, J=8.2Hz, 2H, Ar-H), 7.65 (t, J=2.0Hz,
water. The resulting precipitate was collected by filtration, 1H, Ar-H), 7.68 (t, J=2.0Hz, 1H, Ar-H), 7.47–7.49 (d,
washed well with water and further purified by recrystalliza- J=8.2Hz, 2H, Ar-H), 7.31 (s, 2H, NH2), 6.94 (t, J=2.1Hz, 1H,
tion from ethanol to afford target compounds.
Ar-H), 6.91 (t, J=2.1Hz, 1H, Ar-H), 4.37 (s, 2H, CH2), 3.75 (s,
2-Amino-5-[4-(phenylcarbamoyl)-benzylthio]-1,3,4-thiadi- 3H, CH3); ESI-MS m/z: 373.5 [M+H]+.
azole (3a) White crystals; mp 223.8–225.6°C; Yield 88%;
2-Amino-5-[4-(2-fluorophenylcarbamoyl)-benzylthio]-1,3,4-
IR (KBr) cm–1: 1638, 1401, 1108, 995, 616, 419; H-NMR thiadiazole (3h) White crystals; mp 203.5–205.7°C; Yield
1
1
(DMSO-d6, 400MHz) δ (ppm): 10.23 (s, 1H, Ar-NH), 7.89– 80%; IR (KBr) cm–1: 1637, 1385, 1107, 996, 617, 419; H-NMR
7.91 (d, J=7.7Hz, 2H, Ar-H), 7.76–7.78 (d, J=7.7Hz, 2H, (DMSO-d6, 400MHz) δ (ppm): 9.42 (s, 1H, Ar-NH), 7.90–7.92
Ar-H), 7.48–7.50 (d, J=7.7Hz, 2H, Ar-H), 7.35 (t, J=8.0Hz, (d, J=8.2Hz, 2H, Ar-H), 7.75 (dd, J=1.3, 7.8Hz, 1H, Ar-H),
2H, Ar-H), 7.31 (s, 2H, NH2), 7.10 (t, J=6.8Hz, 1H, Ar-H), (t, 7.48–7.50 (d, J=8.2Hz, 2H, Ar-H), 7.31 (s, 2H, NH2), 7.19 (dt,
J=6.8Hz, 1H, Ar-H), 4.38 (s, 2H, CH2); ESI-MS m/z: 343.4 J=1.3, 8.3Hz,, 1H, Ar-H), 7.10 (dd, J=1.0, 7.4Hz, 1H, Ar-H),
[M+H]+.
6.97 (dt, J=1.0, 7.7Hz, 1H, Ar-H), 4.38 (s, 2H, CH2); ESI-MS
2-Amino-5-[4-(2-methylphenylcarbamoyl)-benzylthio]-1,3,4- m/z: 361.4 [M+H]+.
thiadiazole (3b) White crystals; mp 197.0–199.2°C; Yield
2-Amino-5-[4-(4-fluorophenylcarbamoyl)-benzylthio]-1,3,4-
87%; IR (KBr) cm–1: 1637, 1399, 1107, 991, 617, 419; H-NMR thiadiazole (3i) White crystals; mp 242.5–243.9°C; Yield
1
(DMSO-d6, 400MHz) δ (ppm): 9.87 (s, 1H, Ar-NH), 7.92–7.94 83%; IR (KBr) cm–1: 1641, 1401, 1107, 996, 617, 419; H-NMR
1
(d, J=7.9Hz, 2H, Ar-H), 7.48–7.50 (d, J=7.9Hz, 2H, Ar-H), (DMSO-d6, 400MHz) δ (ppm): 10.29 (s, 1H, Ar-NH), 7.88–
7.32–7.34 (d, J=9.1Hz, 1H, Ar-H), 7.32 (s, 2H, NH2), 7.26– 7.90 (d, J=8.2Hz, 2H, Ar-H), 7.77–7.80 (m, 2H, Ar-H), 7.48–

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Vol. 63, No. 6 (2015)
7.50 (d, J=8.2Hz, 2H, Ar-H), 7.31 (s, 2H, NH2), 7.20 (t, 2H, CH2); ESI-MS m/z: 411.4 [M+H]+.
J=8.9Hz, 2H, Ar-H), 4.38 (s, 2H, CH2); ESI-MS m/z: 361.4
General Procedure for the Synthesis of 4a–p A solu-
tion of 2-chloroselenobenzoyl chloride (5.0mmol) in dry
[M+H]+.
2-Amino-5-[4-(2-chlorophenylcarbamoyl)-benzylthio]-1,3,4- acetonitrile (25mL) was added dropwisely to a stirred
thiadiazole (3j) White crystals; mp 197.1–199.6°C; Yield solution of the corresponding 2-amino-5-[4-(substituted-
1
88%; IR (KBr) cm–1: 1639, 1400, 1132, 995, 617, 419; H-NMR phenylcarbamoyl)-benzylthio]-1,3,4-thiadiazole (3a–p, 5mmol)
(DMSO-d6, 400MHz) δ (ppm): 10.05 (s, 1H, Ar-NH), 7.93– and triethylamine (6mmol) in dry acetonitrile (25mL). The
7.95 (d, J=8.3Hz, 2H, Ar-H), 7.59 (dd, J=1.5, 7.9Hz, 1H, reaction mixture was stirred for 8–10h at room temperature.
Ar-H), 7.56 (dd, J=1.4, 8.0Hz, 1H, Ar-H), 7.50–7.52 (d, After completion, the solvent was evaporated under reduced
J=8.3Hz, 2H, Ar-H), 7.39 (dt, J=1.5, 7.5Hz, 1H, Ar-H), pressure and the residue was washed with water. The insoluble
7.30(dt, J=1.4, 7.9Hz, 1H, Ar-H), 7.31 (s, 2H, NH2),4.39 (s, solid was collected and purified by silica gel column chroma-
2H, CH2); ESI-MS m/z: 377.4 [M+H]+.
tography with petroleum ether (60–90°C)/ethyl acetate (1:3,
2-Amino-5-[4-(3-chlorophenylcarbamoyl)-benzylthio]-1,3,4- volume ratio) as eluent to afford the desired products.
thiadiazole (3k) White crystals; mp 219.7–221.5°C; Yield
2-{2-[4-(Phenylcarbamoyl)-benzylthio]-1,3,4-thiadiazol-
1
84%; IR (KBr) cm–1: 1650, 1401, 1107, 995, 617, 419; H-NMR 5-yl}-1,2-benzisoselenazol-3(2H)-one (4a) Yellow solid; mp
(DMSO-d6, 400MHz) δ (ppm): 10.39 (s, 1H, Ar-NH), 7.96 (t, 276.0–277.9°C; Yield 49%; IR (KBr) cm–1: 1639, 1443, 1387,
J=1.9Hz, 1H, Ar-H), 7.89–7.91 (d, J=8.2Hz, 2H, Ar-H), 7.70 1020, 752, 623; H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.23
1
(dd, J=1.3, 7.1Hz, 1H, Ar-H), 7.50–7.52 (d, J=8.2Hz, 2H, (s, 1H, Ar-NH), 8.10–8.12 (d, J=8.1Hz, 1H, Ar-H), 7.99–8.01
Ar-H), 7.39 (t, J=8.2Hz, 1H, Ar-H), 7.31 (s, 2H, NH2), 7.16 (d, J=7.7Hz, 1H, Ar-H), 7.90–7.92 (d, J=8.0Hz, 2H, Ar-H),
(dd, J=1.3, 7.9Hz, 1H, Ar-H), 4.38 (s, 2H, CH2); ESI-MS m/z: 7.78 (t, J=8.0Hz, 1H, Ar-H), 7.75–7.77 (d, J=8.0Hz, 2H,
377.4 [M+H]+.
Ar-H), 7.59–7.61 (d, J=8.0Hz, 2H, Ar-H), 7.53 (t, J=7.5Hz,
2-Amino-5-[4-(4-chlorophenylcarbamoyl)-benzylthio]-1,3,4- 1H, Ar-H), 7.34 (t, J=7.8Hz, 2H, Ar-H), 7.10 (t, J=7.4Hz, 1H,
thiadiazole (3l) White crystals; mp 230.4–232.5°C; Yield Ar-H), 4.62 (s, 2H, CH2); ESI-MS m/z: 525.4 [M+H]+; Anal.
1
83%; IR (KBr) cm–1: 1653, 1399, 1107, 994, 618, 413; H-NMR Calcd for C23H16N4O2S2Se: C, 52.77; H, 3.08; N, 10.70. Found:
(DMSO-d6, 400MHz) δ (ppm): 10.36 (s, 1H, Ar-NH), 7.88– C, 52.65; H, 3.04; N, 10.77.
7.90 (d, J=8.0Hz, 2H, Ar-H), 7.80–7.82 (d, J=8.1Hz, 2H,
2-{2-[4-(2-Methylphenylcarbamoyl)-benzylthio]-1,3,4-thiadi-
Ar-H), 7.49–7.50 (d, J=8.0Hz, 2H, Ar-H), 7.40–7.42 (d, azol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4b) Yellow solid;
J=8.1Hz, 2H, Ar-H), 7.31 (s, 2H, NH2), 4.38 (s, 2H, CH2); mp 255.5–257.5°C; Yield 50%; IR (KBr) cm–1: 1638, 1457,
1
ESI-MS m/z: 377.4 [M+H]+.
1396, 1019, 750, 625; H-NMR (DMSO-d6, 400MHz) δ (ppm):
2-Amino-5-[4-(4-bromophenylcarbamoyl)-benzylthio]-1,3,4- 9.86 (s, 1H, Ar-NH), 8.10–8.12 (d, J=8.1Hz, 1H, Ar-H), 7.99–
thiadiazole (3m) White crystals; mp 247.9–249.8°C; Yield 8.01 (d, J=7.6Hz, 1H, Ar-H), 7.93–7.95 (d, J=8.1Hz, 2H,
1
79%; IR (KBr) cm–1: 1641, 1401, 1133, 995, 617, 419; H-NMR Ar-H), 7.78 (t, J=7.5Hz, 1H, Ar-H), 7.58–7.60 (d, J=8.1Hz,
(DMSO-d6, 400MHz) δ (ppm): 10.11 (s, 1H, Ar-NH), 7.88– 2H, Ar-H), 7.53 (t, J=7.5Hz, 1H, Ar-H), 7.32–7.34 (d,
7.90 (d, J=8.2Hz, 2H, Ar-H), 7.65–7.68 (d, J=9.0Hz, 2H, J=7.4Hz, 1H, Ar-H), 7.26–7.27 (d, J=7.0Hz, 1H, Ar-H), 7.21
Ar-H), 7.47–7.49 (d, J=8.2Hz, 2H, Ar-H), 7.31 (s, 2H, NH2), (t, J=7.4Hz, 1H, Ar-H), 7.16 (t, J=7.4Hz, 1H, Ar-H), 4.62
6.91–6.94 (d, J=9.0Hz, 2H, Ar-H), 4.37 (s, 2H, CH2); ESI-MS (s, 2H, CH2), 2.22 (s, 3H, CH3); ESI-MS m/z: 539.5 [M+H]+;
m/z: 421.3 [M+H]+.
Anal. Calcd for C24H18N4O2S2Se: C, 53.63; H, 3.38; N, 10.42.
2-Amino-5-[4-(2-nitrophenylcarbamoyl)-benzylthio]-1,3,4- Found: C, 53.50; H, 3.34; N, 10.38.
thiadiazole (3n) Pale yellow crystals; mp 191.0–192.9°C;
2-{2-[4-(3-Methylphenylcarbamoyl)-benzylthio]-1,3,4-thiadi-
Yield 76%; IR (KBr) cm–1: 1638, 1401, 1108, 994, 618, azol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4c) Yellow solid;
1
419; H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.75 (s, 1H, mp 242.3–243.8°C; Yield 45%; IR (KBr) cm–1: 1639, 1445,
1
Ar-NH), 8.01–8.03 (d, J=7.9Hz, 1H, Ar-H), 7.90–7.92 (d, 1393, 1019, 735, 623; H-NMR (DMSO-d6, 400MHz) δ (ppm):
J=8.2Hz, 2H, Ar-H), 7.78 (t, J=6.1Hz, 1H, Ar-H), 7.76–7.78 10.15 (s, 1H, Ar-NH), 8.10–8.12 (d, J=8.1Hz, 1H, Ar-H),
(d, J=6.1Hz, 1H, Ar-H), 7.53–7.55 (d, J=8.2Hz, 2H, Ar-H), 7.99–8.01 (d, J=7.4Hz, 1H, Ar-H), 7.89–7.91 (d, J=8.2Hz,
7.43 (t, J=7.9Hz, 1H, Ar-H), 7.31 (s, 2H, NH2), 4.39 (s, 2H, 2H, Ar-H), 7.78 (t, J=8.1Hz, 1H, Ar-H), 7.60 (s, 1H, Ar-H),
CH2); ESI-MS m/z: 388.4 [M+H]+.
7.58–7.60 (d, J=8.2Hz, 2H, Ar-H), 7.53–7.55 (d, J=7.7Hz,
2-Amino-5-[4-(4-nitrophenylcarbamoyl)-benzylthio]-1,3,4- 1H, Ar-H), 7.53 (t, J=7.7Hz, 1H, Ar-H), 7.22 (t, J=7.8Hz, 1H,
thiadiazole (3o) Pale yellow crystals; mp 229.0–231.2°C; Ar-H), 6.91–6.92 (d, J=7.4Hz, 1H, Ar-H), 4.62 (s, 2H, CH2),
Yield 79%; IR (KBr) cm–1: 1653, 1385, 1108, 995, 637, 2.30 (s, 3H, CH3); ESI-MS m/z: 539.5 [M+H]+; Anal. Calcd
1
413; H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.80 (s, 1H, for C24H18N4O2S2Se: C, 53.63; H, 3.38; N, 10.42. Found: C,
Ar-NH), 8.26–8.29 (d, J=9.2Hz, 2H, Ar-H), 8.05–8.07 (d, 53.72; H, 3.37; N, 10.34.
J=9.2Hz, 2H, Ar-H), 7.92–7.94 (d, J=8.3Hz, 2H, Ar-H),
7.52–7.54 (d, J=8.3Hz, 2H, Ar-H), 7.31 (s, 2H, NH2), 4.40 (s, thiadiazol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4d) Yellow
solid; mp 277.3–279.2°C; Yield 53%; IR (KBr) cm–1: 1635,
2-{2-[4-(4-Methylphenylcarbamoyl)-benzylthio]-1,3,4-
2H, CH2); ESI-MS m/z: 388.4 [M+H]+.
2-Amino-5-[4-(trifluoromethylphenylcarbamoyl)-benzylthio]- 1401, 1108, 991, 731, 616; 1H-NMR (DMSO-d6, 400MHz)
1,3,4-thiadiazole (3p) White crystals; mp 249.7–251.9°C; δ (ppm): 10.14 (s, 1H, Ar-NH), 8.13–8.15 (d, J=8.1Hz, 1H,
Yield 81%; IR (KBr) cm–1: 1641, 1402, 1071, 901, 618, 419; Ar-H), 7.98–8.00 (d, J=6.9Hz, 1H, Ar-H), 7.89–7.91 (d,
1H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.36 (s, 1H, J=8.2Hz, 2H, Ar-H), 7.77 (t, J=8.3Hz, 1H, Ar-H), 7.62–7.64
Ar-NH), 7.88–7.90 (d, J=8.3Hz, 2H, Ar-H), 7.75–7.77 (d, (d, J=8.4Hz, 2H, Ar-H), 7.58–7.60 (d, J=8.2Hz, 2H, Ar-H),
J=8.8Hz, 2H, Ar-H), 7.53–7.55 (d, J=8.8Hz, 2H, Ar-H), 7.53 (t, J=7.7Hz, 1H, Ar-H), 7.13–7.15 (d, J=8.4Hz, 2H,
7.49–7.51 (d, J=8.3Hz, 2H, Ar-H), 7.31 (s, 2H, NH2), 4.38 (s, Ar-H), 4.62 (s, 2H, CH2), 2.28(s, 3H, CH3); ESI-MS m/z: 539.5

Vol. 63, No. 6 (2015)
Chem. Pharm. Bull.
435
[M+H]+; Anal. Calcd for C24H18N4O2S2Se: C, 53.63; H, 3.38; MS m/z: 543.4 [M+H]+; Anal. Calcd for C23H15N4FO2S2Se: C,
N, 10.42. Found: C, 53.55; H, 3.41; N, 10.47.
2-{2-[4-(2-Methoxyphenylcarbamoyl)-benzylthio]-1,3,4-
51.02; H, 2.79; N, 10.35. Found: C, 50.95; H, 2.77; N, 10.30.
2-{2-[4-(2-Chlorophenylcarbamoyl)-benzylthio]-1,3,4-thiadi-
thiadiazol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4e) Yellow azol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4j) Yellow solid;
solid; mp 213.5–215.1°C; Yield 48%; IR (KBr) cm–1: 1636, mp 255.2–257.0°C; Yield 46%; IR (KBr) cm–1: 1638, 1439,
1
1401, 1108, 994, 745, 615; 1H-NMR (DMSO-d6, 400MHz) 1402, 1022, 755, 623; H-NMR (DMSO-d6, 400MHz) δ (ppm):
δ (ppm): 9.42 (s, 1H, Ar-NH), 8.09–8.11 (d, J=8.1Hz, 1H, 10.06 (s, 1H, Ar-NH), 8.10–8.12 (d, J=8.2Hz, 1H, Ar-H),
Ar-H), 7.99–8.01 (d, J=7.5Hz, 1H, Ar-H), 7.92–7.94 (d, 7.99–8.01 (d, J=7.7Hz, 1H, Ar-H), 7.94–7.96 (d, J=8.0Hz, 2H,
J=8.1Hz, 2H, Ar-H), 7.78–7.80 (d, J=7.9Hz, 1H, Ar-H), 7.76 Ar-H), 7.78 (t, J=7.5Hz, 1H, Ar-H), 7.59–7.61 (d, J=8.0Hz,
(t, J=7.1Hz, 1H, Ar-H), 7.58–7.60 (d, J=8.1Hz, 2H, Ar-H), 2H, Ar-H), 7.54–7.57 (d, J=8.8Hz, 2H, Ar-H), 7.54 (t,
7.53 (t, J=7.4Hz, 1H, Ar-H), 7.18 (t, J=8.2Hz, 1H, Ar-H), J=8.8Hz, 1H, Ar-H), 7.38 (t, J=7.2Hz, 1H, Ar-H), 7.30 (t,
7.07–7.09 (d, J=8.1Hz, 1H, Ar-H), 6.96 (t, J=7.7Hz, 1H, J=7.4Hz, 1H, Ar-H), 4.62 (s, 2H, CH2); ESI-MS m/z: 559.4
Ar-H), 4.62 (s, 2H, CH2), 3.82 (s, 3H, CH3); ESI-MS m/z: 555.5 [M+H]+; Anal. Calcd for C23H15ClN4O2S2Se: C, 49.51; H, 2.71;
[M+H]+; Anal. Calcd for C24H18N4O3S2Se: C, 52.08; H, 3.28; N, 10.04. Found: C, 49.60; H, 2.68; N, 10.10.
N, 10.12. Found: C, 52.17; H, 3.26; N, 10.17.
2-{2-[4-(3-Chlorophenylcarbamoyl)-benzylthio]-1,3,4-thiadi-
2-{2-[4-(3-Methoxyphenylcarbamoyl)-benzylthio]-1,3,4- azol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4k) Yellow solid;
thiadiazol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4f) Yellow mp 262.4–264.1°C; Yield 49%; IR (KBr) cm–1: 1621, 1446,
solid; mp 193.0–194.2°C; Yield 50%; IR (KBr) cm–1: 1637, 1338, 1022, 735, 621; 1H-NMR (DMSO-d6, 400MHz) δ
1401, 1107, 994, 768, 615; 1H-NMR (DMSO-d6, 400MHz) (ppm): 10.40 (s, 1H, Ar-NH), 8.10–8.12 (d, J=8.2Hz, 1H,
δ (ppm): 10.19 (s, 1H, Ar-NH), 8.10–8.12 (d, J=8.1Hz, 1H, Ar-H), 7.98–8.00 (d, J=7.5Hz, 1H, Ar-H), 7.95 (s, 1H,
Ar-H), 7.99–8.01 (d, J=7.2Hz, 1H, Ar-H), 7.90–7.92 (d, Ar-H), 7.90–7.92 (d, J=8.1Hz, 2H, Ar-H), 7.77 (t, J=7.4Hz,
J=8.2Hz, 2H, Ar-H), 7.78 (dt, J=1.2, 8.2Hz, 1H, Ar-H), 1H, Ar-H), 7.68–7.70 (d, J=8.8Hz, 1H, Ar-H), 7.60–7.62 (d,
7.59–7.61 (d, J=8.2Hz, 2H, Ar-H), 7.53 (t, J=7.4Hz, 1H, J=8.1Hz, 2H, Ar-H), 7.53 (t, J=7.5Hz, 1H, Ar-H), 7.38 (t,
Ar-H), 7.46 (t, J=1.8Hz, 1H, Ar-H), 7.34–7.36 (d, J=8.8Hz, J=8.1Hz, 1H, Ar-H), 7.15–7.17 (d, J=7.8Hz, 1H, Ar-H), 4.62
1H, Ar-H), 7.24 (t, J=8.1Hz, 1H, Ar-H), 6.68 (dd, J=2.1, (s, 2H, CH2); ESI-MS m/z: 559.4 [M+H]+; Anal. Calcd for
8.2Hz, 1H, Ar-H), 4.62 (s, 2H, CH2), 3.75 (s, 3H, CH3); ESI- C23H15ClN4O2S2Se: C, 49.51; H, 2.71; N, 10.04. Found: C,
MS m/z: 555.5 [M+H]+; Anal. Calcd for C24H18N4O3S2Se: C, 49.64; H, 2.74; N, 9.98.
52.08; H, 3.28; N, 10.12. Found: C, 52.22; H, 3.31; N, 10.06.
2-{2-[4-(4-Chlorophenylcarbamoyl)-benzylthio]-1,3,4-thiadi-
2-{2-[4-(4-Methoxyphenylcarbamoyl)-benzylthio]-1,3,4- azol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4l) Yellow solid;
thiadiazol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4g) Yellow mp 291.0–293.3°C; Yield 50%; IR (KBr) cm–1: 1638, 1401,
1
solid; mp 275.1–277.7°C; Yield 49%; IR (KBr) cm–1: 1639, 1107, 993, 736, 617; H-NMR (DMSO-d6, 400MHz) δ (ppm):
1
1401, 1106, 994, 735, 623; H-NMR (DMSO-d6, 400MHz) 10.35 (s, 1H, Ar-NH), 8.13–8.15 (d, J=8.2Hz, 1H, Ar-H),
δ (ppm): 10.12 (s, 1H, Ar-NH), 8.10–8.12 (d, J=8.1Hz, 1H, 7.98–8.00 (d, J=7.9Hz, 1H, Ar-H), 7.90–7.92 (d, J=8.0Hz,
Ar-H), 7.99–8.01 (d, J=7.2Hz, 1H, Ar-H), 7.89–7.91 (d, 2H, Ar-H), 7.79–7.81 (d, J=8.5Hz, 2H, Ar-H), 7.78 (t,
J=8.3Hz, 2H, Ar-H), 7.77 (t, J=7.5Hz, 1H, Ar-H), 7.64–7.67 J=8.5Hz, 1H, Ar-H), 7.59–7.61 (d, J=8.0Hz, 2H, Ar-H), 7.53
(d, J=9.0Hz, 2H, Ar-H), 7.47–7.49 (d, J=8.3Hz, 2H, Ar-H), (t, J=8.0Hz, 1H, Ar-H), 7.39–7.41 (d, J=8.5Hz, 2H, Ar-H),
7.53 (t, J=7.7Hz, 1H, Ar-H), 6.92–6.95 (d, J=9.0Hz, 2H, 4.62 (s, 2H, CH2); ESI-MS m/z: 559.4 [M+H]+; Anal. Calcd
Ar-H), 4.61 (s, 2H, CH2), 3.74 (s, 3H, CH3); ESI-MS m/z: 555.5 for C23H15ClN4O2S2Se: C, 49.51; H, 2.71; N, 10.04. Found: C,
[M+H]+; Anal. Calcd for C24H18N4O3S2Se: C, 52.08; H, 3.28; 49.59; H, 2.67; N, 10.11.
N, 10.12. Found: C, 51.92; H, 3.25; N, 10.07.
2-{2-[4-(4-Bromophenylcarbamoyl)-benzylthio]-1,3,4-thiadi-
2-{2-[4-(2-Fluorophenylcarbamoyl)-benzylthio]-1,3,4-thiadi- azol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4m) Yellow solid;
azol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4h) Yellow solid; mp 263.9–265.8°C; Yield 51%; IR (KBr) cm–1: 1635, 1401,
1
mp 231.0–233.5°C; Yield 52%; IR (KBr) cm–1: 1637, 1395, 1108, 992, 735, 616; H-NMR (DMSO-d6, 400MHz) δ (ppm):
1
1108, 995, 735, 615; H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.11 (s, 1H, Ar-NH), 8.09–8.12 (d, J=8.2Hz, 1H, Ar-H),
10.11 (s, 1H, Ar-NH), 8.10–8.12 (d, J=8.1Hz, 1H, Ar-H), 7.99–8.01 (d, J=7.5Hz, 1H, Ar-H), 7.89–7.91 (d, J=8.0Hz, 2H,
7.99–8.01 (d, J=7.6Hz, 1H, Ar-H), 7.93–7.95 (d, J=8.1Hz, 2H, Ar-H), 7.77 (t, J=8.0Hz, 1H, Ar-H), 7.64–7.66 (d, J=8.9Hz,
Ar-H), 7.78 (t, J=7.5Hz, 1H, Ar-H), 7.59–7.61 (d, J=8.1Hz, 2H, Ar-H), 7.57–7.59 (d, J=8.0Hz, 2H, Ar-H), 7.53 (t,
2H, Ar-H), 7.59 (t, J=8.1Hz, 1H, Ar-H), 7.53 (t, J=7.7Hz, 1H, J=7.3Hz, 1H, Ar-H), 6.91–6.93 (d, J=8.9Hz, 2H, Ar-H), 4.61
Ar-H), 7.27–7.29 (d, J=7.3Hz, 2H, Ar-H), 7.21 (t, J=8.0Hz, (s, 2H, CH2); ESI-MS m/z: 603.4 [M+H]+; Anal. Calcd for
1H, Ar-H), 4.62 (s, 2H, CH2); ESI-MS m/z: 543.4 [M+H]+; C23H15N4BrO2S2Se: C, 45.86; H, 2.51; N, 9.30. Found: C, 45.97;
Anal. Calcd for C23H15N4FO2S2Se: C, 51.02; H, 2.79; N, 10.35. H, 2.55; N, 9.37.
Found: C, 50.90; H, 2.82; N, 10.41.
2-{2-[4-(2-Nitrophenylcarbamoyl)-benzylthio]-1,3,4-thiadia-
2-{2-[4-(4-Fluorophenylcarbamoyl)-benzylthio]-1,3,4-thiadi- zol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4n) Yellow solid;
azol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4i) Yellow solid; mp 254.0–255.5°C; Yield 46%; IR (KBr) cm–1: 1638, 1456,
mp 291.0–293.5°C; Yield 54%; IR (KBr) cm–1: 1632, 1401, 1338, 1018, 741, 621; 1H-NMR (DMSO-d6, 400MHz) δ
1
1112, 991, 735, 619; H-NMR (DMSO-d6, 400MHz) δ (ppm): (ppm): 10.75 (s, 1H, Ar-NH), 8.09–8.11 (d, J=8.0Hz, 1H,
10.28 (s, 1H, Ar-NH), 8.09–8.11 (d, J=8.1Hz, 1H, Ar-H), Ar-H), 8.00–8.02 (d, J=7.7Hz, 1H, Ar-H), 8.00 (t, J=7.7Hz,
7.99–8.01 (d, J=7.2Hz, 1H, Ar-H), 7.90–7.92 (d, J=8.2Hz, 2H, 1H, Ar-H), 7.91–7.93 (d, J=7.9Hz, 2H, Ar-H), 7.76–7.80 (m,
Ar-H), 7.78 (t, J=8.0Hz, 1H, Ar-H), 7.76–7.80 (m, 2H, Ar-H), 3H, Ar-H), 7.63–7.65 (d, J=7.9Hz, 2H, Ar-H), 7.51–7.55 (t,
7.59–7.61 (d, J=8.2Hz, 2H, Ar-H), 7.53 (t, J=7.4Hz, 1H, J=7.5Hz, 1H, Ar-H), 7.41–7.44 (t, J=7.7Hz, 1H, Ar-H), 4.63
Ar-H), 7.19 (t, J=8.9Hz, 2H, Ar-H), 4.62 (s, 2H, CH2); ESI- (s, 2H, CH2); ESI-MS m/z: 570.4 [M+H]+; Anal. Calcd for

436
Chem. Pharm. Bull.
Vol. 63, No. 6 (2015)
C23H15N5O4S2Se: C, 48.59; H, 2.66; N, 12.32. Found: C, 48.70;
H, 2.63; N, 12.37.
References
1) Anand P., Kunnumakkara A. B., Sundaram C., Harikumar K. B.,
Tharakan S. T., Lai O. S., Sung B., Aggarwal B. B., Pharm. Res.,
25, 2097–2116 (2008).
2-{2-[4-(4-Nitrophenylcarbamoyl)-benzylthio]-1,3,4-thiadia-
zol-5-yl}-1,2-benzisoselenazol-3(2H)-one (4o) Yellow solid;
mp 291.0–292.5°C; Yield 51%; IR (KBr) cm–1: 1638, 1401,
2) Arnér E. S. J., Holmgren A., Eur. J. Biochem., 267, 6102–6109
(2000).
1
1109, 993, 740, 617; H-NMR (DMSO-d6, 400MHz) δ (ppm):
3) Ramanathan R. K., Abbruzzese J., Dragovich T., Kirkpatrick L.,
Guillen J. M., Baker A. F., Pestano L. A., Green S., Von Hoff D. D.,
Cancer Chemother. Pharmacol., 67, 503–509 (2011).
4) He J., Li D. D., Xiong K., Ge Y. J., Jin H. W., Zhang G. Z., Hong
M. S., Tian Y. L., Yin J., Zeng H. H., Bioorg. Med. Chem., 20,
3816–3827 (2012).
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M., Zeng H. H., Invest. New Drugs, 28, 205–215 (2010).
6) Xing F., Li S., Ge X., Wang C., Zeng H., Li D., Dong L., Oral
Oncol., 44, 963–969 (2008).
10.79 (s, 1H, Ar-NH), 8.25–8.27 (d, J=9.3Hz, 2H, Ar-H),
8.15–8.17 (d, J=8.1Hz, 1H, Ar-H), 8.03–8.06 (d, J=9.3Hz,
2H, Ar-H), 7.98–8.00 (d, J=7.8Hz, 1H, Ar-H), 7.93–7.95 (d,
J=8.3Hz, 2H, Ar-H), 7.77 (t, J=8.4Hz, 1H, Ar-H), 7.62–7.64
(d, J=8.3Hz, 2H, Ar-H), 7.52 (t, J=7.9Hz, 1H, Ar-H), 4.63
(s, 2H, CH2); ESI-MS m/z: 570.4 [M+H]+; Anal. Calcd for
C23H15N5O4S2Se: C, 48.59; H, 2.66; N, 12.32. Found: C, 48.48;
H, 2.67; N, 12.25.
2-{2-[4-(4-Trifluoromethylphenylcarbamoyl)-benzylthio]-1,3,4-
7) Urig S., Becker K., Semin. Cancer Biol., 16, 452–465 (2006).
8) Zaharia V., Ignat A., Ngameni B., Kuete V., Moungang M. L.,
Fokunang C. N., Vasilescu M., Palibroda N., Cristea C., Silaghi-Du-
mitrescu L., Ngadjui B. T., Med. Chem. Res., 22, 5670–5679 (2013).
9) Chou L. C., Huang L. J., Hsu M. H., Fang M. C., Yang J. S., Zhuang
S. H., Lin H. Y., Lee F. Y., Teng C. M., Kuo S. C., Eur. J. Med.
Chem., 45, 1395–1402 (2010).
thiadiazol-5-yl}-1,2-benzisoselenazol-3(2H)-one
(4p) Yellow
solid; mp 289.1–290.9°C; Yield 58%; IR (KBr) cm–1: 1635,
1
1407, 1113, 992, 735, 624; H-NMR (DMSO-d6, 400MHz)
δ (ppm): 10.56 (s, 1H, Ar-NH), 8.09–8.11 (d, J=8.1Hz, 1H,
Ar-H), 7.98–8.00 (d, J=7.6Hz, 1H, Ar-H), 7.97–7.99 (d,
J=8.3Hz, 2H, Ar-H), 7.91–7.93 (d, J=8.2Hz, 2H, Ar-H), 7.77
(t, J=8.1Hz, 1H, Ar-H), 7.70–7.72 (d, J=8.3Hz, 2H, Ar-H), 10) Grozav Ignat A., Gaina L., Kuete V., Silaghi-Dumitrescu L., Efferth
T., Zaharia V., Molecules, 18, 4679–4688 (2013).
7.60–7.62 (d, J=8.2Hz, 2H, Ar-H), 7.53 (t, J=7.6Hz, 1H,
Ar-H), 4.61 (s, 2H, CH2); ESI-MS m/z: 593.4 [M+H]+; Anal.
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Acknowledgments This work was supported by the Na-
tional Natural Science Foundation of China (No. 20971097)
and the Tianjin Municipal Natural Science Foundation (No.
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Conflict of Interest The authors declare no conflict of
interest.
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