Synthesis and anticancer activity of 5-(3-indolyl)-1,3,4-thiadiazoles

Article abstract of DOI:10.1016/j.ejmech.2010.07.023

A series of 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles 5a-m were synthesized and their cytotoxicity analyzed against six human cancer cell lines. The reaction of indole-3-carboxylic acid 3 with aryl or heteroaryl hydrazides afforded the N,N′-diacylhydrazines 4, which upon treatment with Lawesson's reagent resulted in the formation of indolyl-1,3,4-thiadiazoles 5a-m in good yields. Indolyl-1,3,4-thiadiazole 5m with 4-benzyloxy-3-methoxyphenyl and 5-bromo indolyl substituents is the most active in suppressing the growth of cancer cells (IC₅₀ 1.5 μM, PaCa2). The compounds 5b, 5e and 5h bearing C-2 substituent as benzyl, 3,4-dimethoxyphenyl and 4-benzyloxy-3- methoxyphenyl, respectively, have shown significant cytotoxicity against multiple cancer cell lines. Introduction of 4-dimethylamino (5d and 5k) and 3,4,5-trimethoxy (5l) groups in the C-2 phenyl ring induced selectivity against MCF7 and MDA-MB-231 cancer cell lines (compounds 5d, 5k and 5l).

Full text of DOI:10.1016/j.ejmech.2010.07.023

European Journal of Medicinal Chemistry 45 (2010) 4664e4668
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and anticancer activity of 5-(3-indolyl)-1,3,4-thiadiazoles
,
a
b
b,
Dalip Kumar a , N. Maruthi Kumar , Kuei-Hua Chang , Kavita Shah
*
**
a Chemistry Group, Birla Institute of Technology and Science, Pilani, Rajasthan 333 031, India
b Department of Chemistry and Purdue Cancer Center, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles 5aem were synthesized and their cytotoxicity
analyzed against six human cancer cell lines. The reaction of indole-3-carboxylic acid 3 with aryl or
heteroaryl hydrazides afforded the N,N0-diacylhydrazines 4, which upon treatment with Lawesson’s
reagent resulted in the formation of indolyl-1,3,4-thiadiazoles 5aem in good yields. Indolyl-1,3,4-thia-
diazole 5m with 4-benzyloxy-3-methoxyphenyl and 5-bromo indolyl substituents is the most active in
Received 29 April 2010
Received in revised form
13 July 2010
Accepted 13 July 2010
Available online 21 July 2010
suppressing the growth of cancer cells (IC50 1.5 mM, PaCa2). The compounds 5b, 5e and 5h bearing C-2
substituent as benzyl, 3,4-dimethoxyphenyl and 4-benzyloxy-3-methoxyphenyl, respectively, have
shown significant cytotoxicity against multiple cancer cell lines. Introduction of 4-dimethylamino (5d
and 5k) and 3,4,5-trimethoxy (5l) groups in the C-2 phenyl ring induced selectivity against MCF7 and
MDA-MB-231 cancer cell lines (compounds 5d, 5k and 5l).
Keywords:
1,3,4-Thiadiazole
Indolyl heterocycles
Anticancer agents
Indolyl azoles
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
(Fig. 1), isolated from culture broths of Streptomyces strain, is
known to increase DNA-topoisomerase complex formation and
Recent drug discovery efforts are highly focused towards design
and synthesis of small molecules as anticancer agents [1]. A wide
range of heterocyclic ring systems has been studied for the devel-
opment of novel chemical entities as a lead molecule in the drug
discovery paradigm. Thiadiazoles are one of the privileged struc-
tural fragments in medicinal chemistry having broad spectrum of
pharmacological activities [2e4]. Particularly, 1,3,4-thiadiazoles are
much explored for their broad spectrum of biological activities
including antiinflammatory [5], antihypertensive [6], antibacterial
[7], anticonvulsant, antimicrobial [8], antidepressants [9], anti-
leishmanial [10] and anticancer [11]. Furthermore, widely explored
2-aminothiadiazoles are in clinical trials for the treatment of
patients with different tumors [12].
Among the important heterocycles, many of the natural and
synthetic indole-based heterocycles with diverse mechanism of
action have been reported as lead anticancer molecules [13e15].
Various indolylazole and bisindolylazoles are known for their
anticancer activities. Camalexin (indolylthiazole) 1a which is
a phytoalexin was detected and isolated from the leaves of Cruci-
ferae Camelina sativa infected with Alternaria brassicae. Analogues
of 1a were evaluated for their cytotoxic activity against human
breast tumor cell lines [16]. A thiazolyl indolequinone, BE 10988 1b
displayed significant anticancer activities [17]. Recently, we have
reported 4-(3-indolyl)oxazoles 1c [18] and 5-(3-indolyl)-1,3,4-
oxadiazoles 1d [19] as potential anticancer agents against many
types of human cancer cell lines.
Encouraging activities of indolylazoles prompted us to investi-
gate new analogues with further modification of five-membered
heterocyclic ring and indolyl moiety in order to optimize the
structure-activity relationship (SAR) leading to potent and selective
anticancer agents. In this paper we report a facile synthesis of
diverse 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles and their
anticancer activities against various human cancer cell lines.
The common method for the preparation of 1,3,4-thiadiazoles
involves the reaction of aldehydes, hydrazine hydrate and
elemental sulfur under conventional and microwave conditions
[20]. Thionation of dibenzoylhydrazines using Lawesson’s reagent
or phosphorus pentasulfide followed by cyclization and dehy-
drosulfurization is reported to produce 1,3,4-thiadiazoles in good
yields [21]. Varma et al. reported microwave accelerated solvent-
free synthesis of 1,3,4-thiadiazoles from the reaction of acid
hydrazides and triethylorthoalkanates in presence of phosphorus
pentasulfide in alumina [22].
2. Chemistry
* Corresponding author. Tel.: þ91 1596 245073 279.
Synthesis of 5-(3-indolyl)thiadiazoles 5aem was achieved
following a convenient three-step procedure starting from
** Corresponding author. Tel.: þ1 765 496 9470.
E-mail addresses: dalipk@bits-pilani.ac.in (D. Kumar), shah23@purdue.edu (K. Shah).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.023

D. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 4664e4668
4665
4. Results and discussion
The activity results mentioned in Table 1 show the cytotoxic
effects of 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles 5aem
against various cancer cell lines. Most of the compounds showed
significant cytotoxic effect. The structure-activity relationship
(SAR) study revealed that the substitution at C-2 position of the
1,3,4-thiadiazole ring plays an important role in imparting the
cytotoxic activity to the compound. The compound 5a possessing
a phenyl ring at C-2 position was found to be selectively cytotoxic
against PaCa2 cell line (IC50 41.7
mM). Replacement of phenyl ring
with benzyl moiety led to the compound 5b with increased
cytotoxicity against all cancer cell lines, the IC50 values are nearly
uniform against LnCaP, MCF7 and PaCa2 cell lines and below
30
mM in PC3, DU145 and MDA-MB-231 cell lines. Next, we
investigated the effect of electron with-drawing and electron-
donating groups by introducing chloro and 4-dimethylamino
substituents at the para position of C-2 aryl ring. It was observed
that compound 5c with p-chlorophenyl is moderately active
Fig. 1. Structures of some 5-(3-Indolyl)azoles.
against four cancer cell lines (<100
with 4-(dimethylamino)phenyl showed an apparent increase in
activity against three cancer cell lines LnCaP (23 M), DU145
(35.6 M) and MCF7 (12.3 M).
mM), whereas, compound 5d
m
m
m
commercially available indole 2 as outlined in the Scheme 1. The
indole-3-carboxylic acids 3 were prepared from the reaction of 2
with trifluoroacetic anhydride followed by hydrolysis with
sodium hydroxide. Reaction of 3 with arylhydrazides in the
presence of versatile coupling reagents 1-ethyl-3-(3-dimethyla-
minopropyl)carbodiimide hydrochloride and 1-hydroxybenzo-
triazole in dry tetrahydrofuran afforded diacylhydrazines 4.
Thionation of diacylhydrazine 4 with Lawesson’s reagent fol-
lowed by oxidative cyclization in dry tetrahydrofuran led to the
indolyl-1,3,4-thiadiazoles 5 in good yields. The reaction of 4 with
Lawesson’s reagent was also screened in different solvents
including toluene, dioxane and xylene but afforded less yields
when compared to tetrahydrofuran. Further, the reaction of 4
with Lawesson’s reagent under solvent-free conditions using
microwave irradiation gave a mixture of by-products along with
desired indolyl-1,3,4-thiadiazole. All the synthesized 5-(3-
indolyl)-2-substituted-1,3,4-thiadiazoles 5aem were character-
ized by their NMR and MS data.
Introducing 3,4-dimethoxyphenyl group at C-2 resulted in
compound 5e with significantly increased activity against all the
cancer cell lines especially against MCF7 with an IC50 value of
6.8 mM. Interestingly, a 3,4-methylenedioxy moiety (compound 5g)
in the C-2 aryl ring drastically reduces the activity. Introduction of
third methoxy group on phenyl ring (compound 5f) also reduced
the activity but enhanced the selectivity against PaCa2 cell line (IC50
14.2
with 4-benzyloxy group (compound 5h) led to substantial gain in
activity and selectivity against MCF7 (IC50 6.5 M) and DU145 (IC50
9.1 M) cell lines. Compound with C-2 pyridyl substituent
(compound 5j) displayed improved activity and selectivity against
PC3 cell line (IC50 < 50 M) when compared with 5a. Shifting the
mM). Increasing the size of 4-methoxy group by replacing it
m
m
m
position of heteroatom in the ring led to 4-pyridyl derivative 5i
with further improved activity. The compound 5k with C-2 4-
dimethylaminophenyl and 5-bromoindole exhibited reduced
activity except selective cytotoxicity against MDA-MB-231 cell line
with an IC50 value of 12.7 mM. Replacing 4-dimethylaminophenyl of
5k with trimethoxyphenyl resulted in 5l with reduced activity,
whereas 4-benzyloxy-3-methoxyphenyl group led to compound
5m with significant improved activity and selectivity against PaCa2
3. Anticancer activity
(IC50 1.5 mM) cancer cell line. The comparison of activity results of 5-
A series of diverse 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles
5aemwere screenedagainst prostate(PC3, DU145and LnCaP), breast
(MCF7 and MDA-MB-231) and pancreatic (PaCa2) cancer cell lines.
These cell lines were cultured in RPMI 1640 medium containing 10%
fetal bovine serum. Cells were seeded in 96-well microtiter plate, at
a target cell density of 5000e10,000 cells per well. After 12 h, test
compounds were added at different concentrations ranging from
100 nM to 1 mM and the cells were further incubated for 48 h. The
anticancer activity was determined for each cell line using formazan
dye (MTT) conversion assay.
(3-indolyl)-1,3,4-thiadiazoles with that of 4-(3-indolyl)oxazoles
[18], 5-(3-indolyl)-1,3,4-oxadiazoles [19] and 5-(3-indolyl)-1,2,4-
triazoles [23] shows that the five-membered heterocyclic ring plays
a vital role in the cytotoxicity and selectivity of indolyl azoles
towards cancer cells. The most potent compounds in various
indolyl azoles bearing a common C-5 indole moiety have different
substituents at C-2 position of five-membered heterocyclic ring. In
general, the anticancer activity of 5-(3-indolyl)-2-substituted-
1,3,4-thiadiazoles 5 is better than that of 4-(3-indolyl)oxazoles [18],
O
N
N
H
N
COOH
R1
R
R
R
R
R1
N
H
S
a
b
c
O
N
H
N
H
N
H
N
H
2
3
4
5
Scheme 1. Synthesis of indolyl-1,3,4-thiadiazoles (5). Reagents and conditions: (a) (i) (CF3CO)2O, DMF; (ii) Aqueous NaOH, reflux; (b) EDCI, HOBt, R1CONHNH2, THF, rt;
(c) Lawesson’s reagent, THF, reflux.

4666
D. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 4664e4668
Table 1
In vitro cytotoxicity data of 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles 5aema against selected human cancer cell lines IC50 M).b
(m
N
N
R
S
R1
N
H
Compound
R1
R
LnCaP
DU145
PC3
MCF7
MDA-MB-231
PaCa2
5a
5b
5c
5d
5e
5f
5g
5h
5i
C6H5
CH2C6H5
4-ClC6H4
4-N,N0(CH3)2C6H4
3,4-(OCH3)2C6H3
3,4,5-(CH3O)3C6H2
3,4-(OCH2O)C6H3
4-BnO-3-OCH3C6H3
3-pyridyl
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
264.9
13.9
53.1
23
21
40
799
19.2
151.7
95
31.3
66.4
8.9
261.5
17
366.7
29
280.5
13.5
149.5
12.3
6.8
144.9
>1000
6.5
91.6
67
28.7
594.7
8.3
445.7
27.8
54.7
124.1
24
54.5
>1000
26.2
96.3
53.8
12.7
19.1
6.2
41.7
13
>1000
188.1
13.8
14.2
231.1
28.9
>1000
451.3
130.5
>1000
1.5
79.6
35.6
10.7
168.5
162
9.1
170
77
22
99.2
704.9
11.9
29.3
157.9
22.3
37.2
39.2
26.6
95.4
7.5
5j
5k
5l
4-pyridyl
4-N,N0(CH3)2C6H4
3,4,5-(CH3O)3C6H2
4-BnO-3-OCH3C6H3
58.4
3.6
5m
Bold values show IC50 of less than 20
m
M.
a
These experiments were conducted in triplicates at three independent times.
b
IC50 values were obtained using a dose response curve by nonlinear regression using a curve fitting program, GraphPad Prism 5.0.
whereas, comparable to 5-(3-indolyl)-1,3,4-oxadiazoles [19] and 5-
(3-indolyl)-1,2,4-triazoles [23].
6.1.2. General procedure for the synthesis of 1,2-diacylhydrazines (4)
A mixture of indole-3-carboxylic acid 3 (1.61 g, 10 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(1.91 g, 10 mmol) and 1-hydroxy-benzotriazole (1.35 g,
10 mmol) in dry tetrahydrofuran (10 mL) was stirred at room
temperature for 15 min. To this reaction mixture, appropriate
arylhydrazide (1 mmol) was added and continued stirring at
room temperature for 6 h. The reaction contents were concen-
trated at reduced pressure, the solid 1,2-diacylhydrazine 4 was
filtered off, washed with water and dried to use as such for the
next step.
5. Conclusion
In summary, we have synthesized a novel series of 5-(30-
indolyl)-2-substituted-1,3,4-thiadiazoles which have displayed
variable extent of cytotoxic activity against various cancer cell lines.
The cytotoxicity results of 5aem demonstrated the importance of
substituents such as 4-benzyloxy-3-methoxyphenyl, 5-bro-
moindole and 4-(dimethylamino)phenyl at C-2 and C-5 positions of
1,3,4-thiadiazoles. Compound 5m with 4-benzyloxy-3-methox-
yphenyl at C-2 position and 5-bromoindole at C-5 position is the
most potent compound of this series. Further structure-activity
studies are required to clearly elucidate the role of heterocyclic
linker in indolyl azoles and identify their molecular targets.
6.1.3. General procedure for the synthesis of indolyl-1,3,4-
thiadiazole (5)
A mixture of 1,2-diacylhydrazines 4 (1 mmol) and Lawesson’s
reagent (0.44 g, 1.1 mmol) in tetrahydrofuran (10 mL) was refluxed
at 80 ꢀC for 5 h. After completion of the reaction as monitored by
TLC, the crude product was adsorbed over silica gel and purified by
column chromatography using ethyl acetate: hexane (7:3; v/v) as
eluent to afford pure product 5.
6. Experimental
6.1. Physical measurements
6.1.3.1. 2-1H-indol-3-yl-5-phenyl-1,3,4-thiadiazole (5a). Yield 65%;
All the laboratory grade reagents were obtained commercially.
The reaction was monitored by thin layer chromatography, which
mp 187e191 ꢀC. 1H NMR (400 MHz, DMSO-d6,
d
ppm): dH ¼ 12.05 (s,
1H, NH), 8.14e8.10 (m, 1H, AreH), 7.94 (d, 1H, J ¼ 2.92 Hz, AreH),
7.49e7.47 (m, 2H, AreH), 7.40e7.36 (m, 3H, AreH), 7.33e7.27 (m,
1H, AreH), 7.24e7.20 (m, 2H, AreH). MS (ESI) calcd for C16H11N3S
278.07 (M þ H)þ found 278.20.
was performed on Merck precoated plates (silica gel. 60 F254
,
0.25 mm) and was visualized by fluorescence quenching under UV
light (254 nm). Column chromatography was performed using
100e200 mesh silica gel and appropriate mixture of hexane and
ethyl acetate for elution. The solvents were evaporated using Buchi
rotary evaporator. Melting points were determined with electro-
thermal capillary melting point apparatus (EeZ melting). 1H NMR
spectra were recorded on a Bruker Advance II (400 MHz) spec-
trometer. The coupling constant (J) values are in Hz. Mass spectra
were obtained on a ‘HewlettePackard’ HP GS/MS 5890/5972.
6.1.3.2. 2-Benzyl-5-1H-indol-3-yl ꢁ1,3,4-thiadiazole (5b). Yield
65%; mp 189e192 ꢀC. 1H NMR (400 MHz, DMSO-d6,
d ppm):
dH ¼ 11.75 (s, 1H, NH), 8.18e8.15 (m, 1H, AreH), 7.86e7.81(m, 2H,
AreH), 7.49e7.46 (m, 1H, AreH), 7.39e7.33 (m, 3H, AreH),
7.31e7.27 (m, 1H, AreH), 7.25e7.17 (m, 2H, AreH). 4.44 (s, 2H, CH2).
MS (ESI) calcd for C17H13N3S 292.08 (M þ H)þ found 292.31.
6.1.1. Preparation of indole-3-carboxylic acid (3)
Indole-3-carboxylic acid and 5-bromoindole-3-carboxylic acid
were prepared by the reported methods [24].
6.1.3.3. 2-(4-Chlorophenyl)-5-1H-indol-3-yl-1,3,4-thiadiazole
(5c). Yield 75%; mp 231e234 ꢀC. 1H NMR (400 MHz, DMSO-d6,
d
ppm): dH ¼ 11.98 (s, 1H, NH), 8.32e8.22 (m, 2H, AreH), 8.14 (d, 1H,

D. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 4664e4668
4667
J ¼ 8.48 Hz, AreH), 8.03 (d, 1H, J ¼ 8.24 Hz, AreH), 7.72e7.64 (m,
2H, AreH), 7.55 (d, 1H, J ¼ 8.2 Hz, AreH), 7.30e7.27 (m, 2H, AreH).
MS (ESI) calcd for C16H10ClN3S 312.02 (M þ H)þ found 312.0.
3.74 (s, 3H, OCH3). MS (ESI) calcd for C19H16BrN3O3S 445.01 (M)þ
found 445.38.
6.1.3.13. 2-(4-(Benzyloxy)-5-(5-bromo-3-indolyl)-3-methox-
6.1.3.4. 2-(4-Dimethylaminophenyl)-5-1H-indol-3-yl-1,3,4-thiadia-
yphenyl)-1,3,4-thiadiazole (5m). Yield 75%; mp 252e254 ꢀC. 1H
zole (5d). Yield 72%; mp 195e199 ꢀC. 1H NMR (400 MHz, DMSO-d6,
NMR (400 MHz, DMSO-d6,
d
ppm): dH ¼ 12.14 (s, 1H, NH), 8.40 (d,
d
ppm): dH ¼ 11.89 (s, 1H, NH), 8.23e8.20 (m, 1H, AreH), 7.99 (d, 2H,
1H, J ¼ 1.6 Hz, AreH), 8.26 (d, 1H, J ¼ 2.8 Hz, AreH), 7.50 (d, 1H,
J ¼ 2.0 Hz, AreH), 7.50e7.46 (m, 4H, AreH), 7.42e7.22 (m, 4H,
AreH), 7.20 (s, 1H, AreH), 5.18 (s, 2H, CH2), 3.74 (s, 3H, OCH3). MS
(ESI) calcd for C24H18BrN3O2S 493.03 (M þ 2)þ found 493.49.
J ¼ 8.8 Hz), 7.62e7.49 (m, 3H, AreH), 7.03e6.97 (m, 2H, AreH),
6.87e6.81 (m, 1H, AreH), 2.98 (s, 6H, NCH3). MS (ESI) calcd for
C18H16N4S 321.10 (M þ H)þ found 321.34.
6.1.3.5. 2-(3,4-Dimethoxyphenyl)-5-1H-indol-3-yl-1,3,4-thiadiazole
6.2. MTT assay
(5e). Yield 72%; mp 173e177 ꢀC. 1H NMR (400 MHz, DMSO-d6,
d
ppm): dH ¼ 12.08 (s, 1H, NH), 8.32e8.17 (m, 2H, AreH), 7.72e7.07
Six human cancer cell lines (LnCaP, DU145, PC3, MCF7, MDA-
MB-231, and PaCa2) were cultured in RPMI 1640 media supple-
mented with 10% heat inactivated fetal bovine serum and 1%
penicillin/streptomycin. They were seeded in 96-well plates at
a density of 4 ꢂ103 cells per well for 12 h. Cells were incubated with
various concentrations of the compounds ranging from 10 nM to
1 mM. After 48 h, MTT (3-(4,5-dimethyldiazol-2-yl)-2,5-diphe-
nyltetra-zoliumbromide) was added to the final concentration of
0.2 mg/mL and incubated for 30 min. The cells were washed twice
(m, 6H, AreH), 3.90 (s, 6H, OCH3). MS (ESI) calcd for C18H15N3O2S
338.08 (M þ H)þ found 338.20.
6.1.3.6. 2-1H-indol-3-yl-5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadia-
zole (5f). Yield 75%; mp 220e221 ꢀC. 1H NMR (400 MHz, DMSO-d6,
d
ppm): dH ¼ 12.11 (s, 1H, NH), 8.35e8.21 (m, 2H, AreH), 8.14 (s, 1H,
AreH), 7.71e6.97 (m, 4H, AreH), 3.90 (s, 6H, OCH3), 3.76 (s, 3H,
OCH3). MS (ESI) calcd for C19H17N3O3S 368.09 (M þ H)þ found
368.30.
with PBS and lysed in 100 mL dimethylsulfoxide, and the absorbance
was measured at 570 nm using Tecan Spectrafluor Plus.
6.1.3.7. 5-1H-indol-3-yl-2-(3,4-methylenedioxyphenyl)-1,3,4-thia-
diazole (5g). Yield 66%; mp 218e220 ꢀC. 1H NMR (400 MHz, DMSO-
Acknowledgements
d6,
d
ppm): dH ¼ 11.66 (s, 1H, NH), 8.24 (d, 2H, J ¼ 8.32 Hz, AreH),
7.94e7.89 (m, 3H, AreH), 7.44 (d, 2H, J ¼ 9.32 Hz, AreH), 6.95 (d,1H,
J ¼ 8.08 Hz, AreH), 6.10 (s, 2H, CH2). MS (ESI) calcd for C17H11N3O2S
322.05 (M þ H)þ found 322.18.
The authors thank Department of Science and Technology, New
Delhi for the financial support and SAIF, Panjab University for
providing analytical support.
6.1.3.8. 2-(4-(Benzyloxy)-3-methoxyphenyl)-5-1H-indol-3-yl-1,3,4-
thiadiazole (5h). Yield 55%; mp 240e245 ꢀC. 1H NMR (400 MHz,
References
DMSO-d6,
d
ppm): dH ¼ 12.05 (s, 1H, NH), 8.30 (d, 1H, J ¼ 2.8 Hz,
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64%; mp 221e224 ꢀC. 1H NMR (400 MHz, DMSO-d6,
d ppm):
dH ¼ 12.01 (s, 1H, NH), 8.56 (d, 2H, J ¼ 8.0 Hz, AreH), 8.26 (d, 1H,
J ¼ 3.6 Hz, AreH), 8.21 (s, 1H, AreH), 7.94 (d, 2H, J ¼ 5.6 Hz, AreH),
7.54e7.47 (m, 3H, AreH). MS (ESI) calcd for C15H10N4S 279.06
(M þ H)þ found 279.09.
6.1.3.10. 2-1H-indol-3-yl-5-(4-pyridyl)-1,3,4-thiadiazole (5j). Yield
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65%; mp 260e263 ꢀC. 1H NMR (400 MHz, DMSO-d6,
d ppm):
dH ¼ 12.08 (s, 1H, NH), 8.77 (d, 2H, J ¼ 5.6 Hz, AreH), 8.32 (d, 1H,
J ¼ 1.2 Hz, AreH), 8.23 (t, 1H, J ¼ 8.8 Hz, AreH), 7.94 (d, 2H,
J ¼ 5.6 Hz, AreH), 7.54 (t, 1H, J ¼ 8.8 Hz, AreH), 7.28e7.26 (m, 2H,
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6.1.3.11. 5-(5-Bromo-3-indolyl)-2-(4-dimethylaminophenyl)
thiadiazole (5k). Yield 60%; mp 217e219 ꢀC. 1H NMR (400 MHz,
DMSO-d6,
1,3,4-
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d
ppm): dH ¼ 11.92 (s, 1H, NH), 8.38 (d, 2H, J ¼ 8.12 Hz,
AreH), 8.24 (d, 2H, J ¼ 8.2 Hz, AreH), 7.50 (d, 1H, J ¼ 2.0 Hz, AreH),
7.42e7.22 (m, 2H, AreH), 7.18 (s, 1H, AreH), 3.08 (s, 6H, CH3). MS
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6.1.3.12. 2-(5-Bromo-3-indolyl)-5-(3,4,5-trimethoxyphenyl)-1,3,4-
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DMSO-d6,
d
ppm): dH ¼ 12.16 (s, 1H, NH), 8.39 (d, 1H, J ¼ 2 Hz,
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7.40e7.38 (m, 2H, AreH), 7.26 (s, 1H, AreH), 3.92 (s, 6H, 2xOCH3),

4668
D. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 4664e4668
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