Sequential one-pot synthesis of bis(indolyl)glyoxylamides: Evaluation of antibacterial and anticancer activities

Article abstract of DOI:10.1016/j.bmcl.2016.04.080

A series of bis(indolyl)glyoxylamides 10a-n has been designed and synthesized. In situ generated indole-3-glyoxalylchloride from the reaction of readily available indole 9 with oxalyl chloride was treated with tryptamine to produce bis(indolyl)glyoxylamides 10a-n in 82-93% yields. All the synthesized bis(indolyl)glyoxylamides were well characterized and tested for their antibacterial activity against Gram-positive and Gram-negative bacterial strains. Compounds 10d, 10g and 10i were found to display potent antibacterial activity against Gram-negative strain. Further, the cytotoxicity of bis(indolyl)glyoxylamides 10a-n were evaluated against a panel of human cancer cell lines. Of the screened analogues, compound 10f (IC₅₀ = 22.34 μM; HeLa, 24.05 μM; PC-3, 21.13 μM; MDA-MB-231 and 29.94 μM; BxPC-3) was identified as the most potent analogue of the series. Exposure of PC-3 cells to either 10a or 10f resulted in increased levels of cleaved PARP1, indicating that bis(indolyl)glyoxylamides induce apoptosis in PC-3 cells. Most importantly, compounds 10d, 10g and 10i were completely ineffective in mammalian cells, suggesting that they target bacterial-specific targets and thus will not display any toxicity in host cells.

Full text of DOI:10.1016/j.bmcl.2016.04.080

Bioorganic & Medicinal Chemistry Letters 26 (2016) 3167–3171
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Sequential one-pot synthesis of bis(indolyl)glyoxylamides:
Evaluation of antibacterial and anticancer activities
Mukund P. Tantak a, Vishakha Gupta a, Kumar Nikhil b, V. Arun a, Rajnish Prakash Singh c,
Prabhat Nath Jha c, Kavita Shah b, , Dalip Kumar a,
⇑
⇑
a Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, India
b Department of Chemistry, Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA
c Department of Biological Sciences, Birla Institute of Technology and Science, Pilani 333031, Rajasthan, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of bis(indolyl)glyoxylamides 10a–n has been designed and synthesized. In situ generated indole-
3-glyoxalylchloride from the reaction of readily available indole 9 with oxalyl chloride was treated with
tryptamine to produce bis(indolyl)glyoxylamides 10a–n in 82–93% yields. All the synthesized bis(indolyl)
glyoxylamides were well characterized and tested for their antibacterial activity against Gram-positive
and Gram-negative bacterial strains. Compounds 10d, 10g and 10i were found to display potent antibac-
terial activity against Gram-negative strain. Further, the cytotoxicity of bis(indolyl)glyoxylamides 10a–n
were evaluated against a panel of human cancer cell lines. Of the screened analogues, compound 10f
Received 18 March 2016
Revised 26 April 2016
Accepted 28 April 2016
Available online 28 April 2016
Keywords:
Bisindoles
Glyoxylamides
Antibacterial
Cancer
(IC50 = 22.34 lM; HeLa, 24.05 lM; PC-3, 21.13 lM; MDA-MB-231 and 29.94 lM; BxPC-3) was identified
as the most potent analogue of the series. Exposure of PC-3 cells to either 10a or 10f resulted in increased
levels of cleaved PARP1, indicating that bis(indolyl)glyoxylamides induce apoptosis in PC-3 cells. Most
importantly, compounds 10d, 10g and 10i were completely ineffective in mammalian cells, suggesting
that they target bacterial-specific targets and thus will not display any toxicity in host cells.
Ó 2016 Elsevier Ltd. All rights reserved.
Cytotoxicity
Apoptosis
Indole is a core substructure in a wide range of biologically
active natural products isolated from marine organisms.1 Particu-
larly, diverse indole alkaloids represent an emerging class of natu-
ral products due to their biological potential as antimicrobial, anti-
HIV, antipsychotic, antidepressant, antioxidant, anti-inflammatory
and antitumour.2 Among the indole alkaloids, bisindoles are a class
of compounds which have received increasing attention due their
diverse and profound biological activities including antimicrobial,
anticancer, anti-HIV antileishmanial and anti-inflammatory.3 Due
to unique structural features and associated activities, bisindole
alkaloids continue to serve as potential targets for synthetic and
biomedical purposes. Literature review on bisindole scaffold
reveals its wide presence in many antibacterial and anticancer lead
molecules.4 Bartik and co-workers isolated three new bisindole
alkaloids namely topsentin (1a), bromotopsentin (1b) and deoxy-
topsentin (1c) from the Mediterranean sponge Topsentia genitrix,
near Banyuls in France.5 Topsentin (1a) exhibited anticancer
tumor cells whereas bromotopsentin (1b, IC50 = 12
lg/mL) and
deoxytopsentin (1c, IC50 = 6.3 g/mL) were found to be cytotoxic
l
against human broncopulmonary (NSCLC-N6) cancer cells. Deoxy-
topsentin 1c also showed potent antibacterial activity against var-
ious bacteria (MIC = 3.12–12.5 l
g/mL).4 Among the four bisindole
alkaloids isolated by Kobayashi and co-workers from Okinawan
tunicate Rhopalaea sp.,6 Rhopaladin B (2a) exhibited inhibitory
activity against cyclin dependent kinase 4 (IC50 = 12.5
c-erbB-2 kinase (IC50 = 7.4 g/mL). Rhopaladin
C6-bromo moiety was found to display activity against Sarcina lutea
and Corynebacterium xerosis bacterial strains (MIC = ꢀ16
g/mL).7
lg/mL) and
l
C (2b) with
l
Hamacanthin A (3) containing a six-membered pyrazinone spacer
unit was isolated from a deep-water marine sponge Hamacantha
sp. and found to possess significant antimicrobial activity against
Candida albicans, Cryptococcus neoformans, and Bacillus subtilis.8
With a similar pyrazinone linker, in 1995 Capon and co-workers
reported the isolation of dragmacidin D (4) from marine sponge
Spongosorites sp. and evaluated their biological activities. Com-
pound 4 was more active towards bacteria including Escherichia
activity (IC50 ꢀ4–40
lM) towards cultured human and murine
coli (MIC = 15.6
Pseudomonas aeruginosa (MIC = 62.5
cytotoxic against P388 murine (IC50 = 1.4
(IC50 = 4.5
g/mL) human lung cancer cells (Fig. 1).9
l
g/mL); Bacillus subtilis (MIC = 3.1
g/mL). Also, it was more
g/mL) and A-549
lg/mL);
l
⇑
Corresponding authors. Tel.: +1 765 496 9470 (K.S.), +91 1596 515238 (D.K.).
E-mail addresses: shah23@purdue.edu (K. Shah), dalipk@pilani.bits-pilani.ac.in
l
l
(D. Kumar).
http://dx.doi.org/10.1016/j.bmcl.2016.04.080
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

3168
M. P. Tantak et al. / Bioorg. Med. Chem. Lett. 26 (2016) 3167–3171
O
NH
N
O
O
R2
N
N
H
R1
N
H
R1
N
H
N
H
N
H
R2
R1 = OH, R2 = H Rhopaladin B (2a)
R1 = H, R2 = OH
Topsentin (1a)
R1 = Br, R2 = OH Bromotopsentin (1b)
R
1 = H, R2 = Br Rhopaladin C (2b)
R
1 = H, R2 = H Deoxytopsentin (1c)
OH
H
H
N
N
H
H
O
N
O
N
Br
OCOCF3
NH
N
N
NH
H2N
Br
N
Br
N
H
H
Hamacanthin A (3)
Dragmacidin D (4)
Figure 1. Representative examples of bisindole alkaloids as antibacterial and anticancer agents.
R1
R2
In recent past numerous bisindoles containing linear as well as
R1
R2
KOH, DMF
R3-X
cyclic linkers have been identified as antibacterial and anticancer
agents (Fig. 2).10 Kumar et al. prepared 3,20-linked bis-indoles 5
which were found to be active against Gram-positive and Gram-
negative bacteria.11 In 2011, Singh group investigated a series of
N-1, C-3 and C-5 trisubstituted bisindoles bearing glyoxylamide
functionality 6 as potent antimicrobial agents.12
N
H
N
R3
8
9a-d,
80-92%
O
H
N
R1
(i) (COCl)2, THF
(ii) tryptamine, N(Et)3
Recently, we have discovered 2-(30-indolyl)-N-arylthiazole-4-
carboxamides and carbazolyl glyoxamides 7 as anticancer and
antibacterial agents.13,14 Inspired from our previous results and
profound antibacterial and anticancer properties of bisindoles, in
this report we designed novel bis(indolyl)glyoxylamides by retain-
ing the key structural features of bisindoles and glyoxylamides as
depicted in Figure 2.
O
R2
N
N
H
R3
10a-n,
82-93%
Scheme 1. Synthesis of bis(indolyl)glyoxylamides 10a–n.
indole-3-glyoxylylchloride with tryptamine afforded bis(indolyl)-
glyoxylamide 10 in 82–93% yields.
Preparation of compound 10 was further simplified by
performing the reaction in a sequential one-pot fashion. From
the reaction of indole 9 and oxalyl chloride in situ generated
Bis(indolyl)glyoxylamides 10a–n were prepared by following
the synthetic route illustrated in Scheme 1. N-Alkyl indoles 9a–d
were prepared by following the reported reaction condition
in 80–92%.14 Initially, the reaction of indole
9 with oxalyl
chloride generated indole-3-glyoxylylchloride. Further reaction of
MeO
OMe
O
O
H
N
N
H
N
H
O
OMe
N
N
H
O
3,2'-Linked bis-indoles (5)
O
Br
Br
N
N
O
H
F
R1
R2
N
HN
O
O
O
N
N
H
R3
Bis(indolyl)glyoxylamides
O
N
O
N
Cl
Carbazolyl glyoxamide (7)
O
NH
O
Trisubstituted bis(indoles) (6)
Br
N
N
H
N
H
Rhopaladin C (2)
Figure 2. Rational design of bis(indolyl)glyoxylamides 10a–n.

M. P. Tantak et al. / Bioorg. Med. Chem. Lett. 26 (2016) 3167–3171
3169
Table 1
In vitro antibacterial activity of bis(indolyl)glyoxylamides
O
H
R1
N
O
R2
N
N
H
10a-n
R3
Compd
R1
R2
R3
ZOI (mm) and MIC (l
g/mL) valuesa
Gram-negative
Gram-positive
S. aureus
E. coli
P. putida
K. pneumoniae
B. subtilis
ZOI
MIC
ZOI
MIC
ZOI
MIC
ZOI
MIC
ZOI
MIC
10a
10b
10c
10d
10e
10f
10g
10h
10i
H
H
H
H
H
OMe
F
H
H
H
H
H
H
MeO
H
H
H
H
H
H
H
CH3
CH2CH3
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-FC6H4CH2
15
15
16
20
14
15
18
14
18
15
13
14
15
15
22
50
100
50
14
15
14
18
15
14
17
12
18
14
15
14
16
15
21
50
14
15
15
18
15
14
17
13
18
14
—
100
50
15
—
14
18
15
—
18
14
17
14
—
50
—
15
—
15
17
14
—
16
14
17
13
—
50
—
>100
25
100
—
OMe
Br
F
H
H
H
H
H
Br
MeO
F
H
H
100
100
12.5
>50
>100
>25
>100
12.5
>100
50
100
12.5
100
>50
25
>100
>12.5
>50
—
>100
>50
>100
16
100
>12.5
>100
—
>25
100
>25
100
—
>50
—
>100
16
12.5
>50
100
12.5
>50
12.5
100
>100
100
50
50
100
>25
100
—
100
—
10j
10k
10l
100
50
100
16
12
15
13
20
13
—
12
22
13
—
14
21
10m
10n
Chloramphenicol
100
16
>100
16
a
The zone of inhibition and MIC values for compounds with significant activity are shown in bold.
indole-3-glyoxalylchloride was subsequently treated with trypta-
mine and furnished bis(indolyl)glyoxylamides 10a–n in 82–93%
yields.15
E. coli (Fig. 3A), P. putida (Fig. 3B), B. subtilis (Fig. 3C) and S. aureus
(Fig. 3D) bacterial strains. In the case of Gram-negative bacteria,
these compounds showed 80–95% bactericidal activity within ini-
tial 2 h. This clearly indicates that these compounds showed fastest
bactericidal action by quickly inhibiting the bacterial proliferation
and thereafter achieving maximum bacterial reduction in the sub-
sequent hour. It is evident from Figure 3 that 10d was more effec-
tive with the higher killing activity when compared to derivatives
10g and 10i against Gram-negative bacteria. Similarly, for the
Gram-positive bacteria, compounds 10d, 10g, and 10i showed
good antibacterial activity by achieving bactericidal effect against
B. subtilis (>80%) and S. aureus (>65%), within initial 2 h of
incubation.
After assessing the antibacterial activity of bis(indolyl) glyoxy-
lamides 10a–n, we next evaluated their cytotoxicity against
human embryonic kidney 293 (HEK 293T), human prostate (PC-3
and castration-resistant prostate C4-2), cervical (HeLa), breast
(MDA-MB-231) and pancreatic BxPC-3 cancer cell lines using
MTT assay. The goal was to not only identify potent antibacterial
compounds but also ensure that they display minimal cytotoxicity
in mammalian cells. Doxorubicin was used as a reference drug and
the activity results are summarized in Table 2. Unsubstituted bis
(indolyl)glyoxalylamide 10a was found to be moderately active
Synthesized bis(indolyl)glyoxylamides 10a-n were initially
screened for in vitro antibacterial activity against two Gram-pos-
itive bacteria (Bacillus subtilis & Staphylococcus aureus) and three
Gram-negative bacteria (Escherichia coli, Pseudomonas putida, &
Klebsiella pneumonia). Chloramphenicol was used as a positive
control. The activity results in form of zone of inhibition (ZOI) and
minimum inhibitory concentration (MIC)) are given in Table 1.
Unsubstituted bis(indolyl)glyoxylamide 10a was moderately
active against the tested bacterial strains. Introduction of methoxy
or bromo group (compounds 10b and 10c) at C-5 position of indole
ring did not improve the activity. Interestingly, compound 10d
with fluorine substituent exhibited strong antibacterial activity
against all the tested bacterial strains with MIC values ranging
from 12.5 to 25 lg/mL (ZOI = 17–20 mm). Improved antibacterial
activity of 10d is likely due to the presence of fluorine, which is
known to enhance lipophilicity and stability of the molecule.16
By changing the position (C-5 to C-6) of methoxy and fluoro groups
in the indole ring resulted to inactive analogues 10e and 10f.
Methylation of indole N–H led to compound 10g with four-fold
(10a vs 10g) enhanced activity against Gram-negative bacteria
E. coli (MIC = 12.5
lg/mL). Replacement of N-methyl with N-ethyl
with IC50 value ranging 38–97 lM against the tested cell lines. Sub-
led to dramatic loss in activity (compound 10h). However, N-alky-
lation with a bulkier 4-chlorobenzyl group resulted in compound
10i with significantly improved (four-fold) activity against Gram-
stitution on indole ring was unfavourable for the activity except
compound 10f with 6-fluoro-indole moiety was found to be more
cytotoxic towards the tested cancer cells.
negative bacteria E. coli and P. putida (MIC = 12.5
l
g/mL;
Compound 10f exhibited moderate cytotoxicity against HeLa,
PC-3, MDA-MB-231 and BxPC-3 cells with IC50 values of 22.34,
24.05, 21.13 and 29.94 lM, respectively. Further, substitution on
indole N–H resulted in inactive compounds 10g–n. Most impor-
tantly, compounds 10d, 10g and 10i, which displayed potent
antibacterial activities, showed no toxicity in any of the human cell
lines even at 100 lM concentration, suggesting that these com-
pounds likely target bacterial-specific pathways. Notably, the com-
pound 10d was found to be stable at pH 4.5 and 7.4 up to 48 h,
however, it is sparingly soluble in water (0.3 lg/mL).
ZOI = 18 mm). Substituents such as bromo (10j), methoxy (10k
and 10m) and fluoro (10l) in the indole ring or replacement of
N-4-chlrobenzyl with N-4-flourobenzyl (10n) resulted in substantial
loss of activity (10i vs 10j–n). From the structure–activity relation-
ship study of bis(indolyl)glyoxyl-amides it was established that
combination of indole with 5-fluoroindole or N-alkyl (methyl or
4-chlorobenzyl) was favorable for the antibacterial activity.
Figure 3 represents the time dependent killing kinetics of
antimicrobial active compounds 10d, 10g and 10i against the

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M. P. Tantak et al. / Bioorg. Med. Chem. Lett. 26 (2016) 3167–3171
Figure 3. Time dependent killing of E. coli, P. putida, B. subtilis and S. aureus upon treatment with 10d, 10g and 10i (3 ꢁ MIC).
Table 2
In vitro anticancer activity of bis(indolyl)glyoxylamides
O
H
N
R1
R2
O
N
N
H
10a-n
R3
IC50
(l
M)a
Compd
R1
R2
R3
HEK 293T
C4-2
HeLa
PC-3
MDA-MB-231
BxPC-3
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
Doxorubicin
H
H
H
H
H
OMe
F
H
H
H
H
H
H
MeO
H
H
H
H
H
H
H
CH3
CH2CH3
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-FC6H4CH2
97.72
>100
>100
>100
>100
69.82
>100
>100
>100
>100
>100
>100
>100
>100
3.1
71.51
>100
>100
>100
>100
46.03
>100
>100
>100
>100
>100
>100
>100
>100
1.85
48.85
>100
>100
>100
>100
22.34
>100
>100
>100
>100
>100
>100
>100
>100
5
38.45
>100
>100
>100
>100
24.05
>100
>100
>100
>100
>100
>100
>100
>100
9.5
48.7
63.95
>100
>100
>100
>100
29.94
>100
>100
>100
>100
>100
>100
>100
>100
13
OMe
Br
F
H
H
H
H
H
Br
MeO
F
H
H
>100
>100
>100
>100
21.13
>100
>100
>100
>100
>100
>100
>100
>100
6.75
a
IC50 values are the mean of three different experiments performed in duplicate.
To determine the mode of cellular death caused by bis(indolyl)
were treated for 48 h, and cleaved PARP1 levels were analyzed
using immunoblot analysis. As shown in Figure 4, exposure of
PC-3 cells to either 10a or 10f resulted in increased levels of
glyoxylamides, compounds 10a (IC50 = 38.45
lM,) and 10f
(IC50 = 24.05 M) with moderate cytotoxicity against PC-3 cells,
l

M. P. Tantak et al. / Bioorg. Med. Chem. Lett. 26 (2016) 3167–3171
3171
5. Veale, C. G. L.; Zoraghi, R.; Young, R. M.; Morrison, J. P.; Pretheeban, M.; Lobb, K.
A.; Reiner, N. E.; Andersen, R. J.; Davies-Coleman, M. T. J. Nat. Prod. 2015, 78,
355.
6. Janosik, T.; Johnson, A.-L.; Bergman, J. Tetrahedron 2002, 58, 2813.
7. Sato, H.; Tsuda, M.; Watanabe, K.; Kobayashi, J. Tetrahedron 1998, 54, 8687.
8. Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M. J. Nat. Prod. 1994, 57, 1437.
9. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179.
10. Ma, Y.; Yakushijin, K.; Miyake, F.; Horne, D. Tetrahedron Lett. 2009, 50, 4343.
11. Mielczarek, M.; Devakaram, R. V.; Ma, C.; Yang, X.; Kandemir, H.; Purwono, B.;
Black, D. S.; Griffith, R.; Lewis, P. J.; Kumar, N. Org. Biomol. Chem. 2014, 12, 2882.
12. Singh, P.; Verma, P.; Yadav, B.; Komath, S. S. Bioorg. Med. Chem. Lett. 2011, 21,
3367.
13. Tantak, M. P.; Wang, J.; Singh, R. P.; Kumar, A.; Shah, K.; Kumar, D. Bioorg. Med.
Chem. Lett. 2015, 25, 4225.
14. Venkataramana Reddy, P.; Tantak, M. P.; Valdez, R.; Singh, R. P.; Singh, O. M.;
Sadana, R.; Kumar, D. RSC Adv. 2016, 6, 9379.
Figure 4. Immunoblot analysis of cleaved PARP1 protein with 10a and 10f in PC-3
cells.
15. General procedure for the preparation of bis(indolyl) glyoxylamides 10a–n: To a
cooled (0 °C) solution of indole 9 (1.7 mmol) in THF (5 mL) was added oxalyl
chloride (0.227 g, 1.7 mmol) and the resulting mixture was stirred at same
temperature for 1 h. Subsequently, tryptamine (0.28 g, 1.7 mmol) and
triethylamine (1 mL, 5.4 mmol) were added at 25 °C and the contents were
allowed to stir for 4 h. Upon completion of the reaction as indicated by TLC,
solvent was removed in vacuuo. The residue so obtained was purified by
column chromatography using ethyl acetate:hexane as an eluent to obtain
pure bis(indolyl)-glyoxalylamides 10a-n in 82-93% yields.
cleaved PARP1, thereby, confirming that both the compounds led
to apoptotic induced cell death in PC-3 cells.
In summary, we have synthesized and investigated antibacte-
rial and anticancer activities of fourteen novel bis(indolyl)glyoxy-
lamides 10a–n. Compounds 10d, 10g and 10i were identified
with significant activities and could be promising candidates as
antibacterial agents. Cell death assay study revealed that 10d
was more effective by exerting higher killing activity against the
Gram-negative bacterial pathogens. Furthermore, in anticancer
activity evaluation of bis(indolyl)glyoxylamides led to compounds
10a and 10f with moderate activity against the tested cancer lines.
Exposure of PC-3 cells to either 10a or 10f resulted in the enhance-
ment of cleaved PARP1 levels, indicating that bis(indolyl)glyoxy-
lamides induced apoptosis in PC-3 cells.
Spectral data for selected compounds: N-(2-(1H-Indol-3-yl)ethyl)-2-(1H-indol-3-
yl)-2-oxoacetamide (10a): Yield 87%, off white solid. Mp 199–201 °C (Lit. 198–
200 °C);3b IR (KBr, v cmꢂ1) 3402, 3393, 3279, 1666, 1620, 1504, 1435, 1234,
1134; 1H NMR (400 MHz, DMSO-d6) d 12.27 (s, 1H), 10.86 (s, 1H), 8.85 (t,
J = 5.3 Hz, 1H), 8.77 (s, 1H), 8.28–8.19 (m, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.54 (d,
J = 6.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.30–7.23 (m, 2H), 7.21 (s, 1H), 7.07 (t,
J = 7.4 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 3.54–3.49 (m, 2H), 2.95 (t, J = 7.3 Hz, 2H);
13C NMR (101 MHz, DMSO-d6) d 182.7, 163.9, 139.0, 136.7, 127.7, 126.7, 123.9,
123.2, 123.0, 121.8, 121.4, 118.8, 118.7, 113.0, 112.6, 112.1, 111.9, 39.9, 25.4;
ESI(FAB) m/z calcd for C20H18N3O2: 332.14 (M+H)+, found 332.15 (M+H)+ and
354.12 (M+Na)+. 5-(1H-Indol-3-yl)-1-(5-methoxy-1H-indol-3-yl)pentane-1,2-
dione (10b): Yield 82%, pale yellow solid, m.p. 157-158 °C; IR (KBr, v cmꢂ1):
3394, 3294, 3202, 1597, 1481, 1435, 1265, 1211, 1142, 802, 741, 447, 401; 1H
NMR (400 MHz, DMSO-d6): d 12.15 (s, 1H), 10.86 (s, 1H), 8.80 (t, J = 5.9 Hz, 1H),
8.71 (d, J = 3.3 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.44 (d,
J = 8.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 7.10–7.06 (m,
1H), 6.99 (t, J = 7.2 Hz, 1H), 6.95–6.85 (m, 1H), 3.80 (s, 3H), 3.54–3.49 (m, 2H),
2.96 (t, J = 7.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) d 182.4, 164.0, 156.4,
139.0, 136.7, 131.5, 127.7, 123.1, 121.4, 118.8, 118.8, 113.8, 113.3, 112.5, 112.0,
111.9, 103.9, 55.8, 39.3, 25.3; ESI(FAB) m/z calcd for C21H19N3O3: 362.39 (M
+H)+, found 362.15 (M+H)+ and 384.12 (M+Na)+. N-(2-(1H-Indol-3-yl)ethyl)-2-
(5-bromo-1H-indol-3-yl)-2-oxoacetamide (10c): Yield 84%, yellow solid, mp
198–200 °C; IR (KBr, v cmꢂ1): 3418, 3256, 1605, 1504, 1435, 1366, 1227, 1219,
1134, 795, 748, 602, 463, 447, 401; 1H NMR (400 MHz, DMSO-d6): d 12.44 (s,
1H), 10.86 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.82 (d, J = 3.1 Hz, 1H), 8.36 (d,
J = 1.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.6,
2.0 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.07 (t, J = 7.0 Hz,
1H), 6.99 (t, J = 7.0 Hz, 1H), 3.54–3.49 (m, 2H), 2.95 (t, J = 7.5 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) d 182.6, 163.5, 140.1, 136.6, 135.5, 128.5, 127.6, 126.5,
123.8, 123.2, 121.4, 118.8, 115.8, 115.2, 112.3, 111.8, 39.3, 25.3; ESI(FAB) m/z
calcd for C20H15BrN3O2: 408.10 (MꢂH)+, found 408.10 (M-H)+. N-(2-(1H-Indol-
3-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)-2-oxoacetamide (10d): Yield 93%, cream
colour solid, mp 241–242 °C; IR (KBr, v cmꢂ1): 3410, 3356, 3279, 1659, 1620,
1504, 1435, 1234, 1180, 1134, 802, 741, 447, 401; 1H NMR (400 MHz, DMSO-
d6): d 12.37 (s, 1H), 10.86 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.84 (s, 1H), 7.92 (dd,
J = 9.7, 2.6 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.8, 4.6 Hz, 1H), 7.35 (d,
J = 8.1 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.17–7.11 (m, 1H), 7.10–7.04 (m, 1H),
7.02–6.96 (m, 1H), 3.55–3.50 (m, 2H), 2.96 (t, J = 7.5 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) d 182.5, 163.6, 160.6, 158.3, 140.4, 136.7, 133.3, 127.7,
127.5, 127.4, 123.2, 121.4, 118.8, 118.7, 114.4, 114.3, 112.7, 112.6, 112.1, 112.0,
111.9, 106.8, 106.6, 39.3, 25.3; ESI(FAB) m/z calcd for C20H17FN3O2: 350.13 (M
+H)+, found 350.12 (M+H)+.
Acknowledgments
We gratefully acknowledge the financial support received from
DBT, New Delhi, India (BT/278/NE/TBP/2011 to D.K.) and NIH, USA
(R03 CA166912 to K.S.).
Supplementary data
Supplementary data (experimental procedures and characteri-
zation data for compounds 10a–n) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/j.
bmcl.2016.04.080.
References and notes
1. (a) Pauletti, P. M.; Cintra, L. S.; Braguine, C. G.; Cunha, W. R.; Januário, A. H. Mar.
Drugs 2010, 8, 1526; (b) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.
H.; Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620.
2. Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489.
3. (a) Yang, C.-G.; Huang, H.; Jiang, B. Curr. Org. Chem. 2004, 8, 1691; (b) Gupta, L.;
Talwar, A.; Palne, S.; Gupta, S.; Chauhan, P. Bioorg. Med. Chem. Lett. 2007, 17,
4075.
4. Gupta, L.; Talwar, A.; Chauhan, P. M. Curr. Med. Chem. 2007, 14, 1789.
16. Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.