A new class of bactericidal agents against S. aureus, MRSA and VRE derived from bisindolylmethane

Article abstract of DOI:10.1007/s00044-013-0764-4

A series of bisindolylmethanes (BIMs) (1a -7j) including hybrid BIMs 6a-6c were prepared for bioevaluation. The results of initial antimicrobial screening of compounds 1a-6c showed compounds 2b, 2m, 4a and 5b to be the most potent inhibitors, exhibiting M

Full text of DOI:10.1007/s00044-013-0764-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1643–1653
DOI 10.1007/s00044-013-0764-4
ORIGINAL RESEARCH
A new class of bactericidal agents against S. aureus, MRSA
and VRE derived from bisindolylmethane
•
Deepak K. Sharma Anil K. Tripathi Rashmi Sharma Reena Chib
•
•
•
•
Reyaz ur Rasool Altaf Hussain Baldev Singh Anindya Goswami
•
•
•
•
Inshad A. Khan Debaraj Mukherjee
Received: 6 June 2013 / Accepted: 23 August 2013 / Published online: 4 September 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of bisindolylmethanes (BIMs) (1a–7j)
including hybrid BIMs 6a–6c were prepared for bioeval-
uation. The results of initial antimicrobial screening of
compounds 1a–6c showed compounds 2b, 2m, 4a and 5b
to be the most potent inhibitors, exhibiting MIC as well as
MBC values equal to or less than that of ciprofloxacin
(0.5–2 lg/mL) against Staphylococcus aureus, MRSA and
VRE. Compound 2m was selected further to study the
effect of N,N0 disubstitution towards antibacterial and
antitumor activity. It was observed that substitution at N,N0
position (7a–7j) of 2m diminishes its antibacterial activity
though in vitro antitumour activity against a panel of
prostate, cervical and lung cancer cell lines remains more
or less intact.
Introduction
The widespread and inappropriate use of antibiotics has
given rise to the development of resistance in a variety of
pathogenic microorganisms (Hancock, 2005). Bacterial
pathogens such as methicillin-resistant Staphylococcus
aureus; vancomycin-resistant enterococci (VRE); multi-
drug-resistant Escherichia coli, Pseudomonas aeruginosa
and Acinetobacter baumannii have acquired the status of
superbugs (Rybak, 2004). While it is easy to find com-
pounds that kill bacteria, it is hard to find novel antibac-
terial classes worthy of development. The arsenal of
antibacterial agents is restricted to antibiotics like linezolid,
daptomycin, quinupristin–dalfopristin, tigecycline and
ceftobiprole as promising agents against VRE and MRSA
(Aksoy and Unal, 2008). Nevertheless, these antibiotics
have limitation regarding poor absorption and serious side
effects. Particularly linezolid, the most potent and fre-
quently used antibiotic, is bacteriostatic against most sus-
ceptible organisms but displays poor bactericidal activity
against some strains (Ament et al., 2002).
Keywords Bisindolylmethanes ꢀ Antimicrobial ꢀ
MRSA ꢀ VRE ꢀ MBC ꢀ Antiproliferative
Indole and its derivatives are known as an important
class of heterocyclic compounds in pharmaceutical as well
as synthetic chemistry (Sundberg, 1996). The most ubiq-
uitous of the known bioactive alkaloids are based on the
indole moiety. Particularly bisindolylmethanes (BIMs)
widely occur in various natural products isolated from
marine sponge alkaloids (Oh et al., 2006) and exhibit a
wide range of biological activities (Azmi et al., 2008;
Rahman and Sarkar, 2005; Gong et al., 2006). In our earlier
communication, we designed synthesis of N,N0-glycoside
derivatives of BIMs for their antiproliferative potential
against various cancer cell lines (Sharma et al., 2012).
However, use of BIM and its derivatives for antibacterial
activities is limited (Kamal et al., 2009). In a programme
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0764-4) contains supplementary
material, which is available to authorized users.
D. K. Sharma ꢀ R. Sharma ꢀ R. Chib ꢀ R. ur Rasool ꢀ
A. Hussain ꢀ D. Mukherjee
Academy of Scientific and Innovative Research (AcSIR),
New Delhi, India
D. K. Sharma ꢀ A. K. Tripathi ꢀ R. Sharma ꢀ R. Chib ꢀ
R. ur Rasool ꢀ A. Hussain ꢀ B. Singh ꢀ A. Goswami ꢀ
I. A. Khan ꢀ D. Mukherjee (&)
CSIR-IIIM (Indian Institute of Integrative Medicine),
Canal Road, Jammu 180001, J&K, India
e-mail: debarajrrl@gmail.com; dmukherjee@iiim.ac.in
123

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Med Chem Res (2014) 23:1643–1653
directed towards the synthesis of indole-based new chem-
ical entities which will be bacteriostatic as well as bacte-
ricidal, we synthesize BIM derivatives which are inhibitors
of S. aureus, MRSA and VRE. Further their SAR has been
carried out for antimicrobial and anticancer properties.
5-bromoindole (viz. 2a) were found to be more active than
those with unsubstituted indole (1a). Keeping 5-bromoin-
dole intact and bringing change in the aldehyde portion, we
observed that compound 2b possessed the highest activity
among the synthesized compounds (2a–3b). Tests with
compounds 2a–3b revealed that BIMs confer higher
activity if prepared from benzaldehydes carrying electron-
withdrawing substituents (2m–2p) than electron-donating
ones (2d–2h). BIMs having electron-withdrawing substit-
uents at para position of benzaldehyde (2m, 2n and 2p)
were found to be active having MIC value in the range
1–8 lg/mL for Gram-positive strains (except compound
2o). In the series of compounds 2m–2o, as the electroneg-
ativity of the substituent increases, an increase in antibac-
terial activity is noted. In case of electron-donating groups,
monosubstituted product 2d was more active than disub-
stituted products (2e–2h). None of the aliphatic aldehydes-
and ketones-derived BIMs (2q–2s and 3a–3b) were found
to be active. From the observed antimicrobial activities of
compounds 1a–3b, we come to the conclusion that products
derived from 5-bromoindole with substituted 4-hydroxy/4-
fluorobenzaldehyde (2b/2m) are most active in this series,
exhibiting MIC of 0.5–2 lg/mL against S. aureus, MRSA
and VRE. Ciprofloxacin was used as a control drug.
Results and discussion
BIMs with a common structure (Scheme 1, Table 1) were
synthesized using our previously developed Fe/Al-pillared
catalyst (Sharma et al. 2013). Variations were made both in
the five position of indole and R1, R2 mentioned in the
Scheme 1.
Due to considerable antifungal (Goel et al., 2012) and
antibacterial (Ronad et al., 2010) properties of benzopyrans
we then used ketone derived from benzopyran core with
indole to obtain new hybride molecules (6a–6c) in mod-
erate yield (Scheme 2) under optimized condition (Sharma
et al., 2013).
For SAR studies, title compounds (1a–6c) were evalu-
ated in vitro for antimicrobial activities. Table 2 shows the
antibacterial activity as minimum inhibitory concentration
(MIC) of the synthesized compounds. BIMs containing
Table 1 Synthesis of bisindolylmethanes using different substituted indoles and carbonyl compounds (ketones and aldehydes)
X
X
R2
R1
"Solvent Free"
(Fe/Al pillared clay-425 οC)
X
O
+
90oC, 10-30min.
R1
NH
HN
R2
N
H
bisindolylmethanes
(1a - 5b, 81-96%)a
Scheme 1:
1a, R1 = phenyl, R2 = X = H, 96 %
2a-p, R2 = H, X = Br
2n, R1 = 4-Cl-phenyl, 94 %
2o, R1 = 4-Br-phenyl, 93 %
2p, R1 = 4-NO2-phenyl, 92 %
2q, R1 = n-C3H7, 89 %
2a, R1 = phenyl, 92 %
2b, R1 = 4-OH-phenyl, 95 %
2c, R1 = 3-OH-phenyl, 92 %
2d, R1 = 4-OMe-phenyl, 91 %
2e, R1 = 2,3-(OMe)2-phenyl, 91 %
2f, R1 = 2,4-(OMe)2-phenyl, 87 %
2g, R1 = 3,4-(OMe)2-phenyl, 89 %
2h, R1 = 2,5-(OMe)2-phenyl, 88 %
2r, R1 = n-C7H15, 86 %
2s, R1 = n-C8H17, 81 %
3a, R1 = CH3, R2 = CH3, 83 %
3b, R1 = phenyl, R2 = CH3, 81 %
4a-b, X = NO2, R2 = H
4a, R1 = 4-OH-phenyl, 92 %
4b, R1 = 4-F-phenyl, 94 %
5a-b, X = CN, R2 = H
2i, R1 = 5-bromo-2-methoxy-phenyl, 87 %
2j, R1 = 4-NMe2-phenyl, 89 %
2k, R1 = cyclohexyl, 85 %
5a, R1 = 4-OH-phenyl, 94 %
5b, R1 = 4-F-phenyl, 95 %
2l, R1 = 2-naphthyl, 86 %
2m, R1 = 4-F-phenyl, 94 %
a
Isolated yield
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Med Chem Res (2014) 23:1643–1653
1645
Scheme 2 Synthesis of hybrid
bisindolylmethanes
a pyrrolidine, benzene, 3h,
reflux b Fe/Al-pillared clay
-425 °C, 90 °C, 30 min
O
OR
HO
OR
O
(a)
+
O
O
ketones
benzopyrans
resorcinols
OR
O
Br
Br
Br
N
H
(b)
5-bromoindole
N
N
H
H
6a, R= H
6b, R= CH3
6c, R= CH2CH3
Further to study the effect of 5-substituent at indole,
BIM derivatives using 5-nitroindole (4a and 4b) and
5-cyanoindole derivatives (5a and 5b) were synthesized
using 4-hydroxybenzadehyde and 4-fluorobenzaldehyde. It
was observed that compounds 4a and 5b are less active
than their halogenated analogue 2b but as active as com-
pound 2m as shown in Table 2. Compounds 4b and 5a
were found to be inactive.
N-sulphonyl (7i–7j) derivatives as shown in Scheme 3.
These compounds were further evaluated for antimicrobial
activity as shown in Table 3.
Table 3 shows that free –NH moiety of BIMs plays a
significant role which is essential for antimicrobial activity.
Any kind of substitution on –NH moiety of BIM will
decrease its biological activity.
In continuation of our previous work of getting indole-
based new chemical entities for antiproliferative potential
(Sharma et al., 2012), N,N0-substituted BIMs were evalu-
ated against various cancer cell lines (Koppikar et al.,
2010) as shown in Table 4. The synthesized analogues (7a-
7j) were found to be less active than their parent compound
2m except compound 7e which shows promising activity
(1.1 lmol, IC50) against HeLa cell line.
Among the series of synthesized hybrid molecules 6a–
6c, compound 6a was found to be highly active. As we
replace the hydroxy group of benzopyran with methoxy
(compound 6b) and ethoxy (compound 6c) groups, anti-
microbial activity decreases.
In a series of synthesized BIM derivatives 1a–6c, some
compounds exhibited varied levels of activity against
Gram-positive bacteria. Minimum bactericidal concentra-
tion (MBC) was determined only for those compounds
exhibiting MIC up to 64 lg/mL which we consider as
moderately active. The MBC value of active compounds are
shown in brackets in Table 2. A compound is considered to
exhibit bactericidal activity if the ratio of MBC and MIC
\4. All the active compounds were found to be bactericidal
in nature. Compound 2b is found to be equally potent in
case of S. aureus and more potent in resistant strain (MRSA
and VRE) than standard drug molecule ciprofloxacin in
terms of MBC values. None of these compounds (1a–6c)
showed antimicrobial activity against Gram-negative bac-
teria (Escherichia coli ATCC 25922 and Pseudomonas
aeruginosa ATCC 27853) and fungal strains.
Experimental section
Chemistry
General procedure for the synthesis of 1a–6c
3-((1H-Indol-3-yl)(phenyl)methyl)-1H-indole (1a) It was
obtained as pink solid, mp 140–142 °C. IR (KBr) m 3378
(NH), 1602(C=C) cm-1. 1H NMR (CDCl3, 500 MHz) d 5.
86 (s, 1H, CH), 6.66 (s, 2H, H-2, 20), 7.11 (t, J = 6.9 Hz,
2H, H-5, 50), 7.14–7.22 (m, 3H, Ar-2, 20, ArH-4), 7.28–7.31
(m, 2H, ArH-3, 30), 7.35–7.42 (m, 6H, H-4, 40, 6, 60, 7, 70),
7.93 (brs, 2H, NH). 13C NMR (CDCl3 125 MHz) indole
[136.9 (C-70), 128.6 (C-2, 20), 127.0 (C-30), 121.2 (C-5),
119.4 (C-6), 118.4 (C-4, 40), 111.8 (C-7), 110.8 (C-3)]
Phenyl [145.3 (C-1), 128.5 (C-2, 20), 126.3 (C-3, 30), 123.9
(C-4)], 31.5 (CH). MS: (m/z) [M?Na]? 345. Anal. Calcd.
for C23H18N2: C, 85.68; H, 5.63; N, 8.69. Found: C, 85.62;
H, 5.60; N, 8.63.
Among potent molecules compound 2m was selected to
study the effect of N,N0-disubstitution towards antibacterial
over other molecules with comparable activity such as 2b,
4a and 5b due to the absence of free hydroxy group in the
former. So we created a library out of an active compound
2m, where nitrogen of the indole is protected with different
substituents like N-alkyl (7a–7c), N-benzyl (7d–7h) and
123

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Med Chem Res (2014) 23:1643–1653
4-(Bis(5-bromo-1H-indol-3-yl)methyl)phenol (2b) It was
obtained as red solid, mp 215–225 °C. IR (KBr) m 3402
Table 2 Antimicrobial activities of BIM derivatives
Compound
MIC (lg/mL)a
(OH), 3388 (NH), 1613(C=C) cm-1 1H NMR (CDCl3
.
S. aureus
MRSA
VRE
500 MHz) d 5.68 (s, 1H, CH), 6.63 (s, 2H, H-2, 20), 6.77 (d,
J = 8.5 Hz, 2H, ArH-3, 30), 7.13 (d, J = 8.5 Hz, 2H, ArH-
2, 20), 7.23 (d, J = 8.7 Hz, 2H, H-7,70), 7.25 (d, J = 8.
7 Hz, 2H, H-6, 60),7.47 (s, 2H, H-4, 40). 13C NMR (CDCl3
125 MHz) 5-Br-indole [135.4 (C-70), 128.6 (C-30), 124.
7(C-2), 124.6 (C-6), 122.3 (C-4), 119.2 (C-5), 112.6 (C-
7),112.6 (C-3)], 4-OH-Phenyl [154.1 (C-4), 129.6(C-1),
124.9 (C-2,20), 115.2 (C-3,30)], 39.0 (CH). ESI MS: (m/z)
[M?Na]? 519. Anal. Calcd. for C23H16Br2N2O: C, 55.67;
H, 3.25; N, 5.65. Found C, 55.57; H, 3.35; N, 5.57.
1a
[256
256
[256
256
[256
256
2(2)b
2a
2b
0.5 (0.5)b
1(1)b
16(32)b
256
1(1)b
2(2)b
32(32)b
256
2c
4(8)b
2d
32(32)b
[256
[256
256
2e
2f
256
256
2g
128
256
2h
128
256
[256
256
2i
128
256
3-(Bis(5-bromo-1H-indol-3-yl)methyl)phenol (2c) It was
obtained as red solid, mp 210–220 °C. IR (KBr) m 3479
2j
64
128
256
2k
16(32)b
16(16)b
1(1)b
4(4)b
8(16)b
4(4)b
[256
[256
[256
[256
[256
1(1)b
[256
[256
1(1)b
2(2)b
4(4)b
8(8)b
0.25 (0.5)b
32(32)b
32(32)b
1(1)b
8(8)b
32(64)b
8(8)b
[256
[256
[256
[256
[256
1(1)b
[256
[256
1(1)b
2(2)b
4(8)b
32(32)b
16(32)b
32(32)b
32(32)b
8(16)b
8(8)b
64(64)b
8(8)b
1
(OH), 3378 (NH), 1611 (C=C) cm-1. H NMR (CDCl3
2l
500 MHz) d 5.68 (s, 1H, CH), 6.53 (s, 1H, ArH-2), 6.57 (d,
J = 8.5 Hz, 2H, ArH-4), 6.61 (d, J = 8.5 Hz, 2H, ArH-6),
6.67 (s, 2H, H-2, 20), 6.9 (m, 1H, ArH-5), 7.23 (d, J = 8.
7 Hz, 2H, H-7,70), 7.25 (d, J = 8.7 Hz, 2H, H-6, 60),7.47
(s, 2H, H-4, 40). 13C NMR (CDCl3 125 MHz) 5-Br-indole
[135.3 (C-70), 128.7 (C-30), 124.5(C-2), 124.2 (C-6), 122.1
(C-4), 119.3 (C-5), 112.7 (C-7),112.6 (C-3)], 3-OH-Phenyl
[154.1 (C-3), 139.6(C-1), 130.2 (C-5), 123.1 (C-6), 114.9
(C-2), 112.9 (C-4)], 39.0 (CH). ESI MS: (m/z) (M?Na)?
519. Anal. Calcd. for C23H16Br2N2O: C, 55.67; H, 3.25; N,
5.65. Found C, 55.61; H, 3.30; N, 5.61.
2m
2n
2o
2p
2q
[256
[256
[256
[256
[256
2(2)b
2r
2s
3a
3b
4a
4b
[256
[256
8(8)b
4(4)b
8(8)b
32(32)b
64(64)b
5a
5-Bromo-3-((5-bromo-1H-indol-3-yl)(4-methoxyphenyl)
methyl)-1H-indole (2d) It was obtained as red solid, mp
276–286 °C. IR (KBr) m 3318 (NH), 1603 (C=C), 1303 (C–
O) cm-1. 1H NMR (CDCl3 200 MHz) d 3.73 (s, -OCH3), 5.
34 (s, CH), 6.62 (s, 2H, H-2, 20), 6.50 (d, J = 8.3 Hz, 2H,
ArH-3, 30), 6.70 (d, J = 8.3 Hz, 2H, ArH-2, 20), 7.21–7.26
(m, 4H, H-6, 60, 7, 70), 7.65 (s, 2H, H-4, 40), 7.98 (s, 2NH).
13C NMR (CDCl3 50 MHz) 5-Br-indole [135.3 (C-70), 128.
7 (C-30), 124.7(C-2), 124.5 (C-6), 122.1 (C-4), 119.3 (C-5),
112.7 (C-7), 112.6 (C-3)], 4-OCH3-Phenyl [157.1 (C-
4),130.1 (C-1) 129.6 (C-2,20), 115.2 (C-3,30), 55.3
(OCH3)], 38.9 (CH). ESI MS: (m/z) [M?Na]?533.3. Anal.
Calcd. for C24H18Br2N2O: C, 56.50; H, 3.56; N, 5.49.
Found C, 55.57; H, 3.55; N, 5.54.
5b
6a
6b
6c
Ciprofloxacin
a
MIC value
b
MBC value
5-Bromo-3-((5-bromo-1H-indol-3-yl)(phenyl)methyl)-1H-
indole (2a) It was obtained as red solid, mp
1
245–256 °C. IR (KBr) m 3416 (NH), 1607(C=C) cm-1. H
NMR (CDCl3, 500 MHz): d 5.86 (s, 1H, CH), 6.91 (s, 2H,
H-2, 20), 7.14–7.19 (m, 3H, Ar-2, 20, ArH-4), 7.20–7.31
(m, 4H, ArH-3, 30, H-6, 60, 7, 70), 7.65 (s, 2H, H-4, 40), 7.
98 (s, 2NH). 13C NMR (CDCl3 125 MHz) 5-Br-indole
[135.2 (C-70), 128.6 (C-30), 124.6 (C-2), 122.6 (C-6), 122.
0 (C-4), 119.6 (C-5), 112.5 (C-7), 112.3 (C-3)], Phenyl
[145.3 (C-1), 128.5 (C-2, 20), 126.3 (C-3, 30), 123.9 (C-
4)], 39.5 (CH). MS: (m/z) [M?Na]? 503. Anal. Calcd. for
C23H16Br2N2: C, 57.53; H, 3.36; N, 5.83. Found: C, 57.
62; H, 3.30; N, 5.73.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(2,3-dimethoxyphenyl)
methyl)-1H-indole (2e) It was obtained as red solid, mp
285–295 °C. IR (KBr) m 3328 (NH), 1613 (C=C), 1317 (C–
O) cm-1. 1H NMR (CDCl3 200 MHz) d 3.73 (s, -OCH3), 3.
78 (s, -OCH3), 5.34 (s, 1H, CH), 6.47–6.59 (m, 3H, ArH-4,
5, 6), 6.92 (s, 2H, H-2, 20), 7.21–7.26 (m, 4H, H-6, 60, 7,
70), 7.65 (s, 2H, H-4, 40), 7.98 (s, 2NH). 13CNMR (CDCl3
50 MHz) 5-Br-indole [135.2 (C-70), 128.7 (C-30), 124.7(C-
2), 124.5 (C-6), 122.0 (C-4), 119.6 (C-5), 112.3 (C-7),112.
123

Med Chem Res (2014) 23:1643–1653
1647
Scheme 3 Synthesis of
N-substituted
F
F
bisindolylmethanes of an active
compound 2m a KOH, DMSO,
rt 3 h
Br
Br
Br
Br
(a)
R-Br/ R-Cl
+
R=alkyl, benzyl,
sulfonyl dvt.
N
R
N
R
NH
HN
(2m)
(7a - 7k)
7a, R= CH3
7d, R=
7b, R=
7c, R=
7f, R=
7i, R=
7e, R=
Cl
F
F
O O
S
7g, R=
7h, R=
MeO
Br
O O
S
7j, R=
MeO
Table 3 Antimicrobial activities N,N0-substituted BIM derivatives
0 (C-3)], 2,3-(OMe)2-Phenyl [150.1 (C-2), 149.4 (C-3),
124.3 (C-1), 122.4 (C-6), 122.1(C-5), 112.5 (C-4), 56.5
(OCH3 at C-2), 56.3 (OCH3 at C-3)], 39.3 (CH). ESI MS:
(m/z) [M?Na]? 563. Ana.l Calcd. for C25H20Br2N2O2: C,
55.58; H, 3.73; N, 5.19. Found C, 55.60; H, 3.75; N, 5.14.
Compound
MIC (lg/mL)a
S. aureus
MRSA
VRE
7a
4 (4)b
8 (8)b
[128
16 (32)b
8 (8)b
[128
64 (64)b
7b–7j
[128
0.25 (0.5)b
Ciprofloxacin
5-Bromo-3-((5-bromo-1H-indol-3-yl)(2,4-dimethoxyphenyl)
methyl)-1H-indole (2f) It was obtained as red solid, mp
295–305 °C. IR (KBr) m 3313 (NH), 1611 (C=C), 1307 (C–
O) cm-1. 1H NMR (CDCl3 200 MHz) d 3.73 (s, 2x-OCH3),
5.34 (s, 1H, CH), 6.16 (s, 1H, ArH-3), 6.20 (d, J = 8.5 Hz,
1H, ArH-5), 6.80 (d, J = 8.5, 1H, ArH-6), 6.92 (s, 2H, H-2,
20), 7.21-7.26 (m, 4H, H-6, 60, 7, 70), 7.65 (s, 2H, H-4, 40),
7.98 (s, 2NH). 13CNMR (CDCl3 50 MHz) 5-Br-indole
[135.2 (C-70), 128.7 (C-30), 124.7 (C-2), 124.5 (C-6), 122.0
(C-4), 119.3 (C-5), 112.7 (C-7), 112.6 (C-3)], 2,4-(OMe)2-
Phenyl [159.4 (C-2), 157.2 (C-4), 131.2 (C-6), 115.7 (C-1),
110.3 (C-5), 101.1 (C-3), 56.4 (OCH3 at C-2), 56.3 (OCH3
at C-4)], 39.0 (CH). ESI MS: (m/z) [M?Na]? 563. Anal.
Calcd. for C25H20Br2N2O2: C, 55.58; H, 3.73; N, 5.19.
Found C, 55.56; H, 3.75; N, 5.14.
a
MIC value
b
MBC value
Table 4 Cytotoxic effects of compounds 2m and 7a–7j on PC-3,
HeLa and A-549 human cancer cells
Compound
IC50 lmola
PC-3
HeLa
A-549
2m
7a
7b
7c
7d
7e
7f
3.9 0.010
38.9 0.361
40.3 0.100
44.9 0.200
43.1 0.100
36.5 0.110
38.5 0.020
43.7 0.044
43.5 0.165
[100
2.7 0.173
25.4 0.111
27.2 0.165
32.4 0.177
28.3 0.176
1.1 0.090
18.5 0.180
49 0.430
48.5 0.265
[100
4.5 0.061
29.4 0.144
32.5 0.035
38.7 0.026
28.2 0.187
8.7 0.008
22.8 0.173
24.7 0.046
36.4 0.090
[100
5-Bromo-3-((5-bromo-1H-indol-3-yl)(3,4-dimethoxyphenyl)
methyl)-1H-indole (2g) It was obtained as red solid, mp
285–295 °C. IR (KBr) m 3321 (NH), 1622 (C=C), 1303 (C–O)
cm-1. 1H NMR (CDCl3 200 MHz) d 3.73 (s, 2x-OCH3), 5.34
(s, 1H, CH), 6.46 (s, 1H, ArH-2), 6.50 (m, 2H, ArH-5, 6), 6.92
(s, 2H, H-2, 20), 7.21–7.26 (m, 4H, H-6, 60, 7, 70), 7.65 (s, 2H,
H-4, 40), 7.98 (s, 2NH). 13CNMR (CDCl3 100 MHz) 5-Br-
indole [135.3 (C-70), 128.7 (C-30), 124.7 (C-2), 124.5 (C-6),
122.1 (C-4), 119.3 (C-5), 112.7 (C-7),112.6 (C-3)], 3,4-
(OMe)2-Phenyl [149.4 (C-3), 146.2 (C-4), 129.7 (C-1), 122.4
(C-6), 115.2 (C-5), 114.3 (C-2), 56.3 (OCH3 at C-3 and C-4)],
7g
7h
7i
7j
[100
[100
[100
a
IC50 values are indicated as the mean ?SD of three independent
experiments
39.1 (CH). ESI MS: (m/z) [M?Na]? 563. Anal. Calcd. for
C25H20Br2N2O2: C, 55.58; H, 3.73; N, 5.19. Found C, 55.61; H,
3.71; N, 5.17.
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Med Chem Res (2014) 23:1643–1653
6 (C-30), 124.6 (C-2), 122.6 (C-6), 122.0 (C-4), 119.6 (C-5),
112.5 (C-7), 112.3 (C-3)], cyclohexyl [41.3 (C-1), 30 (C-2,
20), 28.4 (C-3, 30), 26.2 (C-4)], 37.3 (CH). ESI MS: (m/z)
[M?Na]? 509. Anal. Calcd. for C23H22Br2N2: C, 56.81; H,
4.56; N, 5.76. Found C, 56.86; H, 4.53; N, 5.78.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(2,5-dimethoxyphenyl)
methyl)-1H-indole (2h) It was obtained as red solid, mp
275–285 °C. IR (KBr) m 3348 (NH), 1606 (C=C), 1309 (C–
O) cm-1. 1H NMR (CDCl3 200 MHz) d 3.73 (s, 2x-OCH3),
5.34 (s, 1H, CH), 6.41–6.58 (m, 3H, ArH-3, 4, 6), 6.92 (s,
2H, H-2, 20), 7.21–7.26 (m, 4H, H-6, 60, 7, 70), 7.65 (s, 2H,
H-4, 40), 7.98 (s, 2NH). 13CNMR (CDCl3 50 MHz) 5-Br-
indole [135.1 (C-70), 128.7 (C-30), 124.7 (C-2), 124.5 (C-6),
122.1 (C-4), 119.3 (C-5), 112.7 (C-7),112.6 (C-3)], 2,5-
(OMe)2-Phenyl [150.1 (C-5), 149.2 (C-2), 124.7 (C-1),
115.4 (C-3), 113.0 (C-6), 112.0 (C-4), 56.5 (OCH3 at C-2),
56.5 (OCH3 at C-5], 39.0 (CH). ESI MS: (m/z) [M?Na]?
563. Anal. Calcd. for C25H20Br2N2O2: C, 55.58; H, 3.73;
N, 5.19. Found C, 55.54; H, 3.75; N, 5.16.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(naphthalen-2-yl)me-
thyl)-1H-indole (2l) It was obtained as red solid; mp
170–180 °C. IR (KBr) m 3378 (NH), 1611 (C=C) cm-1. 1H
NMR (CDCl3 200 MHz) d 5.34 (s, 1H, CH), 6.72 (s, 2H,
H-2, 20), 7.18–7.67 (m, 11H, H-6, 60, 7, 70, 7 9 ArH nap-
thyl), 7.69 (s, 2H, H-4, 40), 7.99 (s, 2NH). 13CNMR (CDCl3
50 MHz) 5-Br-indole [135.1 (C-70), 128.6 (C-30), 124.6 (C-
2), 122.7 (C-6), 122.1 (C-4), 119.7 (C-5), 112.5 (C-7), 112.
3 (C-3)], napthyl [135.2 (C-1), 133.9 (C-20), 131.7 (C-60),
128.2 (C-8), 127.7 (C-6), 127.5 (C-3), 127.3 (C-7), 127.1
(C-2), 126.7 (C-4), 125.4 (C-5)], 37.6 (CH). ESI MS: (m/
z) [M?Na]? 557. Anal. Calcd. for C27H18Br2N2: C, 61.16;
H, 3.42; N, 5.28. Found C, 61.18; H, 3.53; N, 5.17.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(5-bromo-2-methoxy-
phenyl)methyl)-1H-indole (2i) It was obtained as red
solid, mp 260–270 °C. IR (KBr) m 3337 (NH), 1603 (C=C),
1307 (C–O) cm-1. 1H NMR (CDCl3 200 MHz) d 3.73 (s, -
OCH3), 5.34 (s, 1H, CH), 6.54 (d, J = 8.5 Hz, 1H, ArH-3),
7.12–7.14 (m, 2H, ArH-4, 6), 6.92 (s, 2H, H-2, 20), 7.21–7.
26 (m, 4H, H-6, 60, 7, 70), 7.65 (s, 2H, H-4, 40), 7.98 (s,
2NH). 13CNMR (CDCl3 50 MHz) 5-Br-indole [135.1 (C-
70), 128.7 (C-30), 124.7 (C-2), 124.5 (C-6), 122.1 (C-4),
119.3 (C-5), 112.7 (C-7),112.6 (C-3)], 5-Br-2-MeO-Phenyl
[157.1 (C-2), 134.2 (C-6), 129.7 (C-4), 125.4 (C-1), 116.0
(C-3), 115.1 (C-5), 56.5 (OCH3)], 39.3 (CH). ESI MS: (m/z)
[M?Na]? 612. Anal. Calcd. for C24H17Br3N2O: C, 48.93;
H, 2.91; N, 4.76. Found C, 48.97; H, 2.85; N, 4.77.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(4-fluorophenyl)methyl)-
1H-indole (2m) It was obtained as red solid, mp
140–150 °C. IR (KBr) m 3318 (NH), 1603 (C=C), 1107 (C–
F)cm-1.1H NMR (CDCl3 400 MHz) d5.71 (s, 1H, CH), 6.49
(s, 2H, H-2, 20), 6.98 (t, J = 8 Hz, 2H, ArH-3,30), 7.17–7.23
(m, 6H, H-6,60,7, 70, ArH-2,20), 7.42(s, 2H, H-4,40). 13CNMR
(CDCl3 100 MHz) 5-Br-indole [135.3 (C-70), 128.4 (C-30),
124.8 (C-2), 122.1 (C-6), 122.07 (C-4), 118.5 (C-5), 112.7
(C-7), 112.7 (C-3)], 4-F-Phenyl [159.6 (C-4), 133.2 (C-1),
130.8 (C-2, 20), 115.1 (C-3, 30)], 39.3 (CH). ESI MS: (m/z)
[M?Na]? 521. Anal. Calcd. for C23H15Br2FN2: C, 55.45; H,
3.03; N, 5.62. Found C, 55.64; H, 3.02; N, 5.68.
4-(Bis(5-bromo-1H-indol-3-yl)methyl)-N,N-dimethylben-
zenamine (2j) It was obtained as red solid, mp
240–250 °C. IR (KBr) m 3318 (NH), 1603 (C=C), cm-1. 1H
NMR (CDCl3 200 MHz) d 2.87 (s, 2xCH3), 5.34 (s, 1H,
CH), 6.47 (d, J = 8.5 Hz, 2H, ArH-2), 6.87 (d, J = 8.
5 Hz, 2H, ArH-2), 6.92 (s, 2H, H-2, 20), 7.21–7.26 (m, 4H,
H-6, 60, 7, 70), 7.65 (s, 2H, H-4, 40), 7.99 (s, 2NH).
13CNMR (CDCl3 50 MHz) 5-Br-indole [135.4 (C-70), 128.
6 (C-30), 124.7 (C-2), 124.6 (C-6), 122.3 (C-4), 119.2 (C-
5), 112.6 (C-7),112.6 (C-3)], 4-NMe2-phenyl [146.4 (C-4),
130.2 (C-2,20), 127.4 (C-1),114.7 (C-3, 30), 40.5 (2xCH3)],
40.1 (CH). ESI MS: (m/z) [M?Na]? 546. Anal. Calcd. for
C25H21Br2N3 C, 57.38; H, 4.05; N, 8.03. Found C, 57.35;
H, 4.03; N, 8.07.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(4-chlorophenyl)methyl)-
1H-indole (2n) It was obtained as red solid, mp
170-180 °C. IR (KBr) m 3318 (NH), 1603 (C=C), 713 (C–
Cl) cm-1. 1H NMR (CDCl3 200 MHz) d 5.71 (s, 1H, CH),
6.60 (s, 2H, H-2, 20), 7.17–7.28 (m, 8H, H-6,60,7,70, ArH
2,20, 3,30), 7.44 (s, 2H, H-4,40), 8.10 (s, 2NH). 13CNMR
(CDCl3 50 MHz) 5-Br-indole [135.3 (C-70), 128.4 (C-30),
124.8 (C-2), 122.1 (C-6), 122.06 (C-4), 118.5(C-5), 112.7
(C-7), 112.7 (C-3)], 4-Cl-Phenyl [141.6 (C-1), 132.2 (C-4),
129.8 (C-2, 20), 125.1 (C-3, 30)] 39.3 (CH). ESI MS: (m/z)
[M?Na]? 537. Anal. Calcd. for C23H15Br2ClN2: C, 53.68;
H, 2.94; N, 5.44. Found C, 53.64; H, 2.92; N, 5.38.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(cyclohexyl)methyl)-
1H-indole (2k) It was obtained as red solid, mp
195–205 °C. IR (KBr) m 3378 (NH), 1623 (C=C), 1317 (C–
O) cm-1. 1H NMR (CDCl3 400 MHz) d 1.23–1.54 (m, 10H,
5xCH2, cyclohexyl), 2.12-2.14 (m, 1H, CH, cyclohexyl), 3.
86 (d, J = 3.2 Hz, 1H, CH), 6.92 (s, 2H, H-2, 20), 7.21–7.26
(m, 4H, H-6, 60, 7, 70), 7.65 (s, 2H, H-4, 40), 7.98 (s, 2NH).
13CNMR (CDCl3 100 MHz) 5-Br-indole [135.2 (C-70), 128.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(4-bromophenyl)methyl)-
1H-indole (2o) It was obtained as red solid, mp
180–190 °C. IR (KBr) m 3318 (NH), 1603 (C=C), 589 (C–
Br) cm-1. 1H NMR (CDCl3 200 MHz) d 5.70 (s, 1H, CH),
6.60 (s, 2H, H-2, 20), 7.13–7.28 (m, 8H, H-6, 60, 7, 70, ArH-2,
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Med Chem Res (2014) 23:1643–1653
1649
20, 3, 30), 7.45 (s, 2H, H-4, 40), 8.10 (s, 2NH). 13CNMR
(CDCl3 50 MHz) 5-Br-indole [135.3 (C-70), 128.0 (C-30),
124.8 (C-2), 122.2 (C-6), 122.1 (C-4), 118.7 (C-5), 112.7
(C-7), 112.5 (C-3)], 4-Br-Phenyl [137.5 (C-1),131.2 (C-4),
130.8 (C-2, 20), 126.1 (C-3, 30)], 39.3 (CH). ESI MS: (m/z)
[M?Na]? 582. Anal. Calcd. for C23H15Br3N2: C, 49.41; H,
2.70; N, 5.01. Found C, 49.43; H, 2.72; N, 5.08.
5-Bromo-3-(1-(5-bromo-1H-indol-3-yl)nonyl)-1H-indole
(2s) It was obtained as yellowish oil. IR (KBr) m 3373
(NH), 1613 (C=C) cm-1.1H NMR (CDCl3 200 MHz) d 0.
83–0.86 (m, 3H, CH3), 1.23-1.34 (m, 12H, 6xCH2), 2.10–2.
30 (m, 2H, CH2), 4.32(t, J = 7.5 Hz, 1H, CH), 6.92(s, 2H,
H-2), 7.21–7.26 (m, 4H, H-6,60,7,70), 7.65 (s, 2H, H-4,40),
7.98 (s, 2NH). 13CNMR (CDCl3 50 MHz) 5-Br-indole
[135.2 (C-70), 128.6 (C-30), 124.6 (C-2), 122.6 (C-6), 122.0
(C-4), 119.6 (C-5), 112.5 (C-7), 112.3 (C-3)], 35.2 (CH-
alkyl), 33.9, 31.8, 29.6, 29.3, 28.2, 22.8, 22.6 (7xCH2-
alkyl), 14.1(CH3-alkyl). ESI MS: (m/z) [M?Na]? 539.
Anal. Calcd. for C25H28Br2N2 C, 58.16; H, 5.47; N, 5.43.
Found C, 58.18; H, 5.37; N, 5.40.
5-Bromo-3-((5-bromo-1H-indol-3-yl)(4-nitrophenyl)methyl)-
1H-indole (2p) It was obtained as red solid, mp
280–290 °C. IR (KBr) m 3328 (NH), 1623 (C=C), 1547,
1372 (NO2) cm-1. 3402, 3047, 2915, 1520, 1454, 1349,
1
1043, 743 cm-1. H NMR (CDCl3 200 MHz) d 5.77 (s,
1H, CH), 6.95 (s, 2H, H-2,20), 7.17-7.39 (m, 6H, H-6, 60, 7,
70, ArH-2, 20), 7.67 (s, 2H, H-4,40),7.87 (d, J = 6 Hz, 2H,
ArH-3,30), 8.10 (s, 2NH). 13CNMR (CDCl3 50 MHz) 5-Br-
indole [135.3 (C-70), 128.0 (C-30), 124.8 (C-2), 122.2 (C-6),
122.1 (C-4), 118.7 (C-5), 112.7 (C-7), 112.5 (C-3)], 4-NO2-
Phenyl [145.5 (C-4),143.2 (C-1), 130.8 (C-2, 20), 121.1 (C-
3, 30)], 39.3 (CH). ESI MS: (m/z) [M?Na]? 548. Anal.
Calcd. for C23H15Br2N3O2: C, 52.60; H, 2.88; N, 8.00.
Found C, 52.43; H, 2.72; N, 8.08.
5-Bromo-3-(2-(5-bromo-1H-indol-3-yl)propan-2-yl)-1H-
indole (3a) It was obtained as yellowish oil. IR (KBr) m
3358 (NH), 1617 (C=C) cm-1.1H NMR (200 MHz,
CDCl3). d 1.23 (s, 6H, 2x CH3), 6.91 (s, 2H, H-2, 20), 7.
20–7.26 (m, 4H, H-6, 60, 7, 70), 7.65 (s, 2H, H-4, 40), 7.98
(s, 2NH). 13CNMR (CDCl3) 5-Br-indole [135.2 (C-70), 128.
6 (C-30), 124.6 (C-2), 122.6 (C-6), 122.0 (C-4), 119.6 (C-
5), 112.5 (C-7), 112.3 (C-3)], 44.1 (C), 30.2 (2xCH3). ESI
MS: (m/z) [M?Na]? 455. Anal. Calcd. for C19H16Br2N2 C,
52.81; H, 3.73; N, 6.48. Found C, 52.86; H, 3.71; N, 6.56.
5-Bromo-3-(1-(5-bromo-1H-indol-3-yl)butyl)-1H-indole
(2q) It was obtained as yellowish oil. IR (KBr) m 3348
(NH), 1623 (C=C) cm-1. 1H NMR (CDCl3 200 MHz) d 0.
95 (t, J = 7.2, 7.4, 3H, CH3), 1.22–1.44 (m, 2H, CH2) 2.
05–2.15 (m, 2H, CH2), 4.34 (t, J = 7.3 Hz, 7.5 Hz, CH), 6.
82 (s, 2H, H-2,20), 7.16–7.26 (m, 4H, H-6,60,7,70), 7.65 (s,
2H, H-4,40), 8.19 (s, 2NH). 13CNMR (CDCl3 100 MHz)
5-Br-indole[135.2 (C-70), 128.6 (C-30), 124.6 (C-2), 122.6
(C-6), 122.0 (C-4), 119.6 (C-5), 112.5 (C-7), 112.3 (C-3)],
37.5 (CH-alkyl), 33.7, 21.3 (2xCH2-alkyl), 14.1 (CH3-
alkyl). ESI MS: m/z (M?Na)?469. Anal. Calcd. for
C20H18Br2N2: C, 53.84; H, 4.07; N, 6.28. Found C, 53.87;
H, 4.03; N, 6.21.
5-Bromo-3-(1-(5-bromo-1H-indol-3-yl)-1-phenylethyl)-
1H-indole (3b) It was obtained as yellowish oil. IR
(KBr) m 3378 (NH), 1627 (C=C) cm-1
.
1H NMR
(200 MHz, CDCl3). d 1.90 (s, 3H, CH3), 6.71 (s, 2H, H-2,
20), 7.10–7.30 (m, 4H, H-6, 60, 7, 70, ArH-2, 20, 3, 30, 4), 7.
65 (s, 2H, H-4, 40), 7.98 (s, 2NH). 13CNMR (CDCl3) 5-Br-
indole [135.2 (C-70), 128.6 (C-30), 124.6 (C-2), 122.6 (C-6),
122.0 (C-4), 119.6 (C-5), 112.5 (C-7), 112.3 (C-3)], Phenyl
[140.8 (C-1), 128.7 (C-3, 30), 127.8 (C-2, 20), 126.1 (C-4)],
49.1 (C), 14.9 (CH3). ESI MS: (m/z) [M?Na]? 517. Anal.
Calcd. for C19H16Br2N2 C, 58.33; H, 3.67; N, 5.67. Found
C, 58.46; H, 3.71; N, 5.56.
4-(Bis(5-nitro-1H-indol-3-yl)methyl)phenol) (4a) It was
obtained as yellow solid, yield 92 %, mp 235–245 °C. IR
5-Bromo-3-(1-(5-bromo-1H-indol-3-yl)octyl)-1H-indole
(2r) it was obtained as yellowish oil. IR (KBr) m 3317
(NH), 1603 (C=C) cm-1. 1H NMR (CDCl3 200 MHz) d 0.
83–0.86 (m, 3H, CH3), 1.23-1.34 (m, 10H, 5xCH2), 2.10–2.
30 (m, 2H, CH2), 4.32(t, J = 7.5 Hz, 1H, CH), 6.92 (s, 2H,
H-2, 20), 7.21–7.26 (m, 4H, H-6,60,7,70), 7.65 (s, 2H,
H-4,40), 7.98 (s, 2NH). 13CNMR (CDCl3 50 MHz) 5-Br-
indole [135.2 (C-70), 128.6 (C-30), 124.6 (C-2), 122.6 (C-6),
122.0 (C-4), 119.6 (C-5), 112.5 (C-7), 112.3 (C-3)], 35.2
(CH-alkyl), 33.9, 31.8, 29.6, 29.3, 28.2, 22.6 (6xCH2-
alkyl), 14.1(CH3-alkyl). ESI MS: (m/z) [M?Na]? 525.
Anal. Calcd. for C24H26Br2N2: C, 57.39; H, 5.22; N, 5.58.
Found C, 57.36; H, 5.23; N, 5.56.
(KBr) m 3472 (OH), 3348 (NH), 1537, 1385 (NO) cm-1
.
1HNMR (CD3OD 400 MHz) d 5.82 (s, 1H, CH), 6.66 (d,
J = 8.4 Hz, 2H, ArH-3, 30), 6.80 (s, 2H, H-2, 20), 7.07 (d,
J = 8.4 Hz, 2H, ArH-2, 20), 7.36 (d, J = 8.4 Hz, 2H, H-7,
70), 7.92-7.89 (d, J = 8.4 Hz, 2H, H-6, 60), 8.14 (s, 2H,
H-4, 40). 13C NMR (DMSO-d6 100 MHz) 5-NO2-indole
[140.0 (C-70), 139.7, (C-5), 127.3 (C-2), 125.7(C-30), 121.0
(C-3), 116.4 (C-4), 116.1 (C-6), 111.9 (C-7)], 4-OH-Phenyl
[155.6, (C-4), 133.9 (C-1), 129.0 (C-2,20), 115.1 (C-3,30)],
37.5 (CH) HRMS (-ESI): Calc. [M-H]- 427.1042. Found
[M-H]- 427.1053. Anal. Calc.for C23H15N4O5: C, 64.48;
H, 3.76; N, 13.08. Found C, 64.43; H, 3.82; N, 13.12.
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Med Chem Res (2014) 23:1643–1653
J = 8.4, 1H,ArH-2), 7.18 (d, J = 8.8 Hz, 2H, H-7, 70), 7.
21 (d, J = 8.8 Hz, 2H, H-6, 60), 7.42 (s, 2H, H-4, 40), 8.05
(s, 2NH). 13C NMR (CDCl3 100 MHz) 5-Br-indole [135.2
(C-70), 128.4 (C-30), 124.9 (C-2), 122.9 (C-6), 121.9 (C-4),
118.4 (C-5), 112.6 (C-7), 110.4(C-3)] Benzopyran [143.7
(C-4), 132.9 (C-2), 127.4 (C-3), 117.3(C-5)], 34.0 (CH2),
28.9 (2xCH3). HRMS (?ESI) Calc. [M?H]? 564.9949.
Found [M?H]? 564.9957. Anal. Calc. for C27H21
Br2N2O2: C, 57.27; H, 3.92; N, 4.95. Found C, 57.26; H, 3.
93; N, 4.96.
3-((4-Fluorophenyl)(5-nitro-1H-indol-3-yl) methyl)-5-nitro-
1H-indole (4b) It was obtained as yellowish green solid,
yield 94 %, mp 240–250 °C. IR (KBr) m 3317 (NH), 1543,
1378 (NO), 1123 (C–F) cm-1
.
1HNMR (DMSO-
d6 ? CDCl3 400 MHz) d 5.87 (s, 1H, CH), 6.77 (s, 2H, H-2,
20), 6.93 (t, J = 8.0 Hz, 2H, ArH-3, 30), 7.22 (t, J = 8.0 Hz,
2H), 7.37 (d, J = 8.8 Hz, 2H, H-7, 70), 7.94 (d, J = 8.8 Hz,
2H, H-6, 60), 8.16 (s, 2H, H-4, 40), 10.97 (s, 2H, 2NH). 13C
NMR (DMSO-d6 100 MHz) 5-NO2-indole [140.0 (C-70),
139.7 (C-5), 127.5 (C-5), 125.7(C-30), 121.0 (C-3), 116.6 (C-
4), 116.1 (C-6), 112.1 (C-7)], 4-F-Phenyl [159.6, (C-4), 133.
2 (C-1), 129.9 (C-2,20), 115.2 (C-3,30)], 37.6 (CH). HRMS
(?ESI): Calc. [M?H]431.1156 ?. Found [M?H]? 431.
1159. Anal. Calc. for C23H16FN4O4: C, 64.19; H, 3.51; N,
13.02. Found C, 64.13; H, 3.41; N, 13.01.
5-Bromo-3-(4-(5-bromo-1H-indol-3-yl)-7-methoxy-2,2-
dimethylchroman-4-yl)-1H-indole (6b) It was obtained
as light yellow solid, yield 64 %, mp 165–175 °C. IR
1
(KBr) m 3371 (NH), 1210 (C–O) cm-1. H NMR (CDCl3
400 MHz) d 1.22-1.27 (m, 6H, 2xCH3), 2.03 (s, 2H, CH2),
3.73 (s, 3H, OCH3), 6.41 (d, J = 8.4 Hz, 1H, ArH-3), 6.91
(s, 1H, ArH-5), 6.95 (s, 2H, H-2, 20), 7.07 (d, J = 8.4,
1H,ArH-2), 7.18 (d, J = 8.8 Hz, 2H, H-7, 70), 7.23 (d, J =
8.8 Hz, 2H, H-6, 60), 7.42 (s, 2H, H-4, 40), 8.03 (s, 2NH).
13C NMR (CDCl3 100 MHz) 5-Br-indole [135.1 (C-70),
128.7 (C-30), 125.0 (C-2), 122.9 (C-6), 121.7 (C-4), 118.5
(C-5), 112.6 (C-7), 110.4(C-3)] Benzopyran [158.7 (C-4),
132.9 (C-2), 123.4 (C-3), 111.3(C-5), 55.9 (OCH3)], 34.0
(CH2), 28.9 (2xCH3). HRMS (?ESI). Calc. [M?H]? 579.
0106. Found [M?H]? 579.0113. Anal Calc. for
C28H23Br2N2O2: C, 57.95; H, 4.17; N, 4.83. Found C, 57.
96; H, 4.17; N, 4.86.
4-(Bis(5-cyano-1H-indol-3-yl)methyl)phenol (5a) It was
obtained as dark red colour solid, yield: 94 %, mp
240–250 °C. IR (KBr) m 3472 (OH), 3348 (NH), 2210 (CN)
1
cm-1. HNMR (DMSO-d6 500 MHz): d 5.89 (s, 1H, CH),
6.68 (d, J = 8.2 Hz, 2H, ArH-3, 30), 7.07 (s, 2H), 7.16 (d,
J = 8.3 Hz, 2H, ArH-2, 20), 7.41 (d, J = 8.4 Hz, 2H, H-6,
60), 7.54 (d, J = 8.4 Hz, 2H, H-7, 70), 7.76 (s, 2H, H-4,40),
11.39 (s, NH), 11.40 (s, NH). 13C NMR (DMSO-d6
125 MHz) 5-CN-indole [138.2 (C-70), 129.0 (C-30), 126.0
(C-4), 124.5 (C-6), 123.5 (C-2), 120.7 (C-3), 100.2 (C-5)],
4-OH-Phenyl [155.6, (C-4), 134.0 (C-1), 129.0 (C-2,20),
119.3 (C-3,30)], 37.7 (CH). HRMS (?ESI): Calc.
[M?H]?389.1402.Found [M?H]? 389.1397. Anal. Calc.
for C25H17N4O: C, 77.30; H, 4.15; N, 14.42. Found C, 77.
23; H, 4.11; N, 14.51.
5-Bromo-3-(4-(5-bromo-1H-indol-3-yl)-7-ethoxy-2,2-dim-
ethylchroman-4-yl)-1H-indole (6c) It was obtained as
colourless solid, yield 64 %, mp 170–180 °C. IR (KBr) m
3348 (NH), 1210 (C–O) cm-11H NMR (CDCl3 400 MHz):
d 1.23–126 (s, 6H, 2xCH3), 1.30 (m, 3H, CH3, ethoxy), 2.
07 (s, 2H, CH2), 3.98 (m, 2H, CH2, ethoxy), 6.41 (d, J = 8.
4 Hz, 1H, ArH-3), 6.91 (s, 1H, ArH-5), 6.95 (s, 2H, H-2,
20), 7.07 (d, J = 8.4, 1H,ArH-2), 7.18 (d, J = 8.8 Hz, 2H,
H-7, 70), 7.23 (d, J = 8.8 Hz, 2H, H-6, 60), 7.42 (s, 2H,
H-4, 40), 8.03 (s, 2NH). 13C NMR (CDCl3 100 MHz) 5-Br-
indole [135.1 (C-70), 128.7 (C-30), 125.0 (C-2), 122.9 (C-6),
121.7 (C-4), 118.5 (C-5), 112.6 (C-7), 110.4(C-3)] Benz-
opyran [158.7 (C-4), 132.9 (C-2), 123.4 (C-3), 111.3(C-5),
64.9 (OCH2), 14.1 (CH3)], 34.0 (CH2), 28.9 (2xCH3).
HRMS (?ESI): Calc. [M?H]? 593.0262. Found [M?H]?
593.0267. Anal. Calc. for C29H25Br2N2O2: C, 58.60; H, 4.
41; N, 4.71. Found C, 57.56; H, 4.37; N, 4.76.
3-((4-Fluorophenyl)(5-cyano-1H-indol-3-yl) methyl)-5-
cyano-1H-indole (5b) It was obtained as pink colour
solid, yield 95 %, mp 245–255 °C. IR (KBr) m 3363 (NH),
1
2210 (CN), 973 (C–F) cm-1. HNMR (CD3OD 400 MHz)
d 5.86 (s, 1H, CH), 6.76 (s, 2H, H-2, 20), 6.94 (t, J = 8.
8 Hz, 2H, ArH-3, 30), 7.27–7.21 (m, 4H, 6, 60, ArH-2,2 ‘),
7.40 (d, J = 8.4 Hz, 2H, H-7, 70), 7.53 (s, 2H, H-4, 40). 13C
NMR (CDCl3 100 MHz) 5-CN-indole [138.2 (C-70), 129.0
(C-30), 126.0 (C-4), 124.5 (C-6), 123.5 (C-2), 120.7 (C-3),
100.2 (C-5)], 4-F-Phenyl [159.6, (C-4), 133.2 (C-1), 129.9
(C-2,20), 115.2 (C-3,30)], 37.6 (CH). HRMS (?ESI): Calc.
[M?H]? 391.1359. Found [M?H]? 391.1342. Anal. Calc.
for C25H16FN4: C, 76.91; H, 3.87; N, 14.35. Found. C, 76.
89; H, 3.85; N, 14.31.
4,4-Bis(5-bromo-1H-indol-3-yl)-2,2-dimethyl chroman-7-
General procedure for the synthesis of 7a–7j
ol (6a) It was obtained as colourless solid, yield 67 %,
mp 145–155 °C. IR (KBr) m 3472 (OH), 3371 (NH) cm-1
.
A mixture of compound 2m (1equiv.) and KOH (2 equiv.)
in DMSO (10 mL) was stirred at room temperature for
15 min. After that addition of alkyl/benzyl/sulphonyl(2
equiv.) was made into reaction mixture. After completion
1H NMR (CDCl3 400 MHz) d 1.23–1.27 (m, 6H, 2xCH3),
2.04 (s, 2H, CH2 of Benzopyran), 6.40 (d, J = 8.4 Hz, 1H,
ArH-3), 6.93 (s, 1H, ArH-5), 6.99 (s, 2H, H-2, 20), 7.06 (d,
123

Med Chem Res (2014) 23:1643–1653
1651
of the reaction, the mixture was extracted with ethyl acetate
(3 9 25 mL) and water. The combined organic layer was
dried with anhydrous sodium sulphate, concentrated in
vacuo and purified by column chromatography (ethyl
acetate:petroleum ether = 0.5:9.5) to afford the pure
product.
(7xCH2), 13.9 (CH3). HRMS (?ESI): Calc. [M?H]? 721.
1991. Found [M?H]?721.1998. Anal. Calc. for
C39H46Br2FN2: C, 64.82; H, 6.56; N, 3.88. Found C, 64.87;
H, 6.61; N, 3.84.
1-Benzyl-3-((1-benzyl-5-bromo-1H-indol-3-yl)(4-fluoro-
phenyl)methyl)-5-bromo-1H-indole (7d) It was obtained
as red solid, yield 78 %, mp 140–150 °C. IR (KBr) m 1570
(C=C), 1139 (C–F) cm-1. 1HNMR (CDCl3 400 MHz) d 5.
13(s, 4H, 2xCH2), 5.70 (s, 1H, CH), 6.52 (s, 2H, H-2, 20), 6.
92–6.94 (m, 4H, ArH-3, 30, 2, 20), 7.01 (d, J = 8.8 Hz, 2H,
H-7, 70), 7.11–7.23(m, 12H, H-6, 60, 2x5H of phenyl), 7.40
(s, 2H, H-4, 40). 13CNMR (CDCl3 100 MHz) 5-Br-indole
[135.3 (C-70), 128.4 (C-30), 124.8 (C-2), 122.1 (C-6), 122.
07 (C-4), 118.5 (C-5), 112.7 (C-7), 112.7 (C-3)], 4-F-
Phenyl [159.6 (C-4), 133.2 (C-1), 130.8 (C-2, 20), 115.1 (C-
3, 30)], 2xbenzyl [136.3 (C-1), 129.1 (C-2, 20), 128.7(C-3,
30), (C-4), 49.5(CH2)], 39.7(CH). HRMS (?ESI). Calc.
[M?H]? 677.0426. Found [M?H]? 677.0428. Anal. Calc.
for C37H26Br2FN2: C, 65.50; H, 4.01; N, 4.13. Found C, 65.
24; H, 4.07; N, 4.15.
5-Bromo-3-((5-bromo-1-methyl-1H-indol-3-yl)(4 fluoro-
phenyl)methyl)-1-methyl-1H-indole (7a) It was obtained
as red solid, yield 84 %, mp175–185 °C. IR (KBr) m1179
(C–F) cm-1. 1HNMR (CDCl3 400 MHz) d 3.49 (s, 6H, 2x-
NCH3), 5.53 (s, 1H, CH), 6.28 (s, 2H, H-2,20), 6.79 (t, J =
8.8 Hz, 2H, Ar H-3,30), 6.98 (d, J = 8.8 Hz, 2H, Ar
H-2,20), 7.02-7.11 (m, 4H, H-6, 60, 7, 70), 7.25 (s, 2H,
H-4,40). 13CNMR (CDCl3 100 MHz) 5-Br-indole [135.3
(C-70), 128.4 (C-30), 124.8 (C-2), 122.1 (C-6), 122.07 (C-
4), 118.5 (C-5), 112.7 (C-7), 112.7 (C-3)],4-F-Phenyl [159.
6 (C-4), 133.2 (C-1), 130.8 (C-2, 20), 115.1 (C-3, 30)], 39.3
(CH)], 42.1 (2xNMe). HRMS (?ESI): Calc. [M?H]?524.
9800. Found [M?H]? 524.9806. Anal. Calc. for
C25H18Br2FN2: C, 57.06; H, 3.64; N, 5.32 found C, 57.13;
H, 3.61; N, 5.11.
1-(4-Fluorobenzyl)-3-((1-(4-fluorobenzyl)-5-bromo-1H-indol-
3-yl)(4-fluorophenyl)methyl)-5-bromo-1H-indole (7e) It was
obtained as red solid, yield 84 %, mp 120–130 °C. IR
5-Bromo-3-((5-bromo-1-pentyl-1H-indol-3-yl)(4-fluoro-
phenyl)methyl)-1-pentyl-1H-indole (7b) It was obtained as
colourless solid, yield 72 %, mp 195–205 °C. IR (KBr) m
1
(KBr) m 1570 (C=C), 1129 (C–F) cm-1. HNMR (CDCl3
1
1179 (C–F) cm-1. H NMR (CDCl3 400 MHz) d 0.85 (t,
400 MHz) d 4.98 (s, 4H, 2XCH2), 5.57 (s, 1H, CH), 6.38
(s, 2H, H-2, 20), 6.79–6.87 (m, 8H, H-7, 70, ArH-3, 30 of
4-F-Phenyl, 2x ArH-3, 30 of 4-F-benzyl), 6.98–7.09 (m, 8H,
H-6, 60, ArH-2, 20 of 4-F-Phenyl, 2x ArH-2, 20 of 4-F-
benzyl), 7.29 (s, 2H, H-4, 40). 13CNMR (CDCl3 100 MHz)
5-Br-indole [135.3 (C-70), 128.4 (C-30), 124.8 (C-2), 122.1
(C-6), 122.07 (C-4), 118.5 (C-5), 112.7 (C-7), 112.7 (C-3)],
4-F-Phenyl [159.6 (C-4), 133.2 (C-1), 130.8 (C-2, 20), 115.
1 (C-3, 30)], 4-F-Phenyl [159.6 (C-4), 133.2 (C-1), 130.8
(C-2, 20), 115.1 (C-3, 30)], 2x 4-F-benzyl [159.5 (C-4), 131.
1 (C-1), 130.8 (C-2, 20), 115.1 (C-3, 30), 49.3(CH2)], 39.
6(CH). HRMS (?ESI) Calc. [M?H]?713.0238. Found
[M?H]? 713.0234. Anal. Calc. for C37H24Br2F3N2: C, 62.
20; H, 3.53; N, 3.92. Found C, 62.24; H, 3.57; N, 3.85.
J = 8 Hz, 6H, CH3), 1.21–1.31 (m, 8H, 4xCH2), 1.72–1.76
(m, 4H, 2xCH2), 3.98 (t, J = 8 Hz, 4H, 2xCH2), 5.71 (s,
1H, CH), 6.49 (s, 2H, H-2, 20), 6.98 (t, J = 8 Hz, 2H, ArH-
3, 30), 7.17–7.23 (m, 6H, H-6, 60, 7, 70, ArH-2, 20), 7.42(s,
2H, H-4,40). 13CNMR (CDCl3 100 MHz) 5-Br-indole [135.
4 (C-70), 128.9 (C-30), 124.3 (C-2), 122.3 (C-6), 117.2, (C-
4), 115.4, (C-5), 112.1 (C-7), 110.9 (C-3)],4-F-Phenyl
[159.6 (C-4),129.8 (C-1), 128.3 (C-2, 20), 115 (C-3, 30)],
39.1 (CH), 46.4, 29.8, 28.9, 22.2, (4xCH2), 13.9 (CH3).
HRMS (?ESI): Calc. [M?H]? 637.1052. Found [M?H]?
637.1058. Anal. Calc. for C33H34Br2FN2: C, 62.08; H, 5.
53; N, 4.39. Found C, 62.13; H, 5.61; N, 6.57.
5-Bromo-3-((5-bromo-1-octyl-1H-indol-3-yl)(4-fluorophenyl)
methyl)-1-octyl-1H-indole (7c) It was obtained as colour-
less solid, yield 68 %, mp 210–220 °C. IR (KBr) m 1123
1-(4-Chlorobenzyl)-3-((1-(4-chlorobenzyl)-5-bromo-1H-in-
dol-3-yl)(4-fluorophenyl)methyl)-5-bromo-1H-indole (7f) It
was obtained as red solid, yield 73 %, mp 135–145 °C. IR
1
(C–F) cm-1. H NMR (CDCl3 400 MHz) d 0.85 (t, J =
8 Hz,3H, CH3), 1.21–1.31 (m, 20H, 10xCH2), 1.72–1.76
(m, 4H, 2xCH2), 3.98 (t, J = 8 Hz, 4H, 2xCH2), 5.74 (s,
1H, CH), 6.48 (s, 2H, H-2, 20), 6.98 (t, J = 8 Hz, 2H, ArH-
H-3, 30), 7.16–7.22 (m, 6H, H-6, 60, 7, 70, ArH-2, 20), 7.43
(s, 2H, H-4, 40). 13CNMR (CDCl3 100 MHz) 5-Br-indole
[135.3 (C-70), 129.1 (C-30), 124.5 (C-2), 122.3 (C-6), 1119.
1, (C-4), 115.4, (C-5), 112.1 (C-7), 110.9 (C-3)], 4-F-
Phenyl [159.6 (C-4),129.1 (C-1), 128.7 (C-2, 20), 115 (C-3,
30)], 39.4 (CH), 46.7, 29.9, 29.8, 28.9,2 6.3, 23.5 22.2,
1
(KBr) m 1571 (C=C), 721 (C–Cl) cm-1. HNMR (CDCl3
400 MHz) d 4.99(s, 4H, 2xCH2), 5.58 (s, 1H, CH), 6.38 (s,
2H, H-2, 20), 6.75 (d, J = 8.4 Hz, 4H, 2xArH-3, 30 of 4-Cl-
benzyl), 6.82 (t, J = 8.8 Hz, 2H, ArH-3, 30of 4-F-phenyl), 6.
86 (d, J = 8.8 Hz, 2H, H-7, 70), 7.02–7.09 (m, 8H, H-6, 60,
ArH-2, 20 of 4-F-phenyl, 2xArH-2,20 of 4-Cl-benzyl), 7.27(s,
2H, H-4, 40). 13CNMR (CDCl3 100 MHz) 5-Br-indole [135.3
(C-70), 128.4 (C-30), 124.8 (C-2), 122.1 (C-6), 122.07 (C-4),
123

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Med Chem Res (2014) 23:1643–1653
118.5 (C-5), 112.7 (C-7), 112.7 (C-3)], 4-F-Phenyl [159.3
(C-4), 133.2 (C-1), 130.8 (C-2, 20), 115.1 (C-3, 30)], 2x 4-Cl-
Benzyl [141.6 (C-1), 130.2 (C-4), 129.8 (C-2, 20), 125.1 (C-3,
30), 49.7 (CH2)], 39.3 (CH). HRMS (?ESI). Calc. [M?H]?
744.9647. Found [M?H]? 744.9646. Anal. Calc. for
C37H24Br2Cl2FN2: C, 59.47; H, 3.37; N, 3.75. Found C, 59.
24; H, 3.27; N, 3.85.
d 5.45 (s, 1H, CH), 6.85 (s, 2H, H-2, 20), 7.05-7.25 (m,
10H, H-7, 70, ArH-2, 20, 3, 30 of 4-F-Phenyl, 2x ArH-3, 30
of 4-F-bezenesulphonyl), 7.45 (d, J = 4 Hz, 2H, H-6, 60),
7.71–7.74 (m, 4H, 2xArH-2,20 of 4-F-bezenesulphonyl), 7.
85 (s, 1H, H-4), 7.88 (s, 1H, H-40). 13CNMR (CDCl3
100 MHz) 5-Br-indole [134.9, (C-70), 129.4 (C-30), 123.8,
(C-2), 122.6, (C-6), 117.2, (C-4), 117.1 (C-5), 115.4 (C-7)],
4-F-Phenyl [161.1 (C-4), 133.4 (C-1), 129.7 (C-2, 20), 115.
4 (C-3, 30)], 2x 4-F-benzenesulphonyl [166.9 (C-4), 134.8
(C-1), 131.3 (C-2, 20), 116.0 (C-3, 30)], 38.7 (CH). HRMS
(?ESI): Calc. [M?H]? 812.9163. Found [M?H]? 812.
9169. Anal. Calc. for C35H20Br2F3N2O4S2: C, 51.61; H, 2.
60; N, 3.44. Found C, 51.67; H, 2.63; N, 3.47.
1-(4-Bromobenzyl)-3-((1-(4-bromobenzyl)-5-bromo-1H-in-
dol-3-yl)(4-fluorophenyl)methyl)-5-bromo-1H-indole
(7g) It was obtained as yellow solid, yield 83 %, mp
185–195 °C. IR (KBr) m 1531 (C=C), 533 (C–Br) cm-1. 1H
NMR (CDCl3 ? DMSO-d6 400 MHz,). d 5.06 (s, 4H,
2xCH2), 5.62 (s, 1H, CH), 6.56 (s, 2H, H-2, 20), 6.76 (d,
J = 8 Hz, 4H, 2xArH-3, 30 of 4-Br-benzyl), 6.86 (t, J = 8.
4 Hz, 2H, ArH-3, 30of 4-F-phenyl), 6.96 (d, J = 8.8 Hz,
2H, H-7, 70), 7.12–7.23 (m, 8H, H-6, 60, ArH-2, 20 of 4-F-
phenyl, 2xArH-2,20 of 4-Br-benzyl, H-4, 40). 13CNMR
(CDCl3 100 MHz) 5-Br-indole [135.3 (C-70), 128.4 (C-30),
124.8 (C-2), 122.1 (C-6), 122.07 (C-4), 118.5 (C-5), 112.7
(C-7), 112.7 (C-3)], 4-F-Phenyl [159.3 (C-4), 133.2 (C-1),
130.8 (C-2, 20), 115.1 (C-3, 30)], 2x 4-Br-Benzyl [137.5 (C-
1),129.2 (C-4), 130.8 (C-2, 20), 126.1 (C-3, 30), 49.4
(CH2)], 39.3 (CH). HRMS (?ESI): Calc. [M?H]? 834.
8616. Found [M?H]? 834.8607. Anal. Calc. for
C37H24Br4FN2 C, 53.14; H, 3.01; 2.27; N, 3.35. Found C,
53.24; H, 3.07; N, 3.25.
1-(4-Methoxybenzenesulphonyl)-3-((1-(4-methoxybenzene
sulphonyl)-5-bromo-1H-indol-3-yl)(4-fluorophenyl)methyl)-
5-bromo-1H-indole (7j) It was obtained as yellow colour
solid, yield 82 %, mp 85–95 °C. IR (KBr) m 1353, 1172
(Sulphonyl), 1121 (C–F) cm-1
.
1H NMR (CDCl3
400 MHz) d 3.65(s, 2x-OCH3, 6H), 5.27 (s, 1H, CH), 6.66
(s, 2H, H-2, 20), 6.73 (d, J = 9.2 Hz, 4H, 2x ArH-3, 30 of
4-MeO-bezenesulphonyl), 6.85 (t, J = 8.4 Hz, 2H, ArH-3,
30 of F-Phenyl), 6.91-6.94 (m, 2H, ArH-2, 20of 4-MeO-
bezenesulphonyl), 7.06–7.08 (m, 2H, ArH-2, 20), 7.23 (d,
J = 8.8 Hz, 2H, H-7, 70), 7.44 (d, J = 8.8 Hz, 2H, H-6, 60),
7.68 (d, J = 8.8 Hz, 2H, H-4, 40). 13CNMR (CDCl3
100 MHz) 5-Br-indole [134.9, (C-70), 129.4 (C-30), 123.8,
(C-2), 122.6, (C-6), 117.2, (C-4), 117.1 (C-5), 115.4 (C-7)],
4-F-Phenyl [161.1, (C-4), 133.4 (C-1), 129.7, (C-2, 20),
115.4, (C-3, 30)], 2x 4-MeO-benzenesulphonyl [165.7, (C-
4), 130.2 (C-1), 129.3 (C-2, 20), 116.0 (C-3, 30)], 38.7 (CH).
HRMS (?ESI): Calc. [M?H]? 836.9563. Found
[M?H]?836.9564 Anal. Calc. for C37H26Br2FN2O6S2 C,
53.00; H, 3.25; N, 3.34 found C, 52.87; H, 4.13; N, 4.97.
1-(4-Methoxybenzyl)-3-((1-(4-methoxybenzyl)-5-bromo-1H-
indol-3-yl)(4-fluorophenyl)methyl)-5-bromo-1H-indole
(7h) It was obtained as red colour solid, yield 80 %, mp
225–235 °C. IR (KBr) m 1578 (C=C), 1210 (C–O) cm-1
.
1H NMR (CDCl3 400 MHz) d 3.79 (s, 6H, 2x-OCH3), 5.07
(s, 4H, 2xCH2), 5.67 (s, 1H, CH), 6.58 (s, 2H, H-2, 20), 6.72
(d, J = 8 Hz, 4H, 2xArH-3, 30 of 4-MeO-benzyl), 6.78 (t,
J = 8.4 Hz, 2H, ArH-3, 30of 4-F-phenyl) 6.89 (d, J = 8.
8 Hz, 2H, H-7, 70), 7.12–7.19 (m, 6H, H-6, 60, ArH-2, 20 of
4-F-phenyl, 2xArH-2,20 of 4-MeO-benzyl), 7.31 (s, 2H,
H-4, 40). 13CNMR (CDCl3 100 MHz) 5-Br-indole [135.3
(C-70), 128.4 (C-30), 124.8 (C-2), 122.1 (C-6), 122.07 (C-
4), 118.5 (C-5), 112.7 (C-7), 112.7 (C-3)], 4-F-Phenyl
[159.3 (C-4), 133.2 (C-1), 130.8 (C-2, 20), 115.1 (C-3, 30)],
2x 4-MeO-Benzyl [157.1(C-4),130.1 (C-1) 129.6 (C-2,20),
115.2 (C-3,30), 55.3 (OCH3),49.4 (CH2)], 39.3 (CH).
HRMS (?ESI) Calc. [M?H]? 737.0638. Found [M?H]?
737.0641. Anal. calc. for C39H30Br2FN2O2: C, 63.43; H, 4.
23; N, 3.79. Found C, 63.34; H, 4.27; N, 3.75.
Biology
Antibacterial assay
antibacterial assayAntibacterial activity assay of the com-
pounds was performed using microdilution method (Clin-
ical and Laboratory Standard Institute, 2009) against three
Gram-positive strains (S. aureus ATCC 29213, Methicillin-
resistant S. aureus and Vancomycin-resistant Enterococcus
faecalis) and two Gram-negative strains (Escherichia coli
ATCC 25922 and Pseudomonas aeruginosa ATCC 27853).
Bacterial suspensions were prepared in sterile normal sal-
ine from 24-h-grown culture. The MIC was determined in
Muller–Hinton Broth (MHB; BD Biosciences, USA). Two-
fold serial dilutions of compounds were prepared in MHB
in ll volume in a 96-well U-bottom microtitre plate
(Tarson, Mumbai, India). The final concentrations of the
1-(4-Fluorobenzenesulphonyl)-3-((1-(4-fluorobenzenesul-
phonyl)-5-bromo-1H-indol-3-yl)(4-fluorophenyl)methyl)-
5-bromo-1H-indole) (7i) It was obtained as red solid,
yield 84 %, mp 65–75 °C. IR (KBr) m 1348, 1170 (Sul-
1
phonyl), 1121 (C–F) cm-1. H NMR (CDCl3 400 MHz,)
123

Med Chem Res (2014) 23:1643–1653
1653
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Conclusions
In conclusion, we have designed the compounds which
showed moderate to excellent antibacterial activity against
Gram-positive bacteria and also in some resistant strains
like MRSA and VRE, but showed no activity on Gram-
negative bacteria and fungal strains. Compounds 2b, 2m,
4a and 5b were found to be the most potent inhibitors,
exhibiting MIC as well as MBC values equal to or less than
that of ciprofloxacin (0.5–2 lg/mL) against S. aureus,
MRSA and VRE. Compound 2b was the most potent,
exhibiting MIC of 0.5, 1 and 2 lg/mL against Gram-
positive bacteria and some resistant strains like MRSA and
VRE. During SAR study it was observed that substitution
at N,N0 position (7a–7j) of 2m diminishes its antibacterial
activity though in vitro antitumor activity against a panel of
prostate, cervical and lung cell lines was found to be in
micromolar range. Compound 7e was showing promising
antiproliferative activity against HeLa cell line.
Acknowledgments Authors are thankful to Director IIIM Jammu
for encouragement and DST (GAP-1145) for funding.
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