Synthesis and cytotoxicity of novel 6H-indolo[2,3-b]quinoxaline derivatives

Article abstract of DOI:10.1007/s00044-012-0373-7

A series of new 6-[(N ₁-aryl-1H-1,2,3-triazol-4-yl)methyl]-6H- indolo[2,3-b]quinoxa-line derivatives 7a _i-ix and 7b _i-vi is synthesized by a simple multi-step protocol starting from isatin 1a or 5-fluoroisatin 1b. These co

Full text of DOI:10.1007/s00044-012-0373-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3712–3718
DOI 10.1007/s00044-012-0373-7
ORIGINAL RESEARCH
Synthesis and cytotoxicity of novel 6H-indolo[2,3-b]quinoxaline
derivatives
•
Sreenivas Avula Jayaram Reddy Komsani Satish Koppireddi
•
•
•
Rambabu Yadla Anantha KoteswaraRao Kanugula
•
Srigiridhar Kotamraju
Received: 30 July 2012 / Accepted: 15 November 2012 / Published online: 1 December 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of new 6-[(N1-aryl-1H-1,2,3-triazol-
4-yl)methyl]-6H-indolo[2,3-b]quinoxa-line derivatives 7ai–ix
and 7bi–vi is synthesized by a simple multi-step protocol
starting from isatin 1a or 5-fluoroisatin 1b. These com-
pounds are screened against lung (A-549), cervical (HeLa),
and prostate (DU-145) human cancer cell lines to evaluate
their cytotoxic effect. Of all the compounds tested, five
compounds showed moderate cytotoxicity against human
reproductive organ cell lines, while others exhibited lower
cytotoxicity against different human cancer cell lines. An
elegant synthesis of these complex molecules and their
cytotoxicity data are presented.
1988). 6H-Indolo[2,3-b]quinoxalines are reported to show
DNA duplex stabilization (Wamberg et al., 2006), anti malarial
(Zarranz et al., 2005), and anticancer activities (Moarbess et al.,
2008; Karki et al., 2009; Toshima et al., 2004). Some indole-
fused quinoxaline compounds are reported to possess antiviral
properties (Harmenberg et al., 1988). Indolo[2,3-b]quinoxa-
lines are reported to be important DNA-intercalating agents
withboth antiviral and cytotoxic properties (Wilhelmsson et al.,
2008; Shibinskaya et al., 2010).
In view of their biological activity, there is a need to prepare
more and more new compounds based on indolo[2,3-b]quin-
oxaline skeleton for evaluating their antibiotic and cytotoxic
activity. Similarly, 1,2,3-triazoles have received attention
because of their wide range of applications as agrochemicals,
pharmaceuticals, dyestuffs, and florescent whiteners. They
have been used as fungicides, herbicides, light stabilizers,
optical brightening agents, and corrosion retardants. Several
1,2,3-triazole derivatives have exhibited significant antimicro-
bial (Sheremet et al., 2004; Allais and Meier, 1969), cytostatic,
virostatic (Diana and Nitz, 1993), antimalarial (Julino and
Stevens, 1998), and anti-inflammatory activities (Syed et al.,
2012). It will be interesting to see indolo[2,3-b]quinoxaline and
1,2,3-triazole moieties, which are considered to be powerful
pharmacophores on their own, to be incorporated into a single
molecule. The present investigation is aimed at synthesizing
novel heterocycles having N-aryl-substituted 1,2,3-triazoles
attached to the 6H-indolo[2,3-b]quinoxaline moiety via a
methylene bridge by a simple protocol as shown in Scheme 1
for evaluating their cytotoxic activity.
Keywords 1,2,3-Triazole Á 6H-indolo[2,3-b]quinoxaline Á
Anti-cancer activity Á Click chemistry
Introduction
Indolo[2,3-b]quinoxaline derivatives exhibit a wide range of
interesting biologic properties (Brown, 2004; Carta et al., 2005;
Varma and Pandey, 1981; Gazit et al., 1996; Abadi, 1998;
Deady et al., 1997; Bergman et al., 2003). These compounds
are similar in stereochemistry of their basic skeleton to a nat-
urally occurring alkaloid ellipticine, which is a known antitu-
mor agent (Bergman and Aakerfeldt, 1987; Harmenberg et al.,
S. Avula Á J. R. Komsani Á S. Koppireddi Á R. Yadla (&)
Fluoroorganics Division, CSIR—Indian Institute of Chemical
Technology, Hyderabad 500607, India
e-mail: ryadla@yahoo.com
Results and discussion
A. K. Kanugula Á S. Kotamraju
6H-indolo[2,3-b]quinoxaline (3a) and 9-fluoro-6H-indolo
[2,3-b]quinoxaline (3b) were prepared by the condensation of
Chemical Biology Division, CSIR—Indian Institute of Chemical
Technology, Hyderabad 500607, India
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Med Chem Res (2013) 22:3712–3718
3713
isatin (1a) or 5-fluoroisatin (1b), respectively, with o-phen-
ylenediamine (2) in glacial acetic acid under microwave
irradiation over a short duration of 3–6 min. The 6H-indo-
lo[2,3-b]quinoxaline (3a) and its 9-fluoro-analog (3b) thus
obtained were individually reacted with propargyl bromide
(4) in the presence of anhydrous potassium carbonate in
dry acetone resulting in the formation of 6-(prop-2-ynyl)-
6H-indolo[2,3-b]quinoxaline (5a) and 9-fluoro-6-(prop-2-
ynyl)-6H-indolo[2,3-b]quinoxaline (5b), respectively, in very
good yield. These N-propargyl-6H-indolo[2,3-b]quinoxaline
derivatives 5a–b were subjected to cycloaddition with a series
of substituted aromatic azides (6i–ix) in the presence of CuI as
catalyst to give exclusively 6-{(1-aryl-1H-1,2,3-triazol-4-yl)
methyl}-6H-indolo[2,3-b]quinoxaline derivatives (7ai–ix and
7bi–vi). The steps involved are depicted schematically in
Scheme 1.
the range d 5.8–5.9 ppm. The IR spectra of the N-propar-
gylic derivatives of indolo[2,3-b]quinoxalines 5a and 5b
contained the acetylenic stretching at 2,111 cm-1. The
aliphatic C–H stretching for methylene group in com-
pounds 7a and 7b appeared at 2,900–2,960 cm-1, while the
aromatic C–H stretching frequencies are observed in
between 3,000 and 3,130 cm-1. Spectral data for all the
new compounds prepared were presented against individ-
ual compounds in experimental section.
Biological activity
6-{(1-Aryl-1H-1,2,3-triazol-4-yl)methyl}-6H-indolo[2,3-b]
quinoxaline derivatives (7a and 7b) were screened against
three human cancer cell lines such as cervical (HeLa), pros-
tate (DU-145) and lung (A-549) by MTT assay to check their
cytotoxic effect at 10.0 lm concentration using DMF as
solvent. Of the 13 compounds tested, 9-fluoro-6-{(1-phenyl-
1H-1,2,3-triazol-4-yl)methyl}-6H-indolo[2,3-b]quinoxaline
All the new compounds were characterized by 1H NMR,
ESI-MS, high-resolution mass spectra (HRMS), and IR
1
spectroscopy. In H NMR spectra, the distinct methylene
bridge protons in compounds 7a and 7b were observed in
R
O
O
NH2
NH2
R
N
N
Gla. AcOH
M.W.
360W, 3min.
N
H
N
H
1a) R = H
1b) R = F
2
3a) R = H
3b) R = F
Br
R1-N3
6 i -ix
R
N
R
N
N
4
Dry Acetone,
K2CO3,Reflex
3hrs
Dry THF, CuI
RT,4hrs
N
N
N
N R1
N
N
5a) R = H
5b) R = F
7ai -ix) R = H
7bi -vi) R = F
CF3
Cl
Br
F
R1 =
i
ii
iv
v
iii
NO2
F
F
F
O
Cl
Cl
F
ix
viii
vi
vii
Scheme 1 Preparation of 6-{(1-aryl-1H-1,2,3-triazol-4-yl)methyl}-6H-indolo[2,3-b]quinoxalines (7a & 7b)
123

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Med Chem Res (2013) 22:3712–3718
HeLa-cervical A-549 lung
Table 1 Cytotoxic activity of
7a and 7b derivatives against
DU-145 prostate, HeLa-
cerivical, and A-549 lung cells
treated for 72 h by MTT assay
at 10 lM concentration
S.
no.
Compound
DU-145 prostate
% Cell
viability
STDEV(
)
% Cell
viability
STDEV(
)
% Cell
viability
STDEV( )
1
Control (DMF)
100
1.1
100
1.1
100
1.5
2.15
8.87
4.59
5.89
0.63
5.07
4.60
8.32
10.86
7.74
0.70
8.27
7.75
6.99
2
Doxorubicin
7aii
9
3.2
12
3.2
6.33
3
77.48
83.17
76.53
85.40
77.38
76.09
77.57
72.64
73.17
84.99
77.51
90.10
77.34
8.34
7.11
1.51
6.13
2.42
2.21
1.34
4.97
2.82
7.71
2.66
3.06
5.29
77.47
77.36
76.92
75.59
80.72
93.61
81.55
92.05
77.70
91.86
86.43
89.42
86.83
4.96
3.79
3.11
3.14
5.41
7.80
5.84
7.96
3.42
1.62
6.44
7.63
4.34
104.37
94.74
83.38
85.45
94.74
83.46
98.35
97.75
91.87
97.09
93.72
94.73
87.86
4
7aiii
5
7aiv
6
7av
7
7avi
8
7avii
7aviii
7bi
9
10
11
12
13
14
15
7bii
7biii
7biv
7bv
7bvi
STDEV Standard deviation
(7bi) and 6-{[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]
methyl}-9-fluoro-6H-indolo[2,3-b]quinoxaline (7bii) exhib-
ited about 30 % cytotoxic effect against DU-145 prostate
cell line.
Experimental
Melting points of all the compounds were recorded on Casia-
Siamia (VMP-AM) melting point apparatus and were uncor-
rected. IR spectra were recorded on a Perkin-Elmer FT-IR
240-C spectrophotometer using KBr optics. 1H NMR spectra
were recorded on Bruker AV 300 MHz/Avance 300 MHz
units in CDCl3 or DMSO-d6 using TMS as internal standard.
All HRMS were recorded on QSTARXL hybrid MS/MS sys-
tem (applied Biosystems, USA) under electrospray ionization
technique. The reactions were monitored by thin layer chro-
matography (TLC) on glass plates precoated with silica gel 60
F254 and the spots were visualized under UV light. Mercksilica
gel (60–120 mesh) was used for column chromatography.
Remaining compounds except 7aiii, 7av, 7biii, and 7bv
exhibited more than 20 % cytotoxic effect at 10.0 lm
concentration in DU-145. Compound 7av was more active
compared to the remaining compounds against HeLa cell
line. However, A-549 cell line has shown to be more
resistant compared to other two cell lines. The cytotoxicity
data are presented in the Table 1.
Based on the above cytotoxicity data, it is observed that
these compounds were more effective toward reproductive
organ cell lines and probably they may act against any of
the reproductive pathways to inhibit their biologic activity.
Preparation of 9-substituted-6H-indolo[2,3-b]
quinoxalines 3a–b: (Manna and Agrawal, 2009)
Conclusion
A mixture of substituted isatin 1 (1 g, 0.006 mol) and
ortho-phenylenediamine 2 (0.734 g, 0.006 mol) in 1.5 ml
glacial acetic acid was taken into a seal tube, mixed well,
placed in microwave oven, and irradiated for about 6 min
at 180 W. The progress of the reaction was monitored by
TLC. After the completion of the reaction, the reaction
mixture was poured in ice-cold water and neutralized with
NaHCO3 solution. The solid was separated, filtered, dried,
and recrystallized from DMF.
Several new 6-{(1-aryl-1H-1,2,3-triazol-4-yl)methyl}-
6H-indolo[2,3-b]quinoxaline derivatives (7ai–ix) and their
9-fluoro-substituted analogs (7bi–vi) were prepared by an
elegant, but simple, strategy in good yield and screened for
their anticancer activity against three human cancer cell
lines. These compounds showed mild to moderate cyto-
toxicity toward the three cell lines studied. Substitution of
fluorine at 9-position in the indolo[2,3-b]quinoxaline
skeleton along with the presence of CF3, Cl, or H in the
3-position of the aryl moiety present on the triazole ring
enhanced their activity substantially against human repro-
ductive organ cancer cell lines.
6H-indolo[2,3-b]quinoxaline 3a
Yellow solid, yield: 95 %, mp: [250 °C (lit. 264 °C)
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Med Chem Res (2013) 22:3712–3718
3715
9-Fluoro-6H-indolo[2,3-b]quinoxaline 3b
Yellow solid, yield: 92 %, mp: [250 °C, IR (KBr)cm-1
3442(–NH), 3094(Ar–H), 2848(–CH–), 1593(C=N),
1488(N=N), 758(C–N); 1H NMR (CDCl3, 300 MHz)
d ppm; 8.88 (br, –NH, 1H), 8.18–8.21 (d, 1H, J =
8.12 Hz), 7.97–8.04 (m, 2H), 7.62–7.75 (m, 2H), 7.51–7.55
(dd, 1H, J = 8.87, 4.15 Hz), 7.35–7.42 (dd, 1H, J = 8.87,
2.44 Hz); ESI-MS: 238 (M??1); HRMS: m/z calcd. for
C14H9N3F [M?H]?: 238.0776, found: 238.0775.
Preparation of 6-{(1-aryl-1H-1,2,3-triazol-4-yl)
methyl}-6H-indolo[2,3-b]quinoxalines (7ai–ix and 7bi–vi
)
:
The corresponding propargylated indolo[2,3-b]quinoxiline
5 (0.583 mmol) was dissolved in dry THF (8 ml) and
catalytic amount of CuI was added. Then, the substituted
aromatic azide 6 (0.583 mmol) in dry THF was slowly
added at room temperature under nitrogen atmosphere and
stirring continued for 12 h. The solvent was removed under
reduced pressure; the residue was diluted with cold dis-
tilled water, and extracted thrice with dichloromethane.
The combined organic layer was dried over anhydrous
Na2SO4 and concentrated to get the product. The crude
product was purified by column chromatography.
Preparation of 9-substituted-6-propargyl-indolo
[2,3-b]quinoxalines 5a–b
Compound 3a (1 g, 0.0045 mol) and propargyl bromide 4
(0.5429 g, 0.0045 mol) were taken in a 100-ml two neck-
R.B. flask containing dry acetone (15 ml). To this, (1.24 g,
0.009 mol) of anhydrous potassium carbonate was added
and the reaction mixture was refluxed for about 4 h. After
the completion of the reaction (followed by TLC), solvent
was removed under reduced pressure; the residue was
poured into distilled ice cold water and extracted with
chloroform. The organic layer was dried over anhydrous
Na2SO4 and concentrated to get the product. The crude
product was purified by column chromatography.
6-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-6H-indolo
[2,3-b]quinoxaline 7ai
Yellow solid, yield: 93 %, mp: 245–246 °C, IR (KBr, m,
cm-1): 3123, 3078, 1582, 1467, 1237, 1051, 752; 1H NMR
(DMSO-d6, 300 MHz) d ppm: 8.43 (d, 1H, J = 6.86 Hz),
8.29 (d, 1H, J = 7.84 Hz), 8.12 (d, 1H, J = 7.84 Hz), 7.86
(s, 1H), 7.61–7.77 (m, 6H), 7.33–7.42 (m, 4H), 5.88 (s,
2H); ESI-MS: 377 (M??1); HRMS: m/z calcd. for
C23H17N6 [M?H]?: 377.1514, found: 377.1533.
6-((1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-
6-(Prop-2-ynyl)-6H-indolo[2,3-b]quinoxaline 5a
6H-indolo[2,3-b]quinoxaline 7aii
Yellow solid, yield: 93 %, mp: 205–206 °C, IR (KBr,
cm-1): 3279 (:C–H), 3058 (Ar–H), 2922 (C–H), 2112
(C:C), 1584 (C=N), 1466, 757 (C–N); H NMR (CDCl3,
300 MHz) d ppm: 8.45–8.47 (d, 1H, J = 7.55 Hz),
8.24–8.28 (dd, 1H, J = 8.30, 1.51 Hz), 8.07–8.11 (dd,
1H, J = 8.30, 1.51 Hz), 7.60–7.76 (m, 4H), 7.43–7.38 (t,
1H, J = 2.26 Hz), 5.29 (d, 1H, J = 2.26 Hz), 2.25 (t, 1H,
J = 2.26 Hz); ESI-MS: 258 (M??1); HRMS: m/z calcd.
for C17H12N3 [M?H]?: 258.10276, found: 258.10257.
Yellow solid, yield: 95 %, mp: 241–242 °C, IR (KBr, m,
cm-1): 3073, 2921, 2854, 1590, 1479, 1405, 1193, 1111,
1044, 752; 1H NMR (DMSO-d6, 300 MHz) d ppm: 8.83 (s,
1H), 8.42 (d, 1H, J = 7.55 Hz), 8.31 (d, 1H, J = 7.93 Hz),
8.17 (d, 1H, J = 8.30 Hz), 7.94 (s, 1H), 7.74–7.86 (m, 5H),
7.55 (m, 2H), 7.44 (m, 1H), 5.91 (s, 2H); ESI-MS: 411
(M??1); HRMS: m/z calcd. for C23H16N6Cl [M?H]?:
411.1124, found: 411.1139.
1
6-((1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-
9-Fluoro-6-(prop-2-ynyl)-6H-indolo[2,3-b]quinoxaline 5b
6H-indolo[2,3-b]quinoxaline 7aiii
Yellow solid, yield: 92 %, mp: 195–196 °C, IR (KBr,
cm-1): 3289 (:C–H), 3190 (Ar–H), 2924 (C–H), 2111
(C:C), 1586 (C=N), 1481, 760 (C–N); H NMR (CDCl3,
Yellow solid, yield: 94 %, mp: 229–230 °C, IR (KBr, m,
cm-1): 3132, 3087, 2924, 2855, 1584, 1517, 1481, 1280,
1
1
1239, 1113, 1048, 759; H NMR (DMSO-d6, 300 MHz)
300 MHz) d ppm: 8.35–8.40 (d, 1H, J = 7.66 Hz),
8.21–8.25 (d, 1H, J = 8.20 Hz), 8.04–8.09 (d, 1H,
J = 8.20 Hz), 7.60–7.70 (m, 3H), 7.35–7.40 (t, 1H,
J = 2.26 Hz), 5.27 (d, 1H, J = 2.26 Hz), 2.25 (t,
1H, J = 2.26 Hz); ESI-MS: 276 (M??1); HRMS: m/z
calcd. for C17H11N3F [M?H]?: 276.0933, found: 276.0931.
d ppm: 8.54 (s, 1H), 8.40 (d, 1H, J = 6.79 Hz), 8.25 (d,
1H, J = 8.12 Hz), 8.15 (d, 1H, J = 7.36 Hz), 7.94 (s, 1H),
7.69–7.84 (m, 6H), 7.40 (t, 1H, J = 6.23 Hz), 7.19 (m,
2H), 5.87 (s, 2H); ESI-MS: 395 (M??1); HRMS: m/z
calcd. for C23H16N6F [M?H]?: 395.1420, found:
395.1425.
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Med Chem Res (2013) 22:3712–3718
1039, 752; 1H NMR (DMSO-d6, 300 MHz) d ppm: 8.80 (s,
1H), 8.42 (d, 1H, J = 7.55 Hz), 8.30 (d, 1H, J = 6.61 Hz),
8.17 (d, 1H, J = 8.12 Hz), 7.74–7.89 (m, 5H), 7.52–7.72
(m, 5H), 7.19 (m, 2H), 7.05 (s, 1H), 5.88 (s, 2H), 5.12 (s,
2H); ESI-MS: 501 (M??1); HRMS: m/z calcd. for
C30H22N6OF [M?H]?: 501.1839, found: 501.1839.
6-((1-(3-(Trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)-6H-indolo[2,3-b]quinoxaline 7aiv
Yellow solid, yield: 92 %, mp: 238–239 °C, IR (KBr, m, cm-1):
3128, 3082, 2915, 2842, 1580, 1515, 1492, 1275, 1218, 1112,
1
1032, 755; H NMR (DMSO-d6, 300 MHz) d ppm: 8.88 (s,
1H), 8.40 (d, 1H, J = 7.74 Hz), 8.26 (d, 1H, J = 7.93 Hz),
8.14–8.18 (m, 3H), 7.70–7.83 (m, 6H), 7.41 (t, 1H,
J = 7.23 Hz), 5.90 (s, 2H); ESI-MS: 445 (M??1); HRMS: m/z
calcd. for C24H16N6F3 [M?H]?: 445.1388, found: 445.1388.
6-((1-(4-Chloro-2-nitrophenyl)-1H-1,2,3-triazol-4-
yl)methyl)-6H-indolo[2,3-b]quinoxaline 7aix
Yellow solid, yield : 89 %, mp: 240–241 °C, IR (KBr, m,
cm-1): 3070, 2930, 2850, 1596, 1579, 1465, 1405, 1111,
1044, 762; 1H NMR (DMSO-d6, 300 MHz) d ppm:
8.46–8.48 (d, 1H, J = 7.55 Hz), 8.30–8.32 (d, 1H,
J = 8.30 Hz), 8.14–8.17 (d, 1H, J = 8.30 Hz), 8.03 (d,
1H, J = 2.26 Hz), 7.82 (s, 1H), 7.63–7.78 (m, 5H),
7.39–7.44 (m, 2H), 5.91 (s, 2H); ESI-MS: 456 (M??1);
HRMS: m/z calcd. for C23H15N7ClO2 [M?H]?: 456.1231,
found: 456.1342.
6-((1-(2-Bromophenyl)-1H-1,2,3-triazol-4-yl)methyl)-6H-
indolo[2,3-b]quinoxaline 7av
Yellow solid, yield: 93 %, mp: 192–193 °C, IR (KBr, m,
cm-1): 3129, 3090, 2925, 2840, 1604, 1520, 1490, 1260,
1
1212, 1114, 1035, 754; H NMR (DMSO-d6, 300 MHz)
d ppm: 8.38 (d, 1H, J = 6.04 Hz), 8.26 (s, 1H), 8.22 (d,
1H, J = 7.55 Hz), 8.12 (d, 1H, J = 8.30 Hz), 7.97 (s, 1H),
7.67–7.82 (m, 5H), 7.35–7.47 (m, 4H), 5.88 (s, 2H); ESI-
MS: 455 (M??1); HRMS: m/z calcd. for C23H16N6Br
[M?H]?: 455.0619, found: 455.0625.
9-Fluoro-6-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-6H-
indolo[2,3-b]quinoxaline 7bi
Yellow solid, yield: 91 %, mp:[250 °C, IR (KBr, m, cm-1
)
6-((1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-
6H-indolo[2,3-b]quinoxaline 7avi
: 3130, 3090, 2934, 2850, 1590, 1520, 1475, 1270, 1110,
1052, 758; 1H NMR (DMSO-d6, 300 MHz) d ppm: 8.44 (s,
1H), 8.25 (d, 1H, J = 7.55 Hz), 8.15 (d, 1H, J = 8.49 Hz),
8.09 (d, 1H, J = 7.55 Hz), 7.82 (s, 1H), 7.67–7.79 (m, 4H),
7.45 (m, 3H), 7.37 (d, 1H, J = 7.17 Hz), 5.88 (s, 2H); ESI-
MS: 395 (M??1); HRMS: m/z calcd. for C23H16N6F
[M?H]?: 395.1420, found: 395.1436.
Yellow solid, yield: 94 %, mp: 203–204 °C, IR (KBr, m,
cm-1): 3132, 3092, 2930, 2848, 1590, 1517, 1498, 1278,
1
1238, 1118, 1045, 763; H NMR (DMSO-d6, 300 MHz)
d ppm: 8.43 (d, 1H, J = 7.17 Hz), 8.28 (d, 1H,
J = 8.30 Hz), 8.11 (d, 1H, J = 8.30 Hz), 7.98 (d, 1H,
J = 2.83 Hz), 7.86 (m, 1H), 7.63–7.79 (m, 4H), 7.35–7.40
(t, 1H, J = 7.17 Hz), 6.92–7.02 (m, 2H), 5.87(s, 2H); ESI-
MS: 413 (M??1); HRMS: m/z calcd. for C23H15N6F2
[M?H]?: 413.1319, found: 413.1320.
6-((1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-9-
fluoro-6H-indolo[2,3-b]quinoxaline 7bii
Yellow solid, yield: 90 %, mp: 215–216 °C, IR (KBr, m,
cm-1): 3128, 3089, 2930, 2850, 1590, 1520, 1488, 1275,
6-((1-(4-Chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-
1
1235, 1116, 1045, 759; H NMR (DMSO-d6, 300 MHz)
yl)methyl)-6H-indolo[2,3-b]quinoxaline 7avii
d ppm: 8.58 (s, 1H), 8.25 (d, 1H, J = 8.30 Hz), 8.15 (d,
1H, J = 8.12 Hz), 8.10 (d, 1H, J = 8.12 Hz), 7.86 (s, 1H),
7.67–7.81 (m, 5H), 7.33–7.48 (m, 3H), 5.88 (s, 2H); ESI-
MS: 429 (M??1); HRMS: m/z calcd. for C23H15N6FCl
[M?H]?: 429.1392, found: 429.1402.
Yellow solid, yield: 92 %, mp: 235–236 °C, IR (KBr, m,
cm-1): 3066, 1580, 1504, 1464, 1405, 1190, 1104, 748; 1H
NMR (DMSO-d6, 300 MHz) d ppm: 8.71 (s, 1H), 8.40 (d,
1H, J = 7.55 Hz), 8.25 (d, 1H, J = 8.12 Hz), 8.14 (d, 1H,
J = 6.98 Hz), 8.04 (dd, 1H, J = 6.42, 6.23 Hz), 7.69–7.88
(m, 5H), 7.38–7.47 (m, 2H), 5.88 (s, 2H); ESI-MS: 429
(M??1); HRMS: m/z calcd. for C23H15N6FCl [M?H]?:
429.1047, found: 429.1049.
9-Fluoro-6-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-
yl)methyl)-6H-indolo[2,3-b]quinoxaline 7biii
Yellow solid, yield: 94 %, mp: 246–247 °C; IR (KBr, m,
cm-1): 3132, 3091, 2928, 2852, 1592, 1518, 1490, 1280,
6-((1-(3-(4-Fluorobenzyloxy)phenyl)-1H-1,2,3-triazol-4-
1
1240, 1111, 1042, 757; H NMR (DMSO-d6, 300 MHz)
yl)methyl)-6H-indolo[2,3-b]quinoxaline 7aviii
d ppm: 8.77 (s, 1H), 8.30 (d, 1H, J = 7.93 Hz), 8.22 (dd,
1H, J = 8.12, 10.57 Hz), 8.18 (d, 1H, J = 8.30 Hz),
7.75–7.89 (m, 5H), 7.64 (dd, 1H, J = 9.25, 9.06 Hz),
Yellow solid, yield: 90 %, mp: 224–225 °C, IR (KBr, m,
cm-1): 3058, 2925, 1605, 1495, 1469, 1412, 1207, 1151,
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Med Chem Res (2013) 22:3712–3718
3717
7.35–7.43 (m, 2H), 5.90 (s, 2H); ESI-MS: 413 (M??1);
HRMS: m/z calcd. for C23H14N6F2 [M?H]?: 413.1426,
found: 413.1432.
cells were washed with Dulbecco’s phosphate buffered
saline (DPBS) and 10 ll of 5 mg/ml MTT solution in
200 ll of culture medium was added and incubated for 1 h
at 37 °C. Cells were solubilized with 200 ll of DMF and
the absorbance was measured at 562 nm in a spectropho-
tometer. The absorbance of the wells containing treated
cells was compared with that of the wells in which the drug
is omitted (control).
9-Fluoro-6-(1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)-6H-indolo[2,3-b] quinoxaline 7biv
Yellow solid, yield: 92 %, mp: 228–229 °C, IR (KBr, m,
cm-1): 3120, 3062, 2914, 2832, 1589, 1515, 1490, 1265,
1
1220, 1122, 1032, 765; H NMR (DMSO-d6, 300 MHz)
Acknowledgments A. Sreenivas, K. Jayaram Reddy, K. Satish, and
K. Koteswara Rao are thankful to CSIR, New Delhi, for providing
Senior Research Fellowship. Ramanujan Fellowship to K. Srigiridhar
from DST, India, is greatly acknowledged.
d ppm: 8.82 (s, 1H), 8.45 (d, 1H, J = 7.74 Hz), 8.28 (d,
1H, J = 7.93 Hz), 8.10–8.15 (m, 3H), 7.70–7.83 (m, 5H),
7.41 (t, 1H, J = 7.23 Hz), 5.90 (s, 2H); ESI-MS: 463
(M??1); HRMS: m/z calcd. for C24H15N6F4 [M?H]?:
463.1294, found: 463.1313.
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Yellow solid, yield: 91 %, mp: 220–221 °C, IR (KBr, m,
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1055, 762; 1H NMR (DMSO-d6, 300 MHz) d ppm: 8.42 (s,
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