InCl3 mediated one-pot multicomponent synthesis, anti-microbial, antioxidant and anticancer evaluation of 3-pyranyl indole derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.07.039

A simple and convenient method for the one-pot three-component synthesis of 3-pyranyl indoles has been accomplished by tandem Knoevenagel-Michael reaction of 3-cyanoacetyl indole, various aromatic aldehydes and malononitrile catalyzed by InCl₃ in ethanol under reflux conditions. The newly synthesized 3-pyranyl indoles were evaluated for anti-microbial, antioxidant, and anticancer activities. Some of the compounds showed good anticancer activity against MCF-7 breast cancer cell lines on comparison with of standard drug.

Full text of DOI:10.1016/j.bmcl.2010.07.039

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5054–5061
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
InCl3 mediated one-pot multicomponent synthesis, anti-microbial,
antioxidant and anticancer evaluation of 3-pyranyl indole derivatives
Neelakandan Vidhya Lakshmi a, Prakasam Thirumurugan a, K. M. Noorulla b, Paramasivan. T. Perumal a,
*
a Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India
b Department of Pharmaceutical Chemistry, C.L. Baid Metha College of Pharmacy, Old Mahabalipuram Road, Jyothi Nagar, Thorapakkam, Chennai, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and convenient method for the one-pot three-component synthesis of 3-pyranyl indoles has
been accomplished by tandem Knoevenagel–Michael reaction of 3-cyanoacetyl indole, various aromatic
aldehydes and malononitrile catalyzed by InCl3 in ethanol under reflux conditions. The newly synthe-
sized 3-pyranyl indoles were evaluated for anti-microbial, antioxidant, and anticancer activities. Some
of the compounds showed good anticancer activity against MCF-7 breast cancer cell lines on comparison
with of standard drug.
Received 26 April 2010
Revised 8 July 2010
Accepted 9 July 2010
Available online 13 July 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
3-Cyanoacetyl indole
Anti-microbial activity
Pyran ring
Aldehyde
N
The structural diversity and biological importance of nitrogen
containing heterocycles have made them attractive targets for syn-
thesis over many years. They are found in various natural products
and have been identified as products of chemical and biological
importance. Multicomponent reactions (MCR) have emerged as a
powerful tool for delivering the molecular diversity needed in
the combinatorial approaches for the preparation of bioactive het-
erocyclic compounds.1,2
R2
NH2
R1
N
N
R2
R3
N
N
N
R1
R1
N
H
H
H
R4
2, 4 bis(3-indolyl)pyrimidines
H
Meridianins A - E
O
N
N
Multifunctionalized 4H-pyrans are important class of com-
pounds present in several natural or synthetic compounds with
important biological or pharmacological activities such as anti-
coagulant, anticancer, antioxidant, spasmolytic, diuretic, and
anti-anaphylactic activities. A number of 2-amino-4H-pyran deriv-
atives are used as photoactive materials, cosmetics, and pigments.3
Hence, the synthesis of 4H-pyrans has received a great attention of
the researchers.
N
N
H
R1
Br
R1
N
H
N
Br
N
H
N
H
H
Hamacanthin B
Nortosentins A-C
O
O
OH
N
S
Interest in synthesizing new indole derivatives continue due to
their biological properties such as anti-inflammatory, anticonvul-
sant, cardiovascular, antibacterial, and also their presence in
various natural products such as alkaloids.4 In particular, 3-substi-
tuted indole derivatives play a key role in the synthesis of
biologically active compounds especially with anticancer, anti-
tumor, hypoglycemic, anti-inflammatory, analgesic and antipyretic
activities.5 Some of the biologically active 3-substituted indole rep-
resentatives are shown in Figure 1.6
O
N
H
R1
N
R1
H
Indomethacin
2, 5 bis(3-indolyl)thiophenes
Figure 1. Representatives of 3-substituted indoles.
CN
O
H2N
Ar
O
NC
O
NH
InCl3
Ethanol, reflux
+
+
NC
CN
Ar
H
N
H
CN
1
2
3
4
* Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail addresses: ptperumal@gmail.com, sibi.gb@gmail.com (P.T. Perumal).
Scheme 1. Synthesis of 3-pyranyl indole derivatives.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.039

N. V. Lakshmi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5054–5061
5055
Table 1
and –NH proton of indole ring, respectively, which proved the
incorporation of indole ring in the structure. The benzylic charac-
teristic carbon was resonated at d 56.8 in the 13C NMR spectrum.
The aromatic protons were appeared in the region of d 112.9-
159.3. Moreover, the presence of a molecular ion peak at m/z
388.4 (M+) in the mass spectrum of 4b confirmed the structure
of 4b. The relative stereochemistry of the product 4b was estab-
lished through single-crystal X-ray analysis (Fig. 2).18
The characteristic peaks of –NH2 and –CN groups were
appeared at 3433, 3316, and 2200, respectively, in the IR spectrum
of 4q.26 In the 1H NMR spectrum of 4q, the benzylic proton
resonated as a singlet at d 4.82. A singlet at d 6.07 appeared for
–OCH2O– protons in 1H NMR spectrum. The signal at d 11.95 cor-
responds to –NH proton of indole ring. The benzylic carbon signal
was appeared at d 55.2 ppm in 13C NMR spectrum of 4q. The aro-
matic carbons were resonated in the region of d 112.8–159.4 in
the 13C NMR spectrum. The mass spectrum displayed the (M+) peak
at m/z 461.2. The stereochemistry of the product was assigned by
analogy of compound 4b.
The newly synthesized compounds have indole and pyran nu-
clei in their structures which possess antibacterial, antioxidant
and anticancer properties.3–5 Hence, we have decided to study
antibacterial, antioxidant and anticancer activities for all the newly
synthesized compounds.
All compounds 4a–q were screened for their antibacterial activ-
ity by paper disc diffusion method19 against two Gram-positive
bacteria (Staphylococcus aureus ATCC 9144, Bacillus cereus ATCC
11778), and two Gram-negative bacteria (Escherichia coli ATCC
25922, Klebsiella pneumoniae ATCC 11298). Ciprofloxacin is used
as reference compound. In this technique, the filter paper (What-
mann No. 1) sterile disks of 6 mm diameter impregnated with
Screening of various Lewis acids and bases in ethanol
Entry
Lewis acids and bases
Yielda,b (%)
1
2
3
4
5
6
7
SnCl2ꢁ2H2O
AlCl3
InCl3
K2CO3
NaOH
Pyridine
NEt3
52
26
85
38
21
74
83
a
Isolated yield.
b
All reactions were carried out with 20 mol % of Lewis acids
and bases for 40 min at reflux temperature.
The wide-ranging biological activity associated with 3-substi-
tuted indole and pyran derivatives, both naturally occurring and
synthetic, ensures that the synthesis of these important ring sys-
tems remains a topic of current interest. Various methods for the
preparation of these compounds have been reported. However,
these methods suffer from tedious synthetic routes, longer reaction
time, drastic reaction conditions, as well as narrow substrate
scope.7–9
Recently, the utility of indium(III) Lewis acids10 in organic syn-
thesis has received a great attention due to their relatively low tox-
icity, stability in air and water and recyclability. To the best of our
knowledge, there have been no reports for the synthesis of indol-3-
yl derivatives including pyranyl moieties using 3-cyanoacetyl in-
dole. In continuation of our research on the development of new
synthetic methods for 3-substituted indoles,11–13 use of green
chemical techniques,14–16 and the application of InCl311,17 in organ-
ic synthesis, herein, we report a simple and facile one pot proce-
dure for the synthesis of 3-pyranyl indole derivatives in ethanol
under reflux condition.
In our initial endeavor, we have investigated a three component
reaction of 3-cyanoacetyl indole 1, benzaldehyde 2a, and malono-
nitrile 3 in different solvent systems like methanol, ethanol, tolu-
ene, and acetonitrile and in presence of various Lewis acids and
bases under reflux condition to afford polyfunctionalized 3-pyra-
nyl indoles 4 (Scheme 1).
the test compounds (100 lg/ml of dimethyl formamide) were
placed in the nutrient agar plates20 and the plates were pre-incu-
bated for 1 h at room temperature and incubated at 37 °C for
24 h for antibacterial activity. The inhibition zones around the
dried disks were measured after 24 h. MIC of the compound was
determined by agar streak dilution method.20 A stock solution of
the synthesized compound (100 l
g mlꢀ1) in dimethyl formamide
was prepared and graded quantities of the test compounds were
incorporated in specified quantity of molten sterile agar (nutrient
agar for antibacterial activity). A specified quantity of the medium
(40–50 °C) containing the compound was poured into a petridish
to give a depth of 3–4 mm and allowed to solidify. Suspension of
the micro-organism were prepared to contain approximately 105
CFU mlꢀ1 (colony forming unit/ml) and applied to plates with seri-
ally diluted compounds in dimethyl formamide to be tested and
incubated at 37 °C for 24 h for bacteria. The MIC was considered
to be the lowest concentration of the test substance exhibiting
no visible growth of bacteria on the plate. The observed zone of
inhibition and MIC are presented in Table 3 which shows the ob-
served antibacterial activities of 3-pyranyl indoles. The diameter
of zone of inhibition was measured in mm. 2-Amino-4-(2-chloro-
phenyl)-6-(1H-indol-3-yl)-4H-pyran-3,5-dicarbonitrile 4e was
found to exhibit the more potent invitro antibacterial activity with
the MIC of 12.4, 16.4, 16.5, and 16.1 against S. aureus, B. cereus,
E. coli, K. pneumoniae, respectively. The compounds 4a, 4d, 4h,
and 4m exhibited significant antibacterial activity when compared
to standard drug ciprofloxacin due to the presence of the substitu-
ents such as –Cl, –F, –OMe groups in the benzene ring. Other com-
pounds showed moderate antibacterial activity.
Among the Lewis acids (Table 1, entry 1, 2, and 3) tried by us,
InCl3 has catalyzed the reaction in shorter reaction time with high
yield. Among the bases (Table 1, entry 4, 5, 6, and 7) triethyl amine
has catalyzed the reaction with high yield. The best results were
obtained by refluxing the reaction mixture in ethanol in presence
of 20 mol % of InCl3.
The scope and limitations of the reaction were further studied
with various substituted aldehyde derivatives. Under optimized
conditions, the reaction proceeded smoothly with various alde-
hydes, including those containing electron withdrawing and elec-
tron releasing groups to provide 3-pyranyl indoles 4a–q in good
yields (68–87%). The results are given in Table 2.
Based on the above results, a plausible mechanism is proposed
(Scheme 2). Initially malononitrile 3 undergoes tautomerisation to
give 3a. 3-Cyanoacetyl indole 1 undergoes Knoevenagel condensa-
tion with aromatic aldehyde 2 to give 1a in presence of InCl3. The
intermediate 1a can be isolated and its formation was proved by
NMR.24 Compound 1a undergoes Michael addition with the tauto-
mer of malononitrile 3a to give 3b. Compound 3b enolises to afford
the intermediate 3c which gives 3d via the nucleophilic addition of
hydroxyl group to the cyano group. Finally 3d rearranges via pro-
ton transfer to yield 3-pyranyl indole 4.
The structures of 3-pyranyl indole derivatives 4a–q were con-
firmed by spectroscopic studies and elemental analysis. IR spec-
trum of 4b showed peaks at 3423, 3332, and 2198 for –NH2 and
–CN groups, respectively.25 The 1H NMR spectrum of compound
4b exhibited two singlets at d 5.38 and 11.97 for benzylic proton
The newly synthesized compounds 4a–q were also tested for
antioxidant activity by observing their interaction with the stable
free radicals DPPH21 and ABTS22 using the standard drug ascorbic
acid (Tables 4 and 5). The antioxidant activity of the test compounds
and standard were assessed on the basis of the radical scavenging ef-
fect of the stable DPPH free radical. To a 50, 100, 200, and 400 lg/ml

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Table 2
Synthesis of 3-pyranyl indole derivatives
Entry
Aldehyde
CHO
Producta
Time (min)
Yieldb (%)
2a
NC
CN
CN
1
30
87
H2N
O
O
NH
NH
4a
4b
CHO
2b
2
40
81
NC
H2N
CHO
2c
3
45
76
NC
CN
H2N
O
NH
4c
4d
CHO
Cl
Cl
2d
4
30
82
NC
CN
CN
H2N
O
NH
CHO
Cl
Cl
NC
2e
5
6
45
30
72
88
H2N
O
NH 4e
Br
CHO
2f
NC
CN
Br
H2N
O
4f
NH
NH
Br
CHO
2g
NC
CN
7
45
71
Br
H2N
O
F
4g
CHO
2h
8
9
35
50
82
68
NC
CN
CN
F
H2N
O
O
NH
NH
4h
4i
CHO
Cl
NC
F
2i
H2N

N. V. Lakshmi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5054–5061
5057
Table 2 (continued)
Entry
Aldehyde
Producta
Time (min)
Yieldb (%)
CHO
2j
10
30
83
NC
CN
CN
H2N
O
O
NH
NH
4j
CHO
2k
NC
11
12
40
45
71
68
H2N
4k
CHO
NO2
2l
NC
CN
O2N
H2N
O
4l
NH
CHO
OMe
2m
13
14
15
45
40
45
81
71
68
NC
CN
OMe
H2N
O
NH 4m
CHO
OMe
OMe
MeO
2n
MeO
CN
NC
H2N
O
4n
NH
CHO
OMe
OMe
MeO
Br
2o
OMe
Br
CN
NC
H2N
O
4o
NH
CHO
N
2p
16
N
35
76
NC
CN
H2N
O
4p
NH
CHO
O
O
Br
2q
Br
O
17
40
72
O
NC
CN
H2N
O
NH 4q
a
The products were characterized by NMR, IR, mass and elemental analysis.
Isolated yield.
b
***
of each test compounds and standard, 1 ml of DPPH and methanol
(0.33%) were added in a test tube. After incubation at 37 °C for
30 min, the absorbance of each solution was determined at
517 nm using spectrophotometer. The corresponding blank reading
was also taken and the results in percentage were expressed as the
ratio of absorbance decrease at 517 nm and the absorbance of DPPH
solution in the absence of 3-pyranylindoles.
The antioxidant activity of the test compounds and standard
were assessed on the basis of the radical scavenging effect of the
stable ABTS free radical. The ABTSÅ+ solution was prepared by mix-
ing 0.02 mol of ABTS salt with 0.01 mol of potassium persulfate in
25 ml of distilled water. The solution was held at room tempera-
ture in the dark for 16 h before use. Then the ABTSÅ+ solution was
diluted with methanol in order to obtain an absorbance between

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N. V. Lakshmi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5054–5061
InCl3
..
InCl3
NH
N
H
CN
CN
enimine
3
3a
CN
CN
InCl3
N
O
InCl3
CN
CN
..
NH
Ar
H
O
O
Ar
O
InCl3
Ethanol, reflux
CN
+
3a
Ar
H
N
N
N
H
H
H
1
2
1a
3b
InCl3
InCl3
NH
H2N
CN
CN
N
O
H+ transfer
O
H+ transfer
O
Ar
NC
H
NC
NH
H
NH
Ar
Ar
CN
CN
N
H
4
3d
3c
Scheme 2. Plausible mechanism for the synthesis of 3-pyranyl indoles 4.
Figure 2. ORTEP diagram of compound 4b.
0.7 and 0.9 at 734 nm using the spectrophotometer. Fresh ABTSÅ+
solutions were prepared for each assay. To a 50, 100, 200, and
acid in DPPH method is found to be less than 50
values of the compounds in ABTS method 4m, 4n, 4o, and 4p were
found to be 900, 858.69, 867.28, and 880.30 g/ml, respectively.
IC50 value of the standard ascorbic acid in ABTS method is found
to be 650 g/ml. The analysis of Tables 4 and 5 leads us to conclude
that radical scavenging activity of 3-pyranyl indoles in both DPPH
and ABTS method increases with increase in the concentration
(Figs. 3, 4 and 5).
The compounds 4b, 4c, 4f, 4h, 4i, and 4n were evaluated for anti-
cancer activity against MCF-7 breast cancer cell lines using the stan-
dard drug doxorubicin (Table 6). In vitro cytotoxicity was
determined using a standard MTT assay23 with protocol appropriate
for the individual test system. MTT [(3-(4,5-dimethylthiazol-2yl)-
2,5-diphenyltetrazoliumbromide] measures the metabolic activity
of the viable cells. During incubation period, viable cells convert
MTT to a water-insoluble formazan dye. In brief, exponentially
growing cells were plated in 96-well plates (104 cells/wells in
lg/ml. The IC50
400
l
g/ml of each test compounds and standard, 1 ml of ABTSÅ+
l
solution was added and allowed to react for 2 h in dark condition.
Then the absorbance was taken at 734 nm using the spectropho-
tometer. The corresponding blank reading was also taken and the
results in percentage were expressed as the ratio of absorbance de-
crease at 734 nm and the absorbance of ABTSÅ+ solution in the ab-
sence of 3-pyranylindoles.
The compounds 4m, 4n, 4o, and 4p showed good radical scav-
enging activity in both DPPH and ABTS method due to the presence
of electron donating groups such as –OMe and –N(CH3)2 in the
benzene ring when compared with the standard drug ascorbic acid
in both DPPH and ABTS method. Other compounds except 4c, 4d,
4g, 4i, and 4l showed moderate antioxidant activity. IC50 values
of the compounds 4m, 4n, 4o, and 4p were found to be less than
l
50 lg/ml in DPPH method. The IC50 value of the standard ascorbic

N. V. Lakshmi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5054–5061
5059
Table 3
Table 5
Antibacterial activity of the synthesized compounds—in vitro activity—zone of
Antioxidant activities of the test compounds and standard using ABTS scavenging
method—% ABTS radical scavenging activity
inhibition in mm (MIC 100
l
g/ml)
Compounds
Gram-positive bacteria
Gram-negative bacteria
Compounds
Concentration
S. aureus
B. cereus
E. coli
K. pneumoniae
50
(%)
l
g/ml
100
(%)
lg/ml
200
(%)
lg/ml
400
(%)
l
g/ml
IC50
g/ml)
(l
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
22 (15.2)
15 (28.6)
14 (32.4)
23 (13.4)
24 (12.4)
20 (21.3)
16 (27.5)
21 (16.8)
19 (23.4)
20 (22.3)
16 (25.0)
19 (24.0)
21 (15.4)
15 (31.8)
20 (21.0)
18 (23.8)
19 (23.5)
26 (0.2)
16 (18.5)
16 (26.2)
15 (23.3)
18 (19.0)
17 (16.4)
14 (28.0)
14 (24.0)
16 (20.3)
14 (22.6)
14 (25.8)
15 (27.8)
13 (35.4)
16 (24.5)
16 (25.4)
14 (24.5)
15 (25.6)
13 (28.7)
25 (0.3)
18 (19.6)
16 (28.0)
16 (29.4)
19 (21.5)
21 (16.5)
15 (25.4)
14 (30.2)
18 (26.2)
15 (27.4)
15 (36.3)
16 (26.0)
16 (27.5)
18 (23.4)
17 (26.7)
16 (29.5)
17 (26.7)
17 (27.3)
27 (0.2)
18 (20.2)
15 (33.2)
15 (30.5)
18 (17.5)
20 (16.1)
16 (26.3)
14 (26.3)
17 (20.1)
15 (30.2)
17 (25.1)
15 (27.2)
15 (25.5)
19 (19.6)
17 (21.2)
19 (33.4)
16 (25.2)
16 (24.8)
26 (0.1)
4a
4b
4c
14.4
4.7
—
19.28
6.8
—
24.5
7.7
—
26.7
10.4
—
993.66
>1000
—
4d
—
—
—
—
—
4e
4f
4g
8.5
14.2
—
10.4
14.57
—
14.5
10.57
—
21.4
22.7
—
>1000
947.09
—
4h
4i
8.4
—
16.2
—
22.4
—
26.7
—
960.00
—
4j
4k
4l
5.2
10.4
—
5.5
17.23
—
6.2
21.43
—
8.5
25.7
—
>1000
>1000
—
4m
4n
4o
4p
4q
Ascorbic
acid
Blank
12.4
14.5
18.5
14.4
5.7
28.8
20.0
19.1
20.5
18.5
6.4
26.4
26.1
24.2
20.5
10.0
31.5
28.7
28.1
26.7
26.7
12.5
33.4
858.69
867.28
880.30
900.00
>1000
650.00
4q
Ciprofloxacin
Blank
—
—
—
—
29.7
(—) Showed no antibacterial activity.
—
—
—
—
—
(—) Showed no scavenging activity.
Table 4
Antioxidant activities of the test compounds and standard using DPPH scavenging
method—% DPPH radical scavenging activity
Compounds
Concentration
50
(%)
lg/ml
100
(%)
l
g/ml
200
(%)
l
g/ml
400
(%)
l
g/ml
IC50
(lg/ml)
4a
38
46
49.7
51.2
308.2
4b
4c
18.78
—
21.82
—
22.84
—
26.39
—
1599.62
—
4d
—
—
—
—
—
4e
4f
4g
27.9
46.7
—
34.01
49.7
—
39.59
54.3
—
45.68
57.8
—
467.49
117.8
—
4h
4i
26.9
—
28.9
—
31.4
—
36.5
—
901.11
—
Figure 3. Free radical scavenging activity of compounds 4j, 4k, 4p, and 4m.
4j
4k
4l
24.8
25.8
—
25.8
27.42
—
28.9
28.32
—
30.4
32.46
—
1590.74
1371.65
—
4m
4n
4o
4p
4q
Ascorbic
acid
Blank
53.6
55.8
51.7
72.1
20.3
77.15
56.88
57.86
53.8
73.12
23.8
79.69
59.89
59.09
57.3
74.64
25.8
82.30
60.25
62.90
64.4
75.66
22.84
85.34
<50
<50
<50
<50
1779.24
<50
—
—
—
—
—
(—) Showed no scavenging activity.
100 ll of medium) and incubated for attachment. Test compounds
and standard drug doxorubicin were prepared prior to the experi-
mentby dissolving in 0.1%DMSO and dilutedwith medium. The cells
were then exposed to different concentrations of the drugs (1–
Figure 4. Free radical scavenging activity of compounds 4e, 4h, 4f, and 4a.
100 lm) in the volume of the 100 ll/well. Cells in the control wells
were received the same volume of the medium containing 0.1%
DMSO. After 24 h, the same volume of the medium was removed
Cytotoxicity % ¼ f½ðcontrol abs ꢀ blank absÞ ꢀ ðtest abs
ꢀ blank absÞꢂ=ðcontrol abs ꢀ blank absÞg ꢃ 100
and cell cultures were incubated with 100
ml) for 4 h at 37 °C. The formazan produced by the viable cells was
soluble by the addition of 100 l DMSO.
ll MTT reagent (1 mg/
The compounds 4b and 4c exhibited good cytotoxicity due to
the presence of naphthalene ring and other compounds showed
moderate activity when compared with the standard drug doxoru-
bicin. The growth inhibition GI50 of the compounds 4b and 4c were
l
The suspension was placed on a micro-vibrator for 5 min and
the absorbance was recorded at 540 nm by the ELISA reader. The
experiment was performed in triplicate. The percentage cytotoxic-
ity was calculated using the formula.
found to be 18.2, 15.5
found to be 0.02 m.
lm, respectively, and for the standard it was
l

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Figure 5. Free radical scavenging activity of compounds 4n, 4o, 4q, and 4b.
Table 6
Report of cytotoxicity against MCF-7 breast cancer cell lines
Compounds
MCF-7
TGI ( m)
GI50
(l
m)
l
LC50 (lm)
4b
4c
4f
4h
4i
4n
18.2
15.5
21.8
28
22.8
20.6
33.9
46.6
48.1
52.4
48.2
37.4
80.2
91.5
>100
>100
>100
72.1
0.74
—
Doxorubicin
Blank
0.02
—
0.21
—
(—) Showed no cytotoxic activity.
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Org. Chem. 2004, 1, 1.
The lethal concentration (LC50) of the compounds 4b and 4c were
found to be 80.2 and 91.5 m, respectively, and for the standard it
was found to be 0.74 m. Lethal concentration of the above title
l
l
compounds are more when compared to standard drug doxorubicin
(Table 6). Thus, the compounds 4b and 4c are much more safety than
the standard drug and showed significant anticancer activity.
In conclusion, we have developed an InCl3 mediated simple and
efficient one-pot synthesis of 3-pyranyl indole derivatives. A
privileged medicinal scaffold was synthesized through a three-
component reaction of 3-cyanoacetyl indole, benzaldehyde and
malononitrile. The synthesized compounds showed good to mod-
erate antibacterial, antioxidant and anticancer activities. Further
studies to delineate the scope and limitations of the present meth-
odology are underway.
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Tetrahedron 2007, 2057.
18. Crystallographic data of compound 4b in this paper have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication no.
CCDC-767159. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 01223 336033 or
email: deposit@ccdc.cam.ac.uk).
Acknowledgments
One of the authors, N.V. thanks the Council of Scientific and
Industrial Research, New Delhi, India, for the research fellowship.
The author N.V. thanks Department of Pharmaceutical Biotechnol-
ogy, C.L. Blaid Metha College of Pharmacy, Chennai for studying
antibacterial and antioxidant activities and the Department of
Molecular Biology, Central Drug Research Institute, Lucknow for
studying anticancer activity.
19. Gillespie, S. H. In Medical Microbiology-Illustrated; Butterworth Heimann Ltd:
United Kingdom, 1994. p 234.
20. Hawkey, P. M.; Lewis, D. A. In Medical Microbiology—a practical approach;
Oxford Univerisity Press: United Kingdom, 1994. p 181.
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Zhu, L. F.; Zhou, B. N.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 1998, 26, 706.
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Yencho, G. C. Food Chem. 2007, 103, 829.
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A. K.; Singh, G.; Kutty, N. G.; Rao, C. M. Eur. J. Med. Chem. 2009, 44, 1.
24. Compound 2a: 1H NMR (500 MHz, DMSO-d6): d 3.41(s, 1H), 7.23–7.27 (m, 2H),
7.53–7.56 (m, 3H), 8.0–8.02 (m, 2H), 8.18–8.22 (m, 2H), 8.45 (s, 1H), 12.31 (s,
1H, -NH, D2O exchangeable); 13C NMR (125 MHz, DMSO-d6): d 112.1, 113.1,
114.1, 118.2, 121.9, 123.0, 124.2, 126.7, 129.7, 130.8, 132.8, 132.9, 136.7, 137.3,
152.7, 181.9.
25. Typical experimental procedure for 4b: A mixture of 3-cyanoacetyl indole 1,
naphthaldehyde 2b (1 mmol) and malononitrile 3 (1.0 mmol) was refluxed in
ethanol in presence of 20 mol % of InCl3. The reaction mixture was refluxed for
futher 40 min and cooled to room temperature. The solid formed in the
reaction mixture was filtered, dried and recrystallized in ethanol to obtain the
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.07.039.
References and notes
1. (a) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (b) Zhu, J. Eur. J.
Org. Chem. 2003, 1133; (c) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem.
2000, 37, 647; (d) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J.
2000, 6, 3321; (e) Shinu, V. S.; Sheeja, B.; Purushothaman, E.; Bahulayan, D.
Tetrahedron Lett. 2009, 50, 4838; (f) Arabanian, A.; Mohammadnejad, M.;
Balalaie, S.; Gross, J. H. Bioorg. Med. Chem. Lett. 2009, 19, 887.

N. V. Lakshmi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5054–5061
5061
pure product in good yield (81%). 2-Amino-6-(1H-indol-3-yl)-4-(naphthalen-1-
yl)4H-pyran-3,5-dicarbonitrile (Table 1, entry 2): White solid mp 242–244 °C; Rf
0.25 (50% AcOEt/Petroleum ether); IR (KBr): 3423, 3332, 2198, 1667, 1527,
reaction mixture was refluxed for 40 min and cooled to room temperature. The
solid formed in the reaction mixture was filtered, dried and recrystallized in
ethanol to obtain the pure product in good yield (72%). 2-Amino-4-(7-bromo-
3a,4-dihydrobenzo[d][1,3]dioxol-5-yl)-6-(1H-indol-3-yl)-4H-pyran-3,5-
1399, 1140, 778, 747 cmꢀ1 1H NMR (500 MHz, DMSO-d6): d 5.38 (s, 1H, -CH),
;
7.15 (t, 1H, J = 6.85 Hz, Ar-H), 7.22 (t, 1H, J = 7.65 Hz, Ar-H), 7.29 (s, 2H, –NH2,
D2o exchangeable), 7.48–7.56 (m, 5H, Ar-H), 7.89–7.98 (m, 3H, Ar-H), 8.10 (d,
1H, J = 7.25 Hz, Ar-H), 8.38 (d, 1H, J = 7.65 Hz, Ar-H), 11.97 (br s, 1H, –NH, –D2O
exchangeable); 13C NMR (125 MHz, DMSO-d6): d 56.8, 84.9, 105.9, 112.6, 119.4,
119.8, 121.5, 122.1, 123.2, 123.6, 125.1, 126.5, 126.9, 128.9, 129.4, 129.8, 131.5,
134.2, 136.5, 156.4, 159.3; MS (EI): m/z 388.42 [M+]; Anal. Calcd for C25H16N4O:
C, 77.30; H, 4.15; N, 14.42. Found: C, 77.50; H, 4.14; N, 14.39.
dicarbonitrile (Table 1, entry 17): Yellow solid; mp 258–260 °C; Rf 0.25 (40%
AcOEt/Petroleum ether); IR (KBr): 3433, 3316, 2200, 1670, 1480, 1150,
742 cmꢀ1 1H NMR (500 MHz, DMSO-d6): d 4.82 (s, 1H, –CH), 6.07 (s, 2H, –
;
CH2), 6.96 (s, 1H, Ar-H), 7.12 (t, 1H, J = 6.85 Hz, Ar-H), 7.18–7.20 (m, 2H, Ar-H),
7.29 (s, 2H, –NH2, –D2O exchangeable), 7.47 (d, 1H, J = 7.65 Hz, Ar-H), 7.93 (d,
1H, J = 8.4 Hz, Ar-H), 8.10 (d, 1H, J = 6.55 Hz, Ar-H), 11.95 (br s, 1H, –NH, D2O
exchangeable); 13C NMR (125 MHz, DMSO-d6): d 31.2, 55.2, 83.2, 102.9, 105.9,
112.8, 112.9, 113.7, 119.1, 119.4, 121.4, 122.2, 123.2, 125.0, 129.9, 136.4, 148.5,
156.6, 159.4; MS (EI): m/z 461.20 [M+], 463.20 [M++2]; Anal. Calcd for
26. Typical experimental procedure for 4q: A mixture of 3-cyanoacetyl indole 1,
and
7-bromobenzo[d[1,3dioxole-5-carbaldehyde
2q
(1 mmol)
and
malononitrile 3 (1.0 mmol) was refluxed in ethanol in presence of InCl3. The
C22H13BrN4O3: C, 57.28; H, 2.84; N, 12.15. Found: C, 57.43; H, 2.87; N, 12.11.