Synthesis and anti-inflammatory activity of 3-indolyl pyridine derivatives through one-pot multi component reaction

Article abstract of DOI:10.1007/s12039-010-0070-3

A simple protocol for the efficient preparation of 2-(1H-Indol-3-yl)-6- methoxy-4-arylpyridine-3,5-dicarbonitrile has been achieved through one-pot multi-component reaction under reflux condition. These compounds showed a good anti-inflammatory activity. Also a series of bis-Hantzsch dihydropyridine derivatives were synthesized and they exhibit analgesic activity. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-010-0070-3

J. Chem. Sci., Vol. 122, No. 6, November 2010, pp. 819–832. © Indian Academy of Sciences.
Synthesis and anti-inflammatory activity of 3-indolyl pyridine
derivatives through one-pot multi component reaction
PRAKASAM THIRUMURUGAN, S MAHALAXMI and PARAMASIVAN T PERUMAL*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020
e-mail: ptperumal@gmail.com
MS received 24 November 2009; revised 27 May 2010; accepted 25 June 2010
Abstract. A simple protocol for the efficient preparation of 2-(1H-Indol-3-yl)-6-methoxy-4-aryl-
pyridine-3,5-dicarbonitrile has been achieved through one-pot multi-component reaction under reflux
condition. These compounds showed a good anti-inflammatory activity. Also a series of bis-Hantzsch
dihydropyridine derivatives were synthesized and they exhibit analgesic activity.
Keywords. Multi component reaction; 3-cyanoacetyl indole; malononitrile; pyridine synthesis; anti-
inflammatory activity; analgesic activity.
12
1. Introduction
and functional materials. Pyridine derivatives con-
taining multi-functional groups such as streptoni-
grin, streptonigrone and lavendamycin are reported
as anticancer drugs, and cerivastatin is reported as
Functionalized nitrogen-heterocycles play a pre-
dominant role in medicinal chemistry and they have
been intensively used as scaffolds for drug deve-
lopment. Multi-component reactions (MCR’s) have
emerged as a powerful tool for delivering the
molecular diversity needed in the combinatorial
approaches for the preparation of bioactive hetero-
8
the HMG-CoA enzyme inhibitor. Moreover, substi-
tuted pyridines are reported as leukotriene B-4 an-
13–15
tagonists.
3-Substituted indole is the one of the ‘privileged
medicinal scaffold,’ found in many biologically
16,17
1
cyclic compounds. Multi-component reactions, such
active compounds and natural products.
Through
2
as the Biginelli, Passerini, Ugi, and Hantzsch,
3
4
appropriate functional group modifications, these
scaffolds are capable of providing ligands for a
number of functionally and structurally discrete bio-
logical receptors. 3-Substitued indole scaffolds are
found in a number of biologically active compounds
5
provide a wide variety of important heterocycles.
For example, the Hantzsch reaction provides dihy-
dropyridines with activity against calcium channels,
multidrug resistance (MDR) proteins, 5-hydroxy-
tryptamine(5-HT) receptors, and anti-inflammatory
18
especially with anticancer, anti-tumour, hypogly-
6–7
targets.
cemic, anti-inflammatory, analgesic and anti-pyretic
19–20
activities (figure 1).
The pyridine nucleus is prevalent in numerous
natural products and is extremely important in
8
chemistry of biological systems. It plays a key role
The wide-ranging biological activity associated
with many pyridine and 3-substituted indole deriva-
tives, both naturally occurring and synthetic, ensures
that the synthesis of this important ring system re-
mains a topic of current interest. Various methods
for the preparation of these compounds have been
reported. However, these methods suffer from tedi-
ous synthetic routes, longer reaction time, drastic re-
catalysing both biological and chemical systems. In
many enzymes of living organisms it is the pros-
thetic pyridine nucleotide (NADP) that is involved
in various oxidation–reduction processes. Other evi-
dence of the potent activity of pyridine in biological
systems is its presence in the important vitamins
niacin and pyridoxine (vitamin B6) and also in
9–11
action conditions, as well as narrow substrate
21–25
highly toxic alkaloids such as nicotine.
The pyri-
scope.
There have been very few reports about
dine substructure is one of the most important hetero-
cycles found in natural products, pharmaceuticals,
the synthesis of indol-3-yl derivatives including
9,18,22–23,26
pyridine moieties.
As part of our ongoing
research on the development of novel synthetic
routes for the synthesis of biologically active hetero-
*For correspondence
819

820
Prakasam Thirumurugan et al
Figure 1. Representatives of 3-substituted indole derivatives
cyclic compounds and use of green chemical tech- were recorded using a electrospray ionisation method
27,28
niques in organic synthesis,
simple and facile one pot procedure for the synthesis points were determined in capillary tubes and are
of indol-3-yl pyridine derivatives in aqueous media uncorrected. Analytical TLC was performed on pre-
we report here a with thermo Finnigan mass spectrometer. Melting
under reflux condition.
coated plastic sheets of silica gel G/UV-254 of
0⋅2 mm thickness (Macherey-Nagel, Germany). Ele-
mental analysis data were recorded using Thermo
Finnigan FLASH EA 1112 CHN instrument.
2. Experimental
2.1 General
2.2 General procedure for the synthesis of indol-3-
yl pyridine and 2,2′-bipyridine derivatives (4a–p)
All the substituted aldehydes, malononitrile, 2-
indanone, indole, CDCl3 and DMSO-d6 were pur-
chased from Aldrich Chemicals. Acetic anhydride
and all other reagents were purchased from S.D.
Fine Chemicals Limited and were used as received.
Methanol was distilled from Mg/I2 under nitrogen
and stored over 3 Å molecular sieves purchased
from Aldrich. IR measurements were done as KBr
pellets for solids using Perkin Elmer Spectrum RXI
A mixture of 3-cyanoacetyl indole (1⋅0 mmol), alde-
hyde (1⋅0 mmol), malononitrile(1⋅0 mmol) and
freshly prepared sodium methoxide (1⋅0 mmol) (or)
sodium hydroxide (1⋅2 mmol) in 30 mL of methanol :
water (2 : 1) was refluxed. After the completion of
the reaction (as monitored by TLC), it was poured
into water, filtered and then dried. The crude product
was further purified by recrystallization with ethanol
and the appropriate isolated yield shown in table 1.
1
13
FT–IR. The H and C NMR spectra were recorded
in CDCl3 and DMSO-d6 using TMS as internal stan-
dard with JEOL 500 MHz and Bruker 500 MHz high
resolution NMR spectrometer. Multiplicities were
abbreviated as follows: singlet (s), doublet (d), triplet
(t), multiplet (m), and broad (br). The mass spectra
2.2a 2-(1H-Indol-3-yl)-6-methoxy-4-phenylpyri-
dine-3,5-dicarbonitrile (table 1, entry 1) 4a: Light
yellow solid; m.p. 244–246°C; Rf 0⋅23 (20%

Synthesis and anti-inflammatory activity of 3-indolyl pyridine derivatives
821
Table 1. Synthesis of indol-3-yl pyridine derivatives.
Entry Aldehyde (1)
Product (4)a
Time (h)
Yield (%)b
89
1
1⋅5
2
3
4
91
86
91
1⋅0
1⋅5
1⋅5
5
6
7
8
79
81
81
79
2⋅5
2⋅0
2⋅0
2⋅0
9
10
11
79
81
72
2⋅0
1⋅0
3⋅0
12
68
2⋅5
(Contd…)

822
Prakasam Thirumurugan et al
Table 1. (Contd…)
Entry
Aldehyde (1)
Product (4)a
Time (h)
Yield (%)b
13
77
2⋅5
14
15
16
66
70
73
2⋅5
4⋅0
4⋅5
aAll the products were characterized by NMR, IR and mass spectroscopy. bIsolated yield
EtOAc/petroleum ether); IR (KBr): 1153, 1229, 96⋅7, 112⋅2, 112⋅3, 114⋅0, 117⋅7, 121⋅6, 122⋅0,
–1
1
1427, 1516, 1629, 2230, 3287 cm ; H NMR 122⋅9, 125⋅9, 128⋅2, 128⋅5, 129⋅2, 131⋅0, 131⋅1,
(500 MHz, DMSO-d6): δ 4⋅21 (s, 3H, –OCH3), 7⋅22– 136⋅4, 140⋅2, 159⋅0, 160⋅5, 164⋅3. MS (ESI LCQ-
+
7⋅24 (m, 2H, –Ar-H), 7⋅52–7⋅60 (m, 6H, –Ar-H), MS): m/z 365⋅20 [M + H] . Anal. Calcd. for
8⋅43–8⋅45 (m, 1H, –Ar-H), 8⋅57 (s, 1H, –Ar-H), C23H16N4O: C 75⋅81 H 4⋅43 N 15⋅38. Found: C
13
12⋅17 (brs, 1H, –NH); C NMR (125 MHz, DMSO- 75⋅90 H 4⋅42 N 15⋅33.
d6): δ 56⋅2, 91⋅7, 97⋅0, 112⋅7, 113⋅0, 114⋅6, 118⋅3,
122⋅2, 122⋅6, 123⋅5, 126⋅4, 128⋅8, 129⋅1, 129⋅2, 2.2c 2-(1H-Indol-3-yl)-6-methoxy-4-(3-methyl-
130⋅9, 132⋅1, 134⋅5, 137⋅2, 159⋅3, 161⋅0, 164⋅8; MS phenyl)pyridine-3,5-dicarbonitrile (table 1, entry 3)
+
(ESI LCQ-MS): m/z 351⋅20 [M + H] . Anal. Calcd. 4c: Pale yellow solid; m.p. 286–288°C; Rf 0⋅23
for C22H14N4O: C 75⋅42 H 4⋅03 N 15⋅99. Found: C (20% EtOAc/petroleum ether); IR (KBr): 1163,
–1
75⋅31 H 4⋅02 N 16⋅04.
1237, 1358, 1434, 1553, 1617, 2366, 3262 cm
1
H NMR (500 MHz, DMSO-d6): δ 2⋅37 (s, 3H,
2.2b 2-(1H-Indol-3-yl)-6-methoxy-4-(4-tolyl phenyl) –Ar-CH3) 4⋅18 (s, 3H, –OCH3), 7⋅20–7⋅26 (m, 2H,
pyridine-3,5-dicarbonitrile (table 2, entry 2) 4b: –Ar-H), 7⋅34–7⋅36 (m, 3H, –Ar-H), 7⋅43 (t, 1H,
Light yellow solid; m.p. 228–230°C; Rf 0.30 (20% J = 7⋅6 Hz, –Ar-H), 7⋅52 (d, 1H, J = 7⋅6 Hz, –Ar-H),
EtOAc/Petroleum ether); IR (KBr): 1145, 1224, 8⋅42 (d, 1H, J = 8⋅4 Hz, –Ar-H), 8⋅55 (s, 1H, –Ar-
–1
1
13
1306, 1422, 1516, 1620, 2221, 3325 cm H NMR H), 12⋅14 (brs, 1H, –NH); C NMR (125 MHz,
(500 MHz, DMSO-d6): δ 2⋅41 (s, 3H, –Ar-CH3) 4⋅21 DMSO-d6): δ 20⋅9, 55⋅7, 91⋅3, 96⋅6, 112⋅2, 112⋅4,
(s, 3H, –OCH3), 7⋅19-7⋅24 (m, 2H, –Ar-H), 7⋅36– 114⋅1, 117⋅7, 121⋅7, 122⋅1, 123⋅0, 125⋅7, 125⋅8,
7⋅52 (m, 5H, –Ar-H), 8⋅42 (d, 1H, J = 8⋅4 Hz, –Ar- 128⋅6, 128⋅9, 131⋅0, 131⋅3, 133⋅9, 136⋅5, 138⋅0,
13
H), 8⋅55 (s, 1H, –Ar-H), 12⋅19 (brs, 1H, –NH)
C
158⋅9, 160⋅7, 164⋅3. MS (ESI LCQ-MS): m/z
+
NMR (125 MHz, DMSO-d6): δ 21⋅0, 55⋅5, 91⋅3, 365⋅20 [M + H] . Anal. Calcd. for C23H16N4O:

Synthesis and anti-inflammatory activity of 3-indolyl pyridine derivatives
823
Table 2. Synthesis of 7,7,7′,7′-tetramethyl-4,4′-bis(aryl)-4,6,7,8,4′,6′,7′,8′-octahydro-1H,1H-[2,2′]biquinolinyl-5,5′-
dione derivatives
Entry
Cinnamil
Product (7)a
Time (h)
Yield (5%)b
1
55
12⋅0
2
3
4
56
48
58
11⋅0
11⋅5
12⋅0
5
6
52
42
11⋅0
14⋅0
aThe products were characterized by IR, NMR, mass and elemental analysis. bIsolated yield.
–1
1
C 75⋅81 H 4⋅43 N 15⋅38. Found: C 75⋅72 H 4⋅44 N 1358, 1434, 1553, 1617, 2366, 3262 cm H NMR
15⋅43.
(500 MHz, DMSO-d6): δ 3⋅80 (s, 3H, –OCH3), 4⋅20
(s, 3H, –OCH3), 7⋅06 (d, 2H, J = 8⋅4 Hz, –Ar-H),
7⋅12 (d, 1H, J = 8⋅2 Hz, –Ar-H), 7⋅19–7⋅22 (m, 1H,
2.2d 2-(1H-Indol-3-yl)-6-methoxy-4(4methoxy-
phenyl) pyridine -3,5-dicarbonitrile (table 1, entry 4) –Ar-H), 7⋅43 (d, 2H, J = 8⋅4 Hz, –Ar-H), 7⋅56 (d,
4d: Yellow solid; m.p. 268–270°C; Rf 0⋅23 (20% 1H, J = 8⋅4 Hz, –Ar-H), 8⋅41–8⋅43 (m, 1H, –Ar-H),
13
EtOAc/petroleum ether); IR (KBr): 1163, 1237, 8⋅58 (s, 1H, –Ar-H), 12⋅31 (brs, 1H, –NH);
C

824
Prakasam Thirumurugan et al
13
NMR (125 MHz, DMSO-d6): δ 55⋅2, 55⋅7, 91⋅1, H), 12⋅22 (brs, 1H, –NH); C NMR (125 MHz,
96⋅4, 112⋅2, 112⋅7, 114⋅1, 117⋅7, 121⋅7, 122⋅0, DMSO-d6): δ 55⋅9, 91⋅8, 96⋅7, 112⋅0, 112⋅5, 113⋅3,
122⋅9, 126⋅0, 128⋅9, 130⋅7, 131⋅9, 132⋅8, 135⋅4, 116⋅8, 121⋅9, 122⋅1, 123⋅2, 125⋅7, 128⋅2, 129⋅5,
137⋅0, 158⋅8, 159⋅4, 164⋅2. MS (ESI LCQ-MS): m/z 131⋅5, 131⋅8, 131⋅9, 132⋅3, 136⋅1, 136⋅5, 157⋅2,
+
381⋅27 [M + H] . Anal. Calcd. for C23H16N4O2: C 158⋅8, 164⋅1; MS (ESI LCQ-MS): m/z 419⋅13
+
72⋅62 H 4⋅24 N 14⋅73. Found: C 72⋅72 H 4⋅22 N [M + H] . Anal. Calcd. for C22H12Cl2N4O: C 63⋅02
14⋅69.
H 2⋅88 N 16⋅91. Found: C 62⋅91 H 2⋅88 N 16⋅9.
2.2e 4-(2-Chlorophenyl)-2-(1H-indol-3-yl)-6-
2.2h 4-(4-Bromophenyl)-2-(1H-indol-3-yl)-6-
methoxypyridine-3,5-dicarbonitrile (table 1, entry 5) methoxypyridine-3,5-dicarbonitrile (table 1, entry 8)
4e: Pale yellow solid; m.p. 214–216°C; Rf 0⋅31 4h: Pale yellow solid; m.p. 238–240°C; Rf 0⋅31
(20% EtOAc/petroleum ether); IR (KBr): 1090, (20% EtOAc/petroleum ether); IR (KBr): 1145,
–1
1145, 1221, 1420, 1519, 2219, 3325 cm H NMR 1235, 1288, 1435, 1522, 1636, 2253, 3222 cm
1
–1
1
(500 MHz, DMSO-d6): δ 4⋅25 (s, 3H, –OCH3), 7⋅23–
H NMR (500 MHz, DMSO-d6): δ 4⋅22 (s, 3H, –
7⋅26 (m, 2H, –Ar-H), 7⋅53–7⋅63 (m, 4H, –Ar-H), OCH3), 7⋅22–7⋅27 (m, 2H, –Ar-H), 7⋅53–7⋅58 (m,
7⋅71 (d, 1H, J = 8⋅4 Hz, –Ar-H), 8⋅47–8⋅49 (m, 1H, 3H, –Ar-H), 7⋅80 (d, 2H, J = 8⋅4 Hz, –Ar-H) 8⋅43 (d,
–Ar-H), 8⋅58 (s, 1H, –Ar-H), 12⋅41 (brs, 1H, –NH); 1H, J = 8⋅4 Hz, –Ar-H), 8⋅56 (s, 1H, –Ar-H), 12⋅14
13
13
C NMR (125 MHz, DMSO-d6): δ 55⋅9, 91⋅9, 97⋅0, (brs, 1H, –NH); C NMR (125 MHz, DMSO-d6): δ
112⋅1, 112⋅6, 113⋅4, 116⋅8, 121⋅9, 122⋅1, 123⋅2, 55⋅7, 91⋅3, 96⋅6, 112⋅2, 112⋅7, 114⋅2, 115⋅8, 117⋅8,
125⋅7, 127⋅9, 129⋅9, 130⋅4, 131⋅0, 131⋅5, 132⋅1, 121⋅7, 122⋅0, 123⋅0, 126⋅0, 130⋅4, 131⋅3, 131⋅4,
133⋅0, 136⋅6, 158⋅3, 158⋅8, 164⋅2. MS (ESI LCQ- 132⋅0, 137⋅0, 158⋅8, 159⋅6, 162⋅2, 164⋅2, 164⋅3; MS
+
MS): m/z 385⋅17 [M + H] . Anal. Calcd. for (ESI LCQ-MS): m/z 431⋅13 [M + H]+. Anal. Calcd
C22H13ClN4O: C 68⋅67 H 3⋅41 N 9⋅21. Found: C for C22H13BrN4O: C 61⋅55 H 3⋅05 N 13⋅05. Found: C
68⋅75 H 3⋅40 N 9⋅17.
61⋅44 H 3⋅06 N 13⋅09.
2.2f 4-(4-Chlorophenyl)-2-(1H-indol-3-yl)-6-
2.2i 4-(4-Fluorophenyl)-2-(1H-indol-3-yl)-6-me-
methoxypyridine-3,5-dicarbonitrile (table 1, entry 6) thoxypyridine-3,5-dicarbonitrile (table 1, entry 9) 4i:
4f: Pale yellow solid; m.p. 260–262°C; Rf 0⋅31 Pale yellow solid; m.p. 256–258°C; Rf 0⋅30 (20%
(20% EtOAc/petroleum ether); IR (KBr): 1093, EtOAc/petroleum ether); IR (KBr): 1152, 1227,
–1
1222, 1366, 1423, 1490, 1517, 1573, 2222, 1370, 1421, 1511, 1603, 2224, 3317 cm H NMR
1
–1
1
3329 cm H NMR (500 MHz, DMSO-d6): δ 4⋅21 (500 MHz, DMSO-d6): δ 4⋅21 (s, 3H, -OCH3), 7⋅21–
(s, 3H, –OCH3), 7⋅23–7⋅25 (m, 2H, –Ar-H), 7⋅53 (d, 7⋅26 (m, 2H, –Ar-H), 7⋅42 (t, 2H, J = 9⋅15 Hz, –Ar-
1H, J = 8⋅4 Hz, –Ar-H), 7⋅62 (q, 4H, J = 8⋅4 Hz, – H), 7⋅52 (d, 1H, J = 6⋅8 Hz, –Ar-H) 7⋅67–7⋅69 (m,
Ar-H) 8⋅43 (d, 1H, J = 8⋅4 Hz, -Ar-H), 8⋅56 (s, 1H, – 2H, –Ar-H), 8⋅43 (d, 1H, J = 8⋅4 Hz, –Ar-H), 8⋅56
13
13
Ar-H), 12⋅15 (brs, 1H, –NH); C NMR (125 MHz, (s, 1H, –Ar-H), 12⋅08 (brs, 1H, –NH); C NMR
DMSO-d6): δ 55⋅7, 91⋅3, 96⋅6, 112⋅1, 112⋅4, 114⋅0, (125 MHz, DMSO-d6): δ 55⋅7, 91⋅5, 96⋅8, 112⋅1,
117⋅6, 121⋅8, 122⋅0, 123⋅0, 125⋅6, 128⋅8, 130⋅2, 114⋅1, 115⋅7, 116⋅0, 117⋅7, 121⋅8, 122⋅1, 123⋅1,
130⋅6, 131⋅3, 132⋅7, 135⋅4, 136⋅5, 158⋅8, 159⋅3, 125⋅8, 130⋅3, 131⋅3, 131⋅4, 136⋅5, 158⋅8, 159⋅6,
+
164⋅2; MS (ESI LCQ-MS): m/z 385⋅20 [M + H] . 161⋅6, 164⋅9; MS (ESI LCQ-MS): m/z 369⋅27
Anal. Calcd. for C22H13ClN4O: C 68⋅67 H 3⋅41 N [M + H] . Anal. Calcd. for C22H13FN4O7: C 71⋅73 H
+
9⋅21. Found: C 68⋅59 H 3⋅42 N 9⋅25.
3⋅56 N 15⋅21. Found: C 71⋅62 H 3⋅57 N 15⋅26.
2.2g 4-(2,4-Chlorophenyl)-2-(1H-indol-3-yl)-6-
2.2j 2-(1H-Indol-3-yl)-6-methoxy-4-(1-naphthyl)
methoxy pyridine-3,5-dicarbonitrile (table 1, entry 7) pyridine-3,5-dicarbonitrile (table 1, entry 10) 4j:
4g: Pale yellow solid; m.p. 272–274°C; Rf 0⋅31 Yellow solid; m.p. 240.242°C; Rf 0.21 (20%
(20% EtOAc/petroleum ether); IR (KBr): 1145, EtOAc/petroleum ether); IR (KBr): 1148, 1228,
–1
1225, 1310, 1422, 1522, 2232, 3313 cm H NMR 1422, 1514, 1633, 2235, 3244 cm
1
–1
1
H NMR
(500 MHz, DMSO-d6): δ 4⋅25 (s, 3H, –OCH3), 7⋅25– (500 MHz, DMSO-d6): δ 4⋅27 (s, 3H, –OCH3), 7⋅20–
7⋅26 (m, 2H, –Ar-H), 7⋅54–7⋅56 (m, 1H, –Ar-H), 7⋅28 (m, 2H, –Ar-H), 7⋅47–7⋅70 (m, 6H, –Ar-H),
7⋅66–7⋅71 (m, 2H, –Ar-H), 7⋅96 (d, 1H, J = 1⋅55 Hz, 8⋅06–8⋅15 (m, 2H, –Ar-H), 8⋅53–8⋅56 (m, 2H, –Ar-
13
–Ar-H) 8⋅46–8⋅48 (m, 1H, –Ar-H), 8⋅58 (s, 1H, –Ar- H), 12⋅15 (brs, 1H, –NH); C NMR (125 MHz,

Synthesis and anti-inflammatory activity of 3-indolyl pyridine derivatives
825
DMSO-d6): δ 55⋅8, 92⋅9, 97⋅9, 112⋅2, 112⋅5, 117⋅4, (s, 1H, –Ar-H), 8⋅11 (d, 1H, J = 7⋅6 Hz, –Ar-H),
13
121⋅0, 121⋅85, 122⋅2, 123⋅2, 124⋅5, 125⋅4, 126⋅7, 8⋅55 (s, 1H, –Ar-H), 12⋅39 (brs, 1H, –NH);
C
127⋅0, 127⋅5, 128⋅6, 129⋅8, 130⋅4, 131⋅4, 131⋅7, NMR (125 MHz, DMSO-d6): δ 56⋅3, 87⋅8, 93⋅4,
133⋅0, 136⋅6, 158⋅9, 159⋅9, 164⋅4; MS (ESI LCQ- 112⋅6, 113⋅1, 113⋅4, 115⋅0, 117⋅4, 118⋅9, 122⋅2,
+
MS): m/z 351⋅20 [M + H] . Anal. Calcd. for 122⋅6, 123⋅5, 126⋅5, 132⋅7, 137⋅3, 145⋅6, 146⋅7,
+
+
C26H16N4O: C 75⋅42 H 4⋅03 N 15⋅99. Found: C 160⋅3, 162⋅8, 165⋅6; MS (EI): m/z 341⋅33 [M + H ];
75⋅31 H 4⋅02 N 16⋅04.
Anal. Calcd. for C20H12N4O2: C 67⋅40 H 3⋅39 N
15⋅72. Found: C 67⋅31 H 3⋅38 N 15⋅74.
2.2k 2-(1H-Indol-3-yl)-6-methoxy-4-(3-nitrophenyl)
pyridine-3,5-dicarbonitrile (table 1, entry 11) 4k: 2.2n 2-(1H-Indol-3-yl)-6-methoxy-4,4′-bipyridine-
Yellow solid; m.p. 242–244°C; Rf 0⋅08 (20% 3,5-dicarbonitrile (table 1, entry 14) 4n: Yellow
EtOAc/petroleum ether); IR (KBr): 1098, 1236, solid; m.p. 172–175°C; Rf 0⋅62 (40% AcOEt/
–1
1
1349, 1433, 1531, 1620, 2216, 3386 cm H NMR petroleum ether); IR (KBr): 1233, 1461, 1552, 1617,
–1
1
(500 MHz, DMSO-d6): δ 4⋅28 (s, 3H, -OCH3), 7⋅28– 2198, 3132 cm H NMR (500 MHz, DMSO-d6): δ
7⋅31 (m, 2H, -Ar-H), 7⋅57–7⋅59 (m, 1H, –Ar-H), 4⋅23 (s, 3H, –OCH3), 7⋅24–7⋅26 (m, 2H, –Ar-H),
7⋅94 (t, 1H, J = 7⋅6 Hz, –Ar-H), 8⋅14 (d, 1H, 7⋅53–7⋅55 (m, 1H, –Ar-H), 7⋅63–7⋅64 (m, 2H, –Ar-
J = 7⋅6 Hz, –Ar-H), 8⋅48–8⋅50 (m, 2H, –Ar-H), 8⋅62 H), 8⋅44–8⋅46 (m, 1H, –Ar-H), 8⋅57 (s, 1H, –Ar-H),
13
(s, 2H, –Ar-H), 12⋅21 (brs, 1H, –NH); C NMR 8⋅81–8⋅83 (m, 2H, –Ar-H), 12⋅18 (brs, 1H, –NH);
13
(125 MHz, DMSO-d6): δ 55⋅9, 91⋅5, 96⋅6, 112⋅1,
C NMR (125 MHz, DMSO-d6): δ 56⋅4, 91⋅5, 96⋅5,
112⋅6, 114⋅0, 117⋅6, 121⋅9, 122⋅1, 123⋅2,123⋅9, 112⋅6, 113⋅1, 114⋅3, 117⋅9, 122⋅5, 122⋅6, 123⋅8,
125⋅3, 125⋅8, 130⋅7 131⋅6, 135⋅4, 135⋅5, 136⋅6, 123⋅7, 126⋅3, 132⋅2, 137⋅1, 142⋅3, 150⋅7, 158⋅7,
+
+
147⋅7, 158⋅1, 158⋅9, 164⋅2; MS (ESI LCQ-MS): m/z 159⋅5, 164⋅7; MS (EI): m/z 352⋅20 [M + H ]; Anal.
+
395⋅13 [M + H] . Anal. Calcd. for C22H13N5O3: C Calcd. for C21H13N5O: C 71⋅79 H 3⋅73 N 19⋅93.
66⋅83 H 3⋅31 N 17⋅71. Found: C 66⋅74 H 3⋅32 N Found: C 71⋅70 H 3⋅74 N 19⋅96.
17⋅75.
2.2o 2-(1H-Indol-3-yl)-6-methoxy-4-(1-methyl-1H-
indol-2-yl)pyridine-3,5-dicarbonitrile (table 1, entry
2.2l 2-(1H-Indol-3-yl)-6-methoxy-4-(2-thienyl)
pyridine-3,5-dicarbonitrile (table 1, entry 12) 4l: 15) 4o: Yellow solid; m.p. 242–245°C; Rf 0⋅75
Yellow solid; m.p. 226–228°C; Rf 0⋅76 (40% (40% AcOEt/Petroleum ether); IR (KBr): 1155,
AcOEt/Petroleum ether); IR (KBr): 1134, 1226, 1227, 1373, 1437, 1523, 1566, 2227, 3285 cm
–1
–1
1
1
1475, 1514, 2222, 3268 cm
H NMR (500 MHz,
H NMR (500 MHz, DMSO-d6): δ 3⋅74 (s, 3H,
DMSO-d6): δ 4⋅17 (s, 3H, –OCH3), 7⋅19–7⋅24 (m, –NCH3), 4⋅25 (s, 3H, –OCH3), 6⋅77 (s, 1H, -Ar-H),
1H, –Ar-H), 7⋅28 (t, 1H, J = 4⋅6 Hz, –Ar-H), 7⋅50 6⋅91 (s, 1H, –Ar-H), 7⋅11–7⋅15 (m, 2H, –Ar-H),
(d, 1H, J = 7⋅6 Hz, –Ar-H), 7⋅58 (d, 1H, J = 3⋅1 Hz, 7⋅26–7⋅28 (m, 2H, –Ar-H), 7⋅53–7⋅57 (m, 2H, –Ar-
–Ar-H), 7⋅95 (d, 1H, J = 4⋅6 Hz, –Ar-H), 8⋅38 (d, H), 8⋅48–8⋅49 (m, 1H, –Ar-H), 8⋅63 (s, 1H, –Ar-H),
13
1H, J = 6⋅9 Hz, –Ar-H), 8⋅56 (s, 1H, –Ar-H), 11⋅67 12⋅20 (brs, 1H, –NH); C NMR (125 MHz, DMSO-
13
(brs, 1H, –NH); C NMR (125 MHz, DMSO-d6): δ d6): δ 31⋅6, 56⋅4, 93⋅2, 98⋅2, 111⋅1, 111⋅2, 113⋅1,
56⋅3, 91⋅7, 97⋅1, 112⋅6, 113⋅2, 114⋅8, 118⋅5, 122⋅6, 114⋅6, 118⋅1, 120⋅8, 121⋅6, 122⋅4, 123⋅6, 123⋅7,
123⋅6, 126⋅5, 128⋅5, 131⋅6, 132⋅2, 132⋅6, 133⋅2, 127⋅3, 132⋅3, 132⋅7, 137⋅1, 138⋅7, 152⋅0, 161⋅6,
+
+
137⋅4, 153⋅6, 159⋅7, 165⋅1; MS (EI): m/z 357⋅20 164⋅9, 166⋅2; MS (EI): m/z 404⋅33 [M + H ]; Anal.
[M + H ]; Anal. Calcd. for C20H12N4OS. C 67⋅40 H Calcd. for C25H17N5O: C 74⋅43 H 4⋅25 N 17⋅36.
+
+
3⋅39 N 15⋅72. Found: C 67⋅31 H 3⋅38 N 15⋅74.
Found: C 74⋅34 H 4⋅26 N 17⋅39.
2.2m 4-(2-Furyl)-2-(1H-indol-3-yl)-6-methoxy-
2.2p 2,4-Di-1H-indol-3-yl-6-methoxypyridine-3,5-
pyridine-3,5-dicarbonitrile (table 1, entry 13) 4m: dicarbonitrile (table 1, entry 16) 4p: Yellow solid;
Yellow solid; m.p. 234–236°C; Rf 0⋅72 (40% m.p. 230–233°C; Rf 0⋅41 (40% AcOEt/Petroleum
AcOEt/Petroleum ether); IR (KBr): 1150, 1229, ether); IR (KBr): 1147, 1227, 1304, 1519, 1555,
–1 1
1424, 2221, 3301 cm H NMR (500 MHz, DMSO- 1611, 2222, 3263, 3364 cm
–1 1
H NMR (500 MHz,
d6): δ 4⋅15 (s, 3H, –OCH3), 6⋅84–6⋅86 (m, 1H, –Ar- DMSO-d6): δ 4⋅22 (s, 3H, -OCH3), 7⋅13 (t, 1H,
H), 7⋅17–7⋅22 (m, 2H, –Ar-H), 7⋅42 (d, 1H, J = 3⋅1 J = 6⋅9 Hz -Ar-H), 7⋅21–7⋅24 (m, 3H, –Ar-H), 7⋅52–
Hz, -Ar-H), 7⋅49 (d, 1H, J = 7⋅6 Hz, –Ar-H), 8⋅11 7⋅54 (m, 2H, –Ar-H), 7⋅57 (d, 1H, J = 7⋅6 Hz, –Ar-

826
Prakasam Thirumurugan et al
H), 7⋅96 (s, 1H, –Ar-H), 8⋅44–8⋅46 (m, 1H, –Ar-H), –CH2), 4⋅58 (d, 2H, J = 6⋅1 Hz, dihydropyridyl-CH),
8⋅59 (s, 1H, –Ar-H), 10⋅89 (brs, 1H, –NH), 11⋅87 6⋅63 (d, 2H, J = 4⋅5 Hz, dihydropyridyl-C=CH),
13
(brs, 1H, –NH); C NMR (125 MHz, DMSO-d6): δ 7⋅18 (m, 4H, Ar-H), 7⋅67 (d, 4H, J = 7⋅6 Hz, Ar-H),
13
56⋅1, 91⋅7, 97⋅7, 109⋅0, 112⋅8, 112⋅9, 113⋅0, 115⋅6, 8⋅55 (brs, 2H, –NH); C NMR (125 MHz, CDCl3):
119⋅2, 120⋅5, 120⋅7, 122⋅1, 122⋅6, 122⋅8, 123⋅4, δ 21⋅0, 21⋅5, 27⋅5, 29⋅2, 29⋅6, 32⋅6, 38⋅1, 41⋅7, 50⋅7,
125⋅3, 126⋅6, 129⋅0, 132⋅0, 136⋅7, 137⋅1, 155⋅3, 107⋅3, 117⋅1, 119⋅4, 127⋅9, 128⋅5, 128⋅8, 128⋅9,
+
+
159⋅8, 162⋅6, 165⋅5; MS (EI): m/z 390⋅20 [M + H ]. 129⋅3, 129⋅7, 131⋅7, 133⋅7, 136⋅3, 141⋅5, 143⋅3,
Anal. Calcd. for C24H15N5O: C 74⋅02 H 3⋅88 N 144⋅9, 150⋅2, 183⋅2, 195⋅3; MS (ESI LCQ-MS): m/z
+
+
17⋅98. Found: C 74⋅11 H 3⋅87 N 17⋅95.
533⋅47 [M + H ]. Anal. Calcd. for C36H40N2O2: C
81⋅17 H 7⋅57 N 5⋅26. Found: C 80⋅28 H 7⋅52
N 5⋅23.
2.3 Synthesis of 6,6′-bis-(1H-indol-3-yl)-4-4′-
diaryl-[2,2′]bipyridinyl-5,5′-dicarbonitrile
2.3c 7,7,7′,7′-Tetramethyl-4,4′-bis(4-methoxyphenyl)-
4,6,7,8,4′,6′,7′,8′-octahydro-1H,1H-[2,2′]biquinolinyl-
5,5′-dione (table 2, entry 3) 7c: Yellow solid; m.p.
226–228°C; Rf 0⋅6 (40% AcOEt/petroleum ether);
IR (KBr): 1176, 1257, 1445, 1562, 3014, 3129 cm
1
H NMR (500 MHz, DMSO-d6): δ 1⋅02 (s, 6H,
A mixture of dimedone (2 mmol), cinnamil (1 mmol)
and 5 g of ammonium acetate under neat condition
was refluxed at 120°C for appropriate time men-
tioned as in table 2. After the completion of the re-
action (as monitored by TLC), it was poured into
water and then filtered washed with acetone and
then dried. The obtained crude solid was purified
further by recrystallisation with DMF and appropri-
ate isolated yield is shown in table 2.
–1
–CH3), 1⋅08 (s, 6H, –CH3), 2⋅15 (Abq, 4H, J = 8⋅1
Hz, –CH), 2⋅36 (s, 4H, –CH2), 3⋅75 (s, 6H, Ar-
OCH3), 4⋅78 (d, 2H, J = 5⋅6 Hz, dihydropyridyl-
CH), 6⋅24 (m, 2H, dihydropyridyl-C=CH), 6⋅81 (m,
4H, Ar-H), 6⋅88 (m, 2H, Ar-H), 7⋅50 (m, 2H, Ar-H)
13
8⋅55 (brs, 2H, –NH); C NMR (125 MHz, CDCl3):
2.3a 7,7,7′,7′-Tetramethyl-4,4′-diphenyl-4,6,7,8,4′,
6′,7’,8′-octahydro-1H,1H-[2,2′]biquinolinyl-5,5′-
dione (Table 2, entry 1) 7a: Yellow solid; m.p.
293–296°C; Rf 0⋅81 (40% AcOEt/Petroleum ether);
IR (KBr): 1126, 1314, 1384, 1485, 1587, 2934,
δ 27⋅5, 28⋅3, 29⋅2, 29⋅7, 32⋅6, 37⋅6, 41⋅7, 50⋅7, 55⋅2,
55⋅4, 107⋅4, 113⋅6, 113⋅9, 114⋅4, 115⋅7, 119⋅0,
127⋅2, 129⋅1, 129⋅5, 130⋅4, 133⋅7, 138⋅6, 144⋅6,
150⋅1, 158⋅4, 161⋅9, 183⋅1, 195⋅3; MS (ESI LCQ-
+
+
–1
1
MS): m/z 565⋅20 [M + H ]. Anal. Calcd. for
C36H40N2O4: C 76⋅57 H 7⋅14 N 4⋅96. Found: C 76⋅66
H 7⋅17 N 4⋅98.
3340 cm ; H NMR (500 MHz, DMSO-d6): δ 0⋅86
(s, 6H, –CH3), 0⋅94 (s, 6H, –CH3), 1⋅88 (Abq, 4H,
J = 8⋅2 Hz, –CH), 2⋅35 (s, 4H, –CH2), 4⋅42 (d, 2H,
J = 5⋅3 Hz, dihydropyridyl–CH), 5⋅26 (d, 2H,
J = 5⋅3 Hz, dihydropyridyl-C=CH), 7⋅05 (m, 2H, Ar-
H), 7⋅13 (d, 4H, J = 7⋅6 Hz, Ar-H), 7⋅18 (m, 4H, Ar-
2.3d 7,7,7′,7′-Tetramethyl-4,4′-bis(4-chlorophenyl)-
4,6,7,8,4′,6′,7′,8′-octahydro-1H,1H-[2,2′]biquinoli-
nyl-5,5′-dione (table 2, entry 4) 7d: Yellow solid;
m.p. 286–289°C; Rf 0⋅81 (40% AcOEt/petroleum
ether); IR (KBr): 1319, 1384, 1484, 1590, 2928,
13
H), 8⋅15 (brs, 2H, –NH); C NMR (125 MHz,
DMSO-d6): δ 27⋅6, 29⋅2, 29⋅6, 32⋅6, 38⋅2, 41⋅8, 50⋅8,
107⋅2, 117⋅1, 119⋅3, 127⋅6,128⋅2, 128⋅5, 128⋅8,
128⋅9, 129⋅2, 129⋅8, 131⋅6, 133⋅5, 136⋅2, 141⋅3,
143⋅2, 144⋅8, 150⋅2, 158⋅2, 162⋅2, 183⋅1, 195⋅2; MS
–1
1
3352 cm H NMR (500 MHz, DMSO-d6): δ 0⋅85
(s, 6H, –CH3), 0⋅95 (s, 6H, –CH3), 1⋅89 (Abq, 4H,
J = 9⋅2 Hz, –CH), 2⋅35 (s, 4H, –CH2), 4⋅46 (d, 2H,
J = 4⋅6 Hz, dihydropyridyl-CH), 5⋅52 (d, 2H,
J = 4⋅6 Hz, dihydropyridyl-C=CH), 7⋅14 (m, 4H,
J = 8⋅4 Hz, Ar-H), 7⋅25 (d, 4H, J = 8⋅4 Hz, Ar-H),
+
+
(ESI LCQ-MS): m/z 505⋅47 [M + H ]. Anal. Calcd.
for C34H36N2O2: C 80⋅92 H 7⋅19 N 5⋅55. Found: C
80⋅81 H 7⋅22 N 5⋅52.
13
2.3b 7,7,7′,7′-Tetramethyl-4,4′-bis(4-methylphenyl)-
4,6,7,8,4′,6′,7′,8′-octahydro-1H,1H-[2,2’]biquinolinyl-
5,5’-dione (table 2, entry 2) 7b: Yellow solid; m.p.
185–187°C; Rf 0⋅84 (40% AcOEt/petroleum ether);
IR (KBr): 1057, 1128, 1386, 1490, 1588, 2935,
8⋅22 (brs, 2H, –NH); C NMR (125 MHz, DMSO-
d6): δ 27⋅3, 28⋅1, 29⋅0, 29⋅5, 32⋅4, 37⋅4, 41⋅5, 50⋅8,
55⋅1, 55⋅3, 107⋅2, 113⋅4, 113⋅8, 114⋅2, 115⋅5, 119⋅1,
127⋅1, 129⋅2, 129⋅4, 130⋅5, 133⋅5, 138⋅5, 144⋅5,
150⋅2, 158⋅2, 161⋅7, 183⋅3, 195⋅4; MS (ESI LCQ-
–1
1
+
+
3320 cm H NMR (500 MHz, DMSO-d6): δ 0⋅91
(s, 6H, –CH3), 0⋅97 (s, 6H, –CH3), 1⋅93 (Abq, 4H,
J = 8⋅6 Hz, –CH), 2⋅19 (s, 6H, Ar-CH3), 2⋅29 (s, 4H,
MS): m/z 573⋅20 [M + H ]. Anal. Calcd. for
C34H34Cl2N2O2: C 71⋅20 H 5⋅98 N 4⋅88. Found: C
71⋅28 H 5⋅95 N 4⋅87.

Synthesis and anti-inflammatory activity of 3-indolyl pyridine derivatives
827
2.3e 7,7,7′,7′-Tetramethyl-4,4′-bis(3,4-dimethoxy-
phenyl)-4,6,7,8,4′,6′,7′,8′-octahydro-1H,1H-[2,2′]
geenan-induced paw oedema is a useful model to as-
sess the contribution of mediators involved in
biquinolinyl-5,5′-dione (table 2, entry 5) 7e: Yellow vascular changes associated with acute infla-
solid; m.p. 211–214°C; Rf 0⋅35 (40% AcOEt/ mmation. Carrageenan is sulphated polysaccharides
petroleum ether); IR (KBr): 1345, 1212, 1496, 1575, obtained from sea weed (rhodophyceae) and when
–1
1
2945, 3345 cm H NMR (500 MHz, DMSO-d6): δ injected causes the release of histamine 5-HT, bra-
1⋅07 (s, 6H, –CH3), 1⋅12 (s, 6H, –CH3), 2⋅12 (Abq, dykininins and prostaglandins. It produce inflamma-
4H, J = 8⋅6 Hz, –CH), 2⋅31 (s, 4H, –CH2), 3⋅68 (s, tion and oedema.
6H, Ar-OCH3), 3⋅73 (s, 6H, Ar-OCH3), 4⋅76 (d, 2H,
J = 5⋅6 Hz, dihydropyridyl–CH), 6⋅21 (m, 2H, dihy- 3.1a Preparation of 1% carrageenan solution:
dropyridyl-C=CH), 6⋅85 (m, 2H, Ar-H), 6⋅94 (m, Carrageenan (1 g) was dissolved in 0.9% saline and
2H, Ar-H), 7⋅56 (m, 2H, Ar-H) 8⋅59 (brs, 2H, the maximum volume administered to the rat was
13
–NH); C NMR (125 MHz, CDCl3): δ 27⋅8, 28⋅6, kept as 0⋅1 ml. The effects of drugs on paw oedema
29⋅4, 29⋅9, 32⋅8, 37⋅7, 42⋅3, 51⋅5,55⋅8, 56⋅1, 56⋅2, induced by carrageenan are shown in table 3. Al-
56⋅8, 108⋅1, 113⋅8, 114⋅0, 114⋅6, 115⋅8, 119⋅1, most all the drugs showed a maximum anti-
127⋅2, 129⋅3, 129⋅7, 130⋅7, 133⋅9, 138⋅9, 144⋅5, inflammatory effect and reduction in swelling. On
150⋅4, 159⋅3, 162⋅4, 184⋅5, 196⋅5; MS (ESI LCQ- the basis of these results, it can be concluded that
+
+
MS): m/z 625⋅40 [M + H ]. Anal. Calcd for greater anti-inflammatory activity was achieved with
C38H44N2O6: C 73⋅05 H 7⋅10 N 4⋅48. Found: C 73⋅18 all the compounds, especially 4h, 4i exhibit almost
H 7⋅16 N 4⋅52.
similar action as that of the standard. The anti-
inflammatory activity of the synthesized 3-
substituted indole derivatives was compared with
indomethacin. The experiment was maintained up to
2.3f 7,7,7′,7′-Tetramethyl-4,4′-bis(4-bromophenyl)-
4,6,7,8,4′,6′,7′,8′-octahydro-1H,1H-[2,2′]biquino-
linyl-5,5′-dione (table 2, entry 6) 7f: Yellow solid; four hours.
m.p. 282–284°C; Rf 0⋅79 (40% AcOEt/petroleum
ether); IR (KBr): 1189, 1259, 1426, 1559, 2975,
3.2 Analgesic activity of bis(indol-3yl dihydropy-
dine) derivatives
–1
1
3189 cm H NMR (500 MHz, DMSO-d6): δ 0⋅89
(s, 6H, –CH3), 0⋅95 (s, 6H, –CH3), 2⋅08 (Abq, 4H,
J = 8⋅1 Hz, –CH), 2⋅32 (s, 4H, –CH2), 4⋅91 (d, 2H,
J = 5⋅6 Hz, dihydropyridyl-CH), 6⋅21 (m, 2H, dihy-
dropyridyl-C=CH), 7⋅08–7⋅12 (m, 2H, Ar-H), 7⋅18–
7⋅22 (m, 4H, Ar-H), 7⋅48 (m, 2H, Ar-H) 8⋅47 (brs,
The analgesic activities of various synthesized com-
pounds were evaluated against acetic acid-induced
writhing test-induced in Albinomice. Glacial acetic
acid (GAA)-induced writhing 1% GAA solution was
injected (ip) and following this typical abdominal
writhing response was observed. The number of
writhes over a period of 20 min following GAA
injection was counted. The data for drug treated
groups were compared with appropriate controls for
statistical significance. The results were analysed by
student's ‘t’ test. The ‘t’ value of at least 0⋅05 or less
was considered as level of significance.
13
2H, –NH); C NMR (125 MHz, CDCl3): δ 26⋅8,
27⋅2, 29⋅1, 29⋅7, 32⋅4, 37⋅3, 41⋅5, 50⋅3, 107⋅1, 112⋅7,
113⋅5, 114⋅1, 115⋅3, 118⋅3, 126⋅3, 128⋅6⋅6, 129⋅9,
130⋅7, 133⋅3, 138⋅3, 144⋅1, 149⋅8, 157⋅2, 160⋅5,
182⋅9, 194⋅3; MS (ESI LCQ-MS): m/z 663⋅28
+
+
[M + H ]. Anal. Calcd. for C34H34Br2N2O4: C 61⋅64
H 5⋅17 N 4⋅23. Found: C 61⋅75 H 5⋅15 N 4⋅21.
3
compounds
Biological evaluation of newly synthesized
3.2a Materials and methods: Animals: Albinomice
25–30 g; Drugs/chemicals: 1% acetic acid; 2%
Tween 80: Aspirin Std Drug (50 m/kg); Synthetic
compounds: 7a–f.
3.1 Anti inflammatory activity of indol-3-yl pyri-
dine derivatives
3.2b Acetic acid-induced writhing test5: The pre-
screened animals were divided into 5 groups of 6
animals each. Aspirin in doses of 50 mg/kg, sus-
pended in 2% Tween 80 was used as the standard
drug and administered orally. Writhing was induced
The anti-inflammatory activities of various synthe-
sized compounds were evaluated against carrageenan-
induced paw oedema in rats. The inflammation was
readily produced in rats in the form of paw oedema
with the help of irritants such as carrageenan. Carra-

828
Prakasam Thirumurugan et al
Table 3. Anti-inflammatory activity of indol-3-yl pyridine derivatives.
Paw volume (mean SEM)
Percentage of inhibition
Doses
(mg/kg)
60 min 120 min 180 min 240 min
(%)
Group
0 min
60 min 120 min 180 min 240 min (%)
(%)
(%)
(1)
(control)
2⋅5%
Tween80
0⋅682
0⋅033
0⋅672
0⋅028
0⋅674
0⋅025
0⋅670
0⋅028
0⋅663
0⋅012
00
00
00
00
(2)
Indomethacin 10 mg/kg
Indomethacin 0⋅678
0⋅012
0⋅632
0⋅032
0⋅540
0⋅022
0⋅430
0⋅010
0⋅360
0⋅022
5⋅95 19⋅88
35
45⋅7
42⋅6
41⋅7
41⋅9
39⋅7
41⋅2
41⋅2
41⋅2
47⋅2
48⋅0
41⋅2
42
4a(3)
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
0⋅667
0⋅010
0⋅637
0⋅022
0⋅573
0⋅031
0⋅501
0⋅021
0⋅380
0⋅032
5⋅2
7⋅4
6⋅9
6⋅1
7⋅5
8⋅3
7⋅6
8⋅9
7⋅6
6⋅7
8⋅7
7⋅7
7⋅5
8⋅0
8⋅2
7⋅8
14⋅9
18⋅2
19⋅4
18⋅3
19⋅4
20⋅9
18⋅2
24
25
4b(4)
4c(5)
0⋅643
0⋅033
0⋅622
0⋅032
0⋅551
0⋅021
0⋅460
0⋅032
0⋅390
0⋅021
31⋅3
32
0⋅651
0⋅022
0⋅625
0⋅018
0⋅543
0⋅018
0⋅455
0⋅018
0⋅385
0⋅018
4d(6)
4e(7)
0⋅668
0⋅012
0⋅631
0⋅021
0⋅550
0⋅032
0⋅453
0⋅019
0⋅400
0⋅012
32⋅2
32⋅6
34⋅6
31⋅5
36⋅1
35⋅8
32⋅6
32⋅7
32⋅8
33⋅1
34⋅3
32⋅8
35⋅8
0⋅661
0⋅010
0⋅621
0⋅018
0⋅543
0⋅012
0⋅451
0⋅031
0⋅390
0⋅018
4f(8)
0⋅643
0⋅033
0⋅616
0⋅042
0⋅533
0⋅018
0⋅438
0⋅021
0⋅380
0⋅012
4g(9)
0⋅657
0⋅022
0⋅621
0⋅031
0⋅551
0⋅019
0⋅459
0⋅019
0⋅390
0⋅031
4h(10)
4i(11)
4j(12)
4k(13)
4l(14)
4m(15)
4n(16)
4o(17)
4p(18)
0⋅648
0⋅033
0⋅612
0⋅021
0⋅512
0⋅018
0⋅428
0⋅042
0⋅350
0⋅026
0⋅659
0⋅041
0⋅621
0⋅026
0⋅532
0⋅019
0⋅430
0⋅032
0⋅345
0⋅026
21
0⋅669
0⋅029
0⋅627
0⋅038
0⋅543
0⋅018
0⋅452
0⋅042
0⋅390
0⋅038
19⋅4
21⋅2
22⋅7
22⋅8
22⋅5
23⋅8
21⋅1
0⋅642
0⋅021
0⋅613
0⋅018
0⋅531
0⋅032
0⋅451
0⋅019
0⋅385
0⋅032
0⋅671
0⋅021
0⋅620
0⋅011
0⋅521
0⋅016
0⋅450
0⋅033
0⋅370
0⋅036
45⋅0
42⋅6
41⋅2
40⋅4
44⋅5
0⋅670
0⋅021
0⋅621
0⋅020
0⋅520
0⋅020
0⋅448
0⋅040
0⋅385
0⋅012
0⋅669
0⋅032
0⋅618
0⋅022
0⋅522
0⋅029
0⋅440
0⋅022
0⋅390
0⋅038
0⋅649
0⋅020
0⋅617
0⋅032
0⋅513
0⋅033
0⋅450
0⋅026
0⋅380
0⋅042
0⋅662
0⋅019
0⋅619
0⋅036
0⋅532
0⋅030
0⋅430
0⋅042
0⋅365
0⋅032
10 min later by intraperetoneal injection of 0⋅1 ml of Group-1: Received subcutaneously 2% Tween 80
1% acetic acid in distilled water. The number of and served as control.
writhes was counted for 10 min immediately after
the acetic acid injection. The percentage protection Group-2: The standard group received intra-
was calculated. Then the grouped animals received peretoneally 50 mg/kg of the bodyweight of
the standard and test drug as follows.
aspirin.

Synthesis and anti-inflammatory activity of 3-indolyl pyridine derivatives
829
Table 4. Analgesic activity of bis(indol-3yl dihydropydine) derivatives.
Group
Animal weight (g)
Dose (mg/kg)
Writhing response Inhibition (%)
1 (control)
2 (aspirin)
3 (7a)
4 (7b)
5 (7c)
6 (7d)
7 (7e)
8 (7f)
25
30
30
30
30
30
30
30
1% Acetic acid
50 mg/kg
38⋅00 0⋅70
10⋅50 0⋅64
12⋅50 0⋅86
11⋅75 0⋅75
11⋅25 0⋅28
12⋅15 0⋅75
11⋅25 0⋅75
10⋅75 0⋅70
00
72⋅36
67⋅10
69⋅07
70⋅39
68⋅02
70⋅22
71⋅71
100 mg/kg
100 mg/kg
100 mg/kg
100 mg/kg
100 mg/kg
100 mg/kg
Scheme 1. Synthesis of indol-3-yl pyridine derivatives
Group-3–8: The 3–8 groups received drugs 7a–f 4. Results and discussion
(100 mg/kg) respectively. All the above test com-
In our previous report, we demonstrated that a mix-
ture of substituted aldehyde, 3-cyanoacetyl indole
and malononitrile in InCl3/methanol under reflux
condition for 2–6 h, afforded indol-3-yl pyridine
pounds were dissolved in 2% Tween 80 and admin-
istered orally. Writhing was induced 30 min later by
intraperetoneal injections of 0⋅1 ml of 1% acetic
acid in distilled water the number of writhes was
counted for 10 min immediately after the acetic
acid injection. The percentage protection was calcu-
lated.
26
derivatives in good yields. To further optimize
conditions we extended the generality of our metho-
dology, we explored an alternative procedure, which
resulted in an operationally efficient process. Thus,
instead of heating the reaction in InCl3/methanol, the
reaction mixture was refluxed in freshly prepared
NaOMe (or) NaOH in methanol : water (2 : 1) ratio
to give best yield of indol-3-yl pyridine derivatives
in shorter reaction time. The isolation of the product
was very simple and easy, without employing any
purification technique like column chromatography.
It was pretty much straightforward as the solid pre-
cipitated was filtered and then dried. The crude was
further purified by recrystallisation with ethanol to
afford highly pure substituted indol-3-yl pyridine
derivative (scheme 1).
Writhing method is one of the most common tests
for evaluating the analgesic efficacy of drugs/
compound in rodents. Narcotic analgesic inhibits
both the types of pain, while NSAIDS such as
paracetamol aspirin inhibit only the peripheral pain.
The abdominal constriction response induced by
glacial acetic acid is a sensitive procedure to estab-
lish peripherally acting analgesics. This response is
thought to involve local peritoneal receptors. The
number of writhing observed during a 10 min period
in control group was 38⋅00 0.70 which corre-
sponds with the finding of other workers.
The compounds 7c, 7e and 7f significantly
reduced the number of writhes. Analgesic activity of
the synthesized bis-Hantzsch dihydropyridine
derivatives was compared with aspirin and found to
be having significant activity.
The substrate scope of the reaction under the
optimized conditions was investigated, and the reac-
tion was amenable to a wide variety of conditions
on various aldehydes. On sequential addition of

830
Prakasam Thirumurugan et al
Scheme 2. A plausible mechanism for the formation of synthesis of indol-3-yl pyridine
derivatives

Synthesis and anti-inflammatory activity of 3-indolyl pyridine derivatives
831
Scheme 3. Synthesis of 7,7′,7′-tetramethyl-4,4′-bis(aryl)-4,6,7,8,4′,6′,7′,8′-
octahydro-1H,1H-[2,2′]biquinolinyl-5,5′-dione derivatives.
the substrates under optimized conditions, the reac-
tion proceeded smoothly with a wide range of func-
tionalized aldehydes, including those containing
ether nitro, halogens and polyaromatic spacers and
the results are summarized in table 1.
Based on the above results, a plausible base and
acid catalysed mechanism was proposed for the
formation indol-3-yl pyridine derivatives (scheme
7
2). Initially, 3-cyano acetyl indole reacts with cor-
responding aldehyde (1a–k) to give a α, β unsatu-
rated ketone (2a) and on further it reacts with
malononitrile (2b) followed by methoxide or metha-
nol attack (2c) to give an intermediate (2d and 2e),
which upon protonation yields Hantzsch dihydro
pyridine derivative (2g). The later deprotonation af-
ford to yield pyridine (4) derivative. However in the
reverse reaction, malononitrile is first allowed to react
with the corresponding aldehyde followed by 3-
cyanoacetyl indole attack did not lead to the formation
of corresponding pyridine derivatives (scheme 2).
The structures of the compounds 4a–p were estab-
Figure 2. ORTEP diagram of compound 4g.
1
13
lished through IR, H NMR, C NMR and elemental
analysis as exemplified for compound 4g as follows:
In the IR spectrum absorptions at 3222 and
Based on above results, we extended our protocol
to the reaction with 1,6-diarylhexa-l,5-diene-
3,4dione, dimedone and ammonium acetate under
reflux condition which gave bis(indol-3yl dihydro-
pydine) derivatives in moderate yields (scheme 3).
Under optimized conditions, the reaction proceeded
smoothly with a wide range of functionalized cin-
namils, including those containing ethers, chlorine
and hydrocarbons and the results are summarized in
table 2.
–1
2253 cm supported the presence of –NH and –C≡N
1
functional groups. The H NMR spectrum exhibited
a broad distinguishable singlet at δ 12⋅14 (D2O
exchangeable) for –NH protons and a sharp distin-
guishable singlet appeared at δ 4⋅22 for methoxy
protons. Aromatic protons were seen in the range of
δ 7⋅22–8⋅56. A distinctive peak at δ 55⋅7 in the
13
C NMR spectrum confirmed the presence of meth-
The structure of compounds (7a–f) were exam-
ined based on the detailed spectroscopic studies as
exemplified for compound 7b as follows: In the IR
spectrum of compound (7b) showed stretching fre-
oxy group. The two cyano groups attached carbon
characteristic peaks were appeared at δ 91⋅3 and
96⋅6. The mass spectrum displayed the molecular
+
ion [M + H] peak at m/z 431⋅3. The structure of the
compound 4g was further established by single crys-
–1
quencies at 3320 and 1588 cm for –NH and C=O
1
bonds. The H NMR spectrum showed chemical
27
tal X-ray diffraction analysis (figure 2) .

832
Prakasam Thirumurugan et al
7. Evans C G and Gestwicki J E 2009 Org. Lett. 11
2957
8. Bringmann G, Reichert Y and Kane V V 2004 Tetra-
hedron 60 3539
9. Zhou Y, Kijima T, Kuwahara S, Watanabe M and
Izumi T 2008 Tetrahedron Lett. 49 3757
10. Franco L H, Joffe E B K, Puricelly L, Tatian M,
Seldes A M and Palermo J A 1998 J. Nat. Prod. 61
1130
11. (a) Farhanullah, Agarwal N, Goel A and Ram V J
2003 J. Org. Chem. 68 2983; (b) Joule J A, Smith G,
Mills K 1995 Heterocyclic chemistry (London: Chap-
man and Hall) 3rd edn, pp. 72–11
shift of δ: 8⋅55 (brs, D2O exchangeable) corresponds
to NH protons. The doublet in chemical shift region
of δ: 4⋅78 and 6⋅63 corresponds to dihydropyridine
ring protons. The sharp two singlets appeared in the
region if δ: 183⋅2 and 195⋅3 correspond to carbonyl
carbons. The aromatic carbons resonated in the
region of δ: 117⋅1–150⋅2. The mass spectrum
showed distinguishable singlet peak at m/z 533⋅47.
5. Conclusions
12. (a)Teague S J 2008 J. Org. Chem. 73 9765; (b)
Movassaghi M, Hill M D and Ahmad O K 2007 J.
Am. Chem. Soc. 129 10096
13. Cooke M W and Hanan G S 2007 Chem. Soc. Rev. 36
1466
14. Constable E C 2007 Chem. Soc. Rev. 36 246
15. (a) Kurth D G and Higuchi M 2006 Soft Matter 2
915; (b) Medlycott E A and Hanan G S 2005 Chem.
Soc. Rev. 34 133; (c) Andres P R and Schubert U S
2004 Adv. Mater. 16 1043
In conclusion, we have synthesized indol-3-yl pyri-
dine in better yields via one pot multi-component
reaction. These compounds showed good anti-
inflammatory activity in comparison with the stan-
dard drug indomethacin. Also, we have prepared se-
ries of bis-Hantzsch dihydropyridine derivatives.
These compounds showed a good analgesic activity
when compared with asprin. Further studies to de-
lineate the scope and limitations of the present 16. Gribble G W 2000 J. Chem. Soc., Perkin Trans. I
1045
methodology are underway.
17. Xiong W N, Yang C G and Jiang B 2001 Bioorg.
Med. Chem. 9 1773
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