Synthesis, anti-inflammatory and anticancer activity evaluation of some mono-And bis-Schiff's bases

Article abstract of DOI:10.1007/s00044-011-9899-3

Several mono-Schiff's bases (3a-i) and bis-Schiff's bases (5a-f) were synthesized using microwave irradiation technique (3a-h, 5a-c) and by simply grinding at room temperature for a few minutes (3i, 5d-f). All these compounds were characterized by spectroscopic means and elemental analysis. They were screened for anti-inflammatory and anticancer activities (against five human cancer cell lines). Compound 5f exhibited good anti-inflammatory and compounds 3f, 5a-f exhibited good anticancer activity. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9899-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3620–3628
DOI 10.1007/s00044-011-9899-3
ORIGINAL RESEARCH
Synthesis, anti-inflammatory and anticancer activity evaluation
of some mono- and bis-Schiff’s bases
•
Sham M. Sondhi Surbhi Arya Reshma Rani
•
•
•
Nikhil Kumar Partha Roy
Received: 28 March 2011 / Accepted: 8 November 2011 / Published online: 27 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Several mono-Schiff’s bases (3a–i) and bis-
Schiff’s bases (5a–f) were synthesized using microwave
irradiation technique (3a–h, 5a–c) and by simply grinding
at room temperature for a few minutes (3i, 5d–f). All these
compounds were characterized by spectroscopic means and
elemental analysis. They were screened for anti-inflam-
matory and anticancer activities (against five human cancer
cell lines). Compound 5f exhibited good anti-inflammatory
and compounds 3f, 5a–f exhibited good anticancer activity.
(Jayasekhar et al., 1997; Shalaby and El-Eraky, 1997;
Khedekar et al., 2003; Vazzana et al., 2004; Hegazy et al.,
2005; Bhandari et al., 2008), antimicrobial (Bawa and
Kumar, 2009; Magd–El–Din et al., 2009), antitumor
(Kumar and Rajkumar, 2006; Jiang et al., 2008), prosta-
glandin D2 production (Tanaka et al., 2005), lipoxygenase
(Hadjipavlou-Litina and Geronikaki, 1998; Geronikaki
et al., 2003) and MIF tautomerase (Dios et al., 2002)
inhibition activities. Schiff’s bases are also employed as
ligands for the complexation of metal ions (Aydogan et al.,
2001). Tempted by wide variety of biological activities
exhibited by Schiff’s bases and in continuation of our
efforts (Sondhi et al., 2010a, b, c, d, 2011) in search of
potent molecules exhibiting anti-inflammatory and anti-
cancer activities, a number of mono- and bis-Schiff’s bases
have been synthesized and screened for anti-inflammatory
and anticancer activities which we wish to report in this
article.
Keywords Schiff’s bases ꢀ Bis-Schiff’s bases ꢀ
Anti-inflammatory ꢀ Anticancer evaluation
Introduction
Any kind of health problem is associated with pain, e.g.
inflammatory diseases and cancer. To manage pain, various
drugs, i.e. phenylbutazone, indomethacin, aspirin, ibupro-
fen, etc. are available in the market. These drugs cannot be
used continuously for a long time as they can cause ulcer
(a major side effect) (Wolf, 1981). There are not many
drugs available in the market for the effective treatment of
cancer. Various research groups are making efforts in
search of potent molecules which can be developed as
effective and safer anticancer and anti-inflammatory drugs.
Schiff’s bases are reported to exhibit anti-inflammatory
Result and discussion
Microwave oven used has 100, 180, 300, 450, 600, 850 and
1000 W power levels. For optimization of reaction condi-
tions for synthesis of mono- and bis-Schiff’s bases, reaction
mixtures were irradiated at 100, 180, 300, and 450 W for
different intervals of time and progress of reaction was
monitored by Thin layer chromatography (TLC). In case of
5b product formation started at 300 W power level and in
case of 3a–h and 5a product formation started at 450 W but
in case of 5c product formation took place at 600 W power
level. Irradiation time was optimized by monitoring the
progress of reaction by TLC. Optimized reaction conditions
obtained for various compounds are reported herewith.
4-Hydroxy-3-methoxy benzaldehyde (1a; Scheme 1) and
S. M. Sondhi (&) ꢀ S. Arya ꢀ R. Rani
Department of Chemistry, Indian Institute of Technology,
Roorkee, Uttrakhand 247667, India
e-mail: sondifcy@iitr.ernet.in
N. Kumar ꢀ P. Roy
Department of Biotechnology, Indian Institute of Technology,
Roorkee, Uttrakhand 247667, India
123

Med Chem Res (2012) 21:3620–3628
3621
R
CHO
NH2 R1
+
1a-c
2a-c
MeO
MWI
=
HO
1a R=
1b R=
2a R1
CH2
O
2b R1= N
MeO
OMe
N
CH2 CH2 CH2
O
HN
N
CH2 CH2
1c R=
2c R1=
R
CH
N
R1
3a-i
MeO
MeO
3a R=
R1=
3b R=HO
R1=N
CH2
N CH2 CH2 CH2
HO
O
MeO
MeO
OMe
3c R=
3e R=
3g R=
R1= HN
N
CH2 CH2
3d R=
3f R=
3h R=
R1=
CH2
HO
O
N
HN
N CH2 CH2
MeO
OMe
MeO
OMe
N CH2 CH2 CH2
R1=
R1=
R1=
O
O
N
N
CH2 CH2 CH2
CH2
R1=
O
O
HN
N CH2 CH2
3i R=
R1=
Scheme 1 Synthesis of Schiff’s bases
tetrahydrofurfuryl amine (2a; Scheme 1) were taken in
equimolar ratio and mixed together thoroughly in a petri
dish. This reaction mixture was subjected to microwave
irradiation at 450 W power level for 4 min. Progress of the
reaction was monitored by TLC. The reaction mixture was
further irradiated at 450 W for 4 min two times. The total
irradiation time is 12 min. TLC of reaction mixture showed
completion of reaction. This reaction mixture was dissolved
in CHCl3 and washed with water. Chloroform layer was
dried over anhydrous sodium sulphate. Solvent was
removed under reduced pressure to give pure condensed
product 3a in 85% yield. 1H NMR (500 MHz; DMSO-d6) of
3a shows signals at d (ppm): 1.590–1.632 (m, 1H, one H of
CH2), 1.775–1.839 (m, 2H, CH2), 1.920–1.947 (m, 1H, one
H of CH2), 3.506–3.544 (m, 1H, one H of CH2), 3.570–3.631
(m, 2H, CH2), 3.711–3.754 (m, 1H, one H of CH2), 3.798
(s, 3H, –OCH3), 4.044–4.067 (m, 1H,[CH–), 6.814–6.831
(d, 1H, Ar), 7.103–7.123 (dd, 1H, Ar), 7.323–7.327 (d, 1H,
Ar), 8.154 (s, 1H, –CH=) GC–MS m/z 235 (M?, 3.39%). FT-
IR spectra show absorption band at 3422 (–OH), 1650
(–C=N–), 1543 and 1508 (Ar) cm-1. Spectral data of 3a
fully support the structure assigned to it. Similarly, con-
densation of 4-hydroxy-3-methoxy benzaldehyde (1a) with
1-(3-aminopropyl) imidazole (2b) and 1-(2-aminoethyl)
piperazine (2c); 2,5-dimethoxy benzaldehyde (1b) with 2a–
c; 2-furaldehyde (1c) with 2a, b gave condensation products
3b, c; 3d–f and 3g, h, respectively. Power level, irradiation
time, yield, spectral and analytical data of compounds
3b–h are reported in ‘‘experimental’’ section of this article.
Spectral and analytical data of 3b–h fully support the struc-
tures assigned to them. 2-Furaldehyde (1c) and 1-(2-ami-
noethyl) piperazine (2c) were mixed together in equimolar
123

3622
Med Chem Res (2012) 21:3620–3628
ratio. The reaction mixture was hand ground for 15 min in a
pestle mortar. The reaction mixture gets heated up during
grinding. It was further allowed to stand at room temperature
for half an hour. This thick mass was dissolved in CHCl3 and
washed with water. CHCl3 layer was dried over sodium
sulphate (anhydrous). Removal of solvent under reduced
pressure gave condensed product furan-2-ylmethylene-
Ar), 7.399–7.415 (d, 1H, Ar), 7.488–7.503 (d, 1H, Ar), 7.599
(s, 2H, Ar), 9.088–9.136 (2s looks like a doublet, 2H,
–CH= ? –CH=), 9.902 (s, 1H, exch, OH,), 10.155 (s, 1H,
exch, OH,), 13.901 (s, 1H, exch, NH) GC–MS m/z 367 (M?,
2.15%). FT-IR spectra show absorption band at 3341 (NH),
1671 (–C=N–), 1588 and 1573 (Ar) cm-1. Spectral data of
5a fully support the structure assigned to it. Similarly,
condensation of 4-hydroxy-3-methoxy benzaldehyde (1a)
with 1,4-bis (3-aminopropyl) piperazine (4b; Scheme 2) and
2,5-dimethoxy benzaldehyde (1b) with 3,5-diamino-1,2,4
triazole (4a; Scheme 2) gave bis-Schiff’s bases 5b and c in
79 and 80% yield, respectively. Spectral and analytical data
of 5b and c reported in ‘‘experimental’’ section of this article
fully support the structures assigned to them.
1
2(piperazin-1-yl ethyl) amine (3i) in 86% yield. H NMR
(500 MHz; DMSO-d6) of 3i shows signals at d (ppm):
2.339–2.519 (m, 10H, 5 9 CH2), 3.605–3.632 (m, 2H, =N–
CH2–), 6.604–6.615 (q, 1H, Ar), 6.890–6.897 (d, 1H, Ar),
7.806–7.809 (d, 1H, Ar), 8.155 (s, 1H, –CH=) GC–MS m/z
207 (M?, 31.89%). FT-IR spectra show absorption band at
3440 (NH), 1650 (–C=N–), 1458 (Ar) cm-1. Spectral data
of 3i is in full agreement with the structure assigned to it.
4-Hydroxy-3-methoxy benzaldehyde (1a) and 3, 5-diamino-
1,2,4-triazole (4a; Scheme 2) were taken together in 2:1
molar ratio, respectively, and mixed together thoroughly.
This reaction mixture was subjected to microwave irradia-
tion at 450 W power level for 5 9 4 min. TLC of reaction
mixture indicate completion of reaction. This solid product
was recrystallized from methanol to give pure product 5a
(Scheme 2) in 88% yield. 1H NMR (500 MHz, DMSO-d6) d
(ppm): 3.876 (s, 6H, OCH3 ? OCH3), 6.917–6.966 (q, 2H,
2,5-Dimethoxy benzaldehyde (1b) and 1,4-bis (3-ami-
nopropyl) piperazine (4b) were mixed together in 2:1 molar
ratio, respectively. This reaction mixture was hand ground in
a small pestle mortar for half an hour. The crude product so
obtained was crystallized from chloroform to give pure bis-
Schiff’s base 5d (Scheme 2) in 83% yield. 1H NMR
(500 MHz, CDCl3)
d (ppm): 1.875–1.932 (m, 4H,
2 9 CH2), 2.346–2.518 (m, 12H, 6 9 CH2), 3.643–3.669 (t,
4H, 2 9 CH2), 3.817 (s, 6H, 2 9 OCH3), 3.834 (s, 6H,
2 9 OCH3), 6.852–6.870 (d, 2H, Ar), 6.940–6.964 (dd,
+
H2N
R2 NH2
2 R
1a-c
CHO
4a-b
MWI
or
MeO
N
RT
1a R = HO
4a R2=
4b R2=
N
N
H
MeO
OMe
1b R =
1c R =
(H2C)3
N
N (CH2)3
O
R CH N R2 N CH R
5a-f
MeO
MeO
HO
N
HO
5a R=
5c R=
5e R=
R2=
R2=
R2=
5b R=
5d R=
5f R=
R2=
R2=
R2=
(H2C)3
(H2C)3
(H2C)3
N
N
N
N (CH2)3
N (CH2)3
N (CH2)3
N
N
N
N
H
N
MeO
OMe
MeO
OMe
N
H
N
O
O
N
H
Scheme 2 Synthesis of bis-Schiff’s bases
123

Med Chem Res (2012) 21:3620–3628
3623
2H, Ar), 7.429–7.486 (d, 2H, Ar), 8.643 (s, 2H, 2 9 –CH=)
GC–MS m/z 496 (M?, 0.50%). FT-IR spectra show
absorption band at 1628 (–C=N–), 1499 and 1464
(Ar) cm-1. Spectral data of 5d fully support the structure
assigned to it.
oedema model (Winter et al., 1962) and results are sum-
marized in Table 1. In vitro anticancer activity (Skehan
et al., 1990; Monks et al. 1991) evaluation of compounds
3a–i and 5a-f was carried out against five human cancer
cell lines consisting of lung (NCI H-522), ovary (PA1),
breast (T47D), colon (HCT-15) and liver (HepG2). Per-
centage (%) growth inhibition of cancer cell lines was
determined at a concentration of 1 9 10-5M and results
are summarized in Table 1.
Similarly, condensation of 2-furaldehyde (1c) with 3,5-
diamino-1,2,4 triazole and 1,4-bis(3-aminopropyl) pipera-
zine gave bis-Schiff’s bases 5e and f, respectively, in 77
and 87% yield. Spectral and analytical data of 5e and
f reported in experimental section of this article fully
support the structures assigned to them.
It is observed that compounds 3h and 5f exhibited good
anti-inflammatory activity. This may be due the fact that furan
ring is attached through a flexible three carbon chain which
may be making these compounds favourable electronically
and stereochemically for interaction with the active site and
thus showing good anti-inflammatory activity.
All the compounds were also prepared by using micro-
wave reactor model CEM DISCOVER MODEL NO
908010. Reaction temperature for 5b, 3a–h, 5a and c was
75, 80 and 100°C respectively. Irradiation time for each
compound was same as mentioned in experimental section
of this article.
Results in Table 1 indicate that compounds 3f (lung NCI
H-522), 5a–f (ovary PA1) and 5c (breast T47D) exhibited
good anticancer activity against the cell lines mentioned in
the brackets. These activities may be due to the fact that
these molecules meet stereochemical and electronic
requirements of the target in a better way as compared to
other molecules.
Over-expression of prostaglandin cascade and COX-2
are involved in carcinogenesis (Brown and DuBios, 2005;
Grosch et al., 2006; Harris 2009), non-steroidal anti-
inflammatory drugs (non-selective or selective cox-2
inhibitors) exhibit strong potential for chemoprevention of
cancer (Xiao et al., 2006; Harris et al., 2007, 2008). In
view of above information from literature it is considered
worthwhile to screen newly synthesized compounds for
anti-inflammatory and anticancer activities. Compounds
3a–i and 5a–f were screened for anti-inflammatory activity
at a dose of 50 mg/kg p.o. using carrageenan-induced paw
Conclusion
Synthesis of mono- and bis-Schiff’s bases 3a–h and 5a–c
by microwave irradiation and 3i and 5d–f by hand ground
Table 1 Anti-inflammatory
and in vitro anticancer activity
of compounds 3a–i and 5a–f
Compound no.
Anti-inflammatory activity Lung
(%) at 50 mg/kg p.o.
Ovary Breast Colon
T47D
Liver
HCT-15 HepG2
NCI H-522 PA1
3a
14
00
18
16
00
21
26
28
22
26
25
22
20
11
30
39
–
17
22
25
15
24
49
15
29
19
09
01
15
13
26
05
–
13
16
39
38
25
16
16
13
35
40
51
53
62
48
43
–
25
15
25
33
29
28
12
16
21
38
18
41
24
30
09
–
24
01
04
00
03
04
04
01
05
04
05
05
07
03
06
–
01
11
30
25
24
22
20
01
18
14
03
10
08
25
10
–
3b
3c
3d
3e
3f
3 g
3 h
3i
5a
5b
5c
5d
5e
5f
Ibuprofen
Cyclophosphamide
Cycloheximide
Actinomycin-D
5-Fluorouracil
07
20
59
51
21
82
93
27
36
30
21
22
07
05
49
21
24
14
42
33
–
Bold values represent
compounds showing good
anti-inflammatory and
anticancer activity
–
–
123

3624
Med Chem Res (2012) 21:3620–3628
at room temperature is reported in this article. Anti-inflam-
matory and anticancer activity evaluations of 3a–i and
5a–f were carried. Compounds 3h and 5f showed good anti-
inflammatory activity and compounds 3f (lung NCI H-522),
5a–f (ovary PA1) and 5c (breast T47D) showed good anti-
cancer activity.
By following above procedure compounds 3b–h were
synthesized.
4-[(3-Imidazol-1-yl-propylimino)-methyl]-2-methoxy phe-
nol (3b) Power level 450 W, Irradiation time 2 min,
solvent for TLC CHCl3/MeOH (9.5:0.5), Yield 88%,
liquid, IR (KBr) mmax: 3394 (–OH), 1640 (–C=N–), 1593
1
and 1513 (Ar) cm-1. H NMR (500 MHz; DMSO-d6) d
Experimental
(ppm): 2.038–2.093 (m, 2H, CH2), 3.467–3.496 (m, 2H,
CH2), 3.824 (s, 3H, –OCH3), 4.047–4.075 (t, 2H,
J = 7 Hz, CH2), 6.828–6.844 (d, 1H, J = 8 Hz, Ar), 6.901
(s, 1H, Ar), 7.130–7.149 (dd, 1H, J = 1.5 Hz, 8 Hz, Ar),
7.172–7.177 (t, 1H, J = 1.5 Hz, Ar), 7.345–7.349 (d, 1H,
Chemistry
Melting points (mp) were determined on a JSGW apparatus
and are uncorrected. Microwave oven model M 197DL
(SAMSUNG) and microwave reactor model CEM DIS-
COVER MODEL NO 908010 were used for microwave
irradiation. IR spectra were recorded using a perkin Elmer
1600FT spectrometer. 1H and 13C NMR spectra were
recorded on a Bruker WH 500 spectrometer at a ca 5–15%
(W/V) solution in DMSO-d6 and CDCl3 (TMS as internal
standard). GC–MS was recorded on Perkin Elmer Calrus 500
mass spectrometer. Elemental analysis was carried out on a
vario ELIII elementar. TLC was performed on silica gel G
for TLC (Merck) and spots were visualized by iodine vapour.
Starting materials i.e. 1a–c, 2a–c and 4a–b were purchased
from Aldrich Chemical Company and were used as such.
J = 2 Hz, Ar), 7.614 (s, 1H, Ar), 8.181 (s, 1H, –CH=). 13
C
NMR (125 MHz, DMSO-d6) d: 31.9 (C), 44.2 (C), 48.6
(C), 55.4 (C), 57.1 (C), 109.9 (C), 115.2 (C), 119.3 (C),
122.8 (C), 128.2 (C), 137.2 (C), 147.9 (C), 149.6 (C) and
161.0 (C) GC–MS m/z 259(M?, 1.55%). Anal. calcd for
C14H17N3O2 C 64.86; H 6.56; N 16.21 Found C 64.80; H
6.60; N 16.25.
2-Methoxy-4-[(2-piperazin-1-yl-ethylimino)-methyl]-phenol
(3c) Power level 450 W, Irradiation time 5 9 2 min, sol-
vent for TLC CHCl3/MeOH (9.5:0.5), Yield 83%, mp 50°C,
IR (KBr) mmax: 3410 (NH, OH), 1644 (–C=N–), 1584 and
1
1505 (Ar) cm-1. H NMR (500 MHz; CDCl3) d (ppm):
2.541 (bs, 4H, 2 9 CH2), 2.673–2.702 (t, 2H, J = 7.0 Hz,
CH2), 2.908–2.927 (t, 4H, J = 5 Hz, 2 9 CH2), 3.735–
3.764 (t, 2H, J = 7 Hz, CH2), 3.933 (s, 3H, –OCH3),
6.921–6.937 (d, 1H, J = 8 Hz, Ar), 7.077–7.093 (d, 1H,
J = 8 Hz, Ar), 7.400 (s, 1H, Ar), 8.190 (s, 1H, –CH=) 13C
NMR (125 MHz, DMSO-d6) d: 25.1 (C), 45.1 (C), 53.6 (C),
55.3 (C), 57.8 (C), 59.3 (C), 66.9 (C), 109.7 (C), 115.2 (C),
122.7 (C), 128.4 (C), 147.9 (C), 149.7 (C) and 161.0 (C) GC–
MS m/z 263 (M?, 6.60%). Anal. calcd. For C14H21N3O2 C
63.87; H 7.98; N 15.96 Found C 63.82; H 8.05; N 16.05.
General procedure for synthesis of Schiff’s bases (3a–h)
2-Methoxy-4[(tetrahydrofuran-2-ylmethylimino)-methyl] phe-
nol (3a) 4-Hydroxy-3-methoxy benzaldehyde (304 mg;
2 mmol) and tetrahydrofurfuryl amine (0.20 ml; 2 mmol)
were mixed thoroughly and irradiated at 450 W for
4 9 3 min. This reaction mixture was taken in CHCl3 and
washed with water. CHCl3 layer was dried over anhydrous
sodium sulphate. Removal of CHCl3 under reduced pres-
sure gave pure compound 3a.
Power level 450 W, Irradiation time 4 9 3 min, solvent
for TLC CHCl3/MeOH (9.5:0.5), Yield (85%), liquid, IR
(KBr) mmax: 3422 (–OH), 1650 (–C=N–), 1543 and 1508
2,5-Dimethoxy-benzylidene-(tetrahydrofuran-2yl methyl)-
amine (3d) Power level 450 W, Irradiation time
4 9 3 min, solvent for TLC CHCl3/MeOH (9.5:0.5), Yield
81%, liquid, IR (KBr) mmax: 1638 (–C=N–), 1496 and 1464
(Ar) cm-1 1H NMR (500 MHz; DMSO-d6) d (ppm):
.
(Ar) cm-1 1H NMR (500 MHz; DMSO-d6) d (ppm):
.
1.590–1.632 (m, 1H, one H of –CH2–), 1.775–1.839 (m, 2H,
–CH2–), 1.920–1.947 (m, 1H, one H of –CH2–), 3.506–3.544
(m, 1H, one H of –CH2–), 3.570–3.631 (m, 2H, –CH2–),
3.711–3.754 (m, 1H, one H of –CH2–), 3.798 (s, 3H,
–OCH3), 4.044–4.067 (m, 1H,[CH–), 6.814–6.831 (d, 1H,
J = 8.5 Hz, Ar), 7.103–7.123 (dd, 1H, J = 1.5, 8.5 Hz, Ar),
1.590–1.659 (m, 1H, one H of CH2), 1.752–1.878 (m, 2H,
CH2), 1.928–1.968 (m, 1H, one H of CH2), 3.565–3.605
(m, 2H, CH2), 3.641–3.677 (m, 1H, one H of CH2),
3.727–3.759 (s ? m, 4H, –OCH3 ? one H of CH2), 3.803
(s, 3H, –OCH3), 4.053–4.103 (m, 1H, [CH–), 7.027–7.039
(m, 2H, Ar), 7.350–7.356 (d, 1H, J = 3 Hz, Ar), 8.584 (s, 1H,
–CH=) 13C NMR (125 MHz, DMSO-d6) d: 25.2 (C), 28.8 (C),
55.3 (C), 56.0 (C), 65.4 (C), 67.2 (C), 77.8 (C), 110.2 (C), 113.2
(C), 117.9 (C), 124.4 (C), 152.8 (C), 153.0 (C) and 156.7 (C),
GC–MS m/z 249 (M?, 13.65%) Anal. calcd. For C14H19NO3 C
67.46; H 7.63; N 5.62 Found C 67.50; H 7.72; N 5.60.
7.323–7.327 (d, 1H, J = 2 Hz, Ar), 8.154 (s, 1H, –CH=). 13
C
NMR (125 MHz, DMSO-d6) d: 25.1 (C), 28.7 (C), 32.0 (C),
42.6 (C), 55.5 (C), 60.3 (C), 64.9 (C), 67.1 (C), 77.2 (C), 77.9
(C), 109.8 (C), 115.1 (C), 147.9 (C) and 161.2 (C) GC–MS
m/z 235 (M?, 3.39%). Anal. calcd. for C13H17NO3 C 66.38;
H 7.23; N 5.95 Found C 66.30; H 7.30; N 6.05.
123

Med Chem Res (2012) 21:3620–3628
3625
2,5-Dimethoxy-benzylidene-(3-imidazol-1-yl-propyl)-amine
(3e) Power level 450 W, Irradiation time 4 9 3 min,
solvent for TLC CHCl3/MeOH (9.5:0.5), Yield 85%, liquid,
liquid, IR (KBr) mmax: 1658 and 1636 (–C=N–), 1513
(Ar) cm-1 1H NMR (500 MHz; DMSO-d6) d (ppm):
.
2.014–2.070 (m, 2H, CH2), 3.451–3.479 (m, 2H, CH2),
4.013–4.042 (m, 2H, CH2), 6.618–6.628 (q, 1H,
J = 1.5 Hz, 3.0 Hz, Ar), 6.896–6.900 (t, 1H, J = 1 Hz,
Ar), 6.922–6.928 (d, 1H, J = 3 Hz, Ar), 7.199–7.203 (t,
1H, J = 2 Hz, Ar), 7.634 (s, 1H, Ar), 7.826–7.829 (d, 1H,
J = 1.5 Hz, Ar), 8.155 (s, 1H, –CH=) 13C NMR
(125 MHz, DMSO-d6) d: 31.8 (C), 43.9 (C), 57.4 (C),
111.9 (C), 114.3 (C), 119.3(C), 128.4(C), 137.2(C),
145.2(C), 150.5(C) and 151.3(C) GC–MS m/z 203 (M?,
74.83%) Anal. calcd. For C11H13N3O C 65.02; H 6.40; N
20.68 Found C 65.08; H 6.46; N 20.70.
1
IR (KBr) mmax: 1636 (–C=N–), 1496 (Ar) cm-1. H NMR
(500 MHz; DMSO-d6) d (ppm): 2.046–2.074 (m, 2H, CH2),
3.503–3.529 (t, 2H, J = 7 Hz, CH2), 3.740 (s, 3H, –OCH3),
3.806 (s, 3H, –OCH3), 4.034–4.062 (t, 2H, J = 7 Hz, CH2),
6.899 (s, 2H, Ar), 7.037–7.047 (t, 1H, J = 2.5 Hz, Ar), 7.207
(s, 1H, Ar), 7.364–7.369 (d, 1H, J = 2.5 Hz, Ar), 7.633
(s, 1H, Ar), 8.598 (s, 1H, –CH=) 13C NMR (125 MHz,
DMSO-d6) d: 31.7 (C), 43.5 (C), 55.2 (C), 56.1 (C), 57.6 (C),
110.1 (C), 113.1 (C), 117.9 (C), 119.2 (C), 124.2 (C), 128.2
(C), 137.1 (C), 152.7 (C), 152.9 (C) and 156.34 (C) GC–MS
m/z 273 (M?, 18.53%) Anal. calcd. For C15H19N3O2 C
65.93; H 6.95; N 15.38 Found C 66.02; H 7.00; N 15.42.
Synthesis of furan-2-yl methylene-(2-piperazin-1-yl-ethyl)
amine (3i) Furan-2-carboxaldehyde (0.20 ml; 2 mmol)
and 1-(2-aminoethyl) piperazine (0.26 ml; 2 mmol) were
taken together and grinded for about 10 min. The reaction
contents get heated during mixing and grinding. This
reaction mixture was allowed to stand at room temperature
for about half an hour. Reaction contents were taken in
CHCl3 (15 ml) and washed with water (2 9 5 ml). Chlo-
roform layer was dried over anhydrous sodium sulphate
and the solvent was removed under reduced pressure to
give pure product 3i.
2,5-Dimethoxy-benzylidene-(2-piperazin-1-yl-ethyl)-amine (3f)
Power level 450 W, Irradiation time 4 9 4 min, solvent for
TLC CHCl3/MeOH (9.0:1.0), Yield 80%, liquid, IR (KBr)
m
max: 3415 (–NH–), 1637 (–C=N–), 1495 and 1463
(Ar) cm-1. 1H NMR (500 MHz; CDCl3) d (ppm): 2.516 (bs,
4H, 2 9 CH2), 2.660–2.689 (t, 2H, J = 7 Hz, CH2),
2.878–2.897 (t, 4H, J = 5 Hz, 2 9 CH2), 3.751–3.782 (m,
2H, CH2), 3.789 (s, 3H, –OCH3), 3.812 (s, 3H, –OCH3),
6.830–6.848 (d, 1H, J = 9 Hz, Ar), 6.919–6.943 (dd, 1H,
J = 3 Hz, 9 Hz, Ar), 7.449–7.455 (d, 1H, J = 3 Hz, Ar),
8.680 (s, 1H, –CH=) 13C NMR (125 MHz, DMSO-d6) d:
45.5 (C), 48.5 (C), 54.3 (C), 55.3 (C), 56.0 (C), 58.4 (C), 59.3
(C), 99.5 (C), 110.2 (C), 113.3 (C), 117.9 (C), 124.5 (C),
152.8 (C), 153.0 (C) and 156.4 (C) GC–MS m/z 277
(M?, 3.72%) Anal. calcd. For C15H23N3O2 C 64.98; H 8.30;
N 15.16 Found C 65.08; H 8.36; N 15.20.
Grinding by hand at room temperature, solvent for TLC
CHCl3/MeOH (9.2:0.8), Yield (86%), liquid, IR (KBr)
1
m
max: 3440 (–NH–), 1650 (–C=N–), 1458 (Ar) cm-1. H
NMR (500 MHz; DMSO-d6) d (ppm): 2.339–2.519 (m,
10H, 5 9 CH2), 3.605–3.632 (m, 2H,=N–CH2–),
6.604–6.615 (q, 1H, J = 2 Hz, 3.5 Hz, Ar), 6.890–6.897
(d, 1H, J = 3.5 Hz, Ar), 7.806–7.809 (d, 1H, J = 1.5 Hz,
Ar), 8.155 (s, 1H, –CH=) 13C NMR (125 MHz, DMSO-d6)
d: 15.1 (C), 48.6 (C), 53.2 (C), 58.4 (C), 64.9 (C), 99.5 (C),
111.9 (C), 113.9 (C), 145.1 (C), 150.4 (C) and 151.4
(C) GC–MS m/z 207 (M?, 31.89%) Anal. calcd. For
C11H17N3O C 63.76; H 8.21; N 20.28 Found C 63.85; H
8.42; N 20.01.
Furan-2-yl methylen-(tetrahydro-furan-2-yl)-amine (3g)
Power level 450 W, Irradiation time 3 9 2 min, solvent for
TLC CHCl3/MeOH (9.5:0.5), Yield 87%, liquid, IR (KBr)
1
m
max: 1635 (–C=N–), 1511 and 1466 (Ar) cm-1. H NMR
(500 MHz; DMSO-d6) d (ppm): 1.591–1.632 (m, 1H, one
H of CH2), 1.797–1.839 (m, 2H, CH2), 1.937 (m, 1H, one
H of CH2), 3.523–3.549 (m, 1H, one H of CH2),
3.591–3.635 (m, 2H, CH2), 3.709–3.752 (m, 1H, one H of
CH2), 4.032–4.055 (m, 1H, –CH=), 6.611–6.622 (q, 1H,
J = 2 Hz, 3.5 Hz, Ar), 6.910–6.916 (d, 1H, J = 3 Hz, Ar),
7.816–7.819 (d, 1H, J = 1.5 Hz, Ar), 8.140 (s, 1H, –CH=)
13C NMR (125 MHz, DMSO-d6) d: 25.1 (C), 28.4 (C),
41.1 (C), 42.5 (C), 67.1 (C), 67.2 (C), 76.9 (C), 77.2 (C),
99.5 (C) and 161.2 (C) GC–MS m/z 179 (M?, 32.22%)
Anal. calcd. For C10H13NO2 C 67.03; H 7.26; N 7.82
Found C 67.08; H 7.30; N 7.80.
Synthesis of N3, N5-bis (4-hydroxy, 3-methoxy benzyli-
dene)-1H-1,2,4-triazole-3,5-diamine (5a) 4-Hydroxy-3-
methoxy benzaldehyde (304 mg; 2 mmol) and 3,5-dia-
mino-1,2,4-triazole (99 mg; 1 mmol) were mixed together
thoroughly. This reaction was irradiated for 5 9 4 min at a
power level of 450 W. Condensation product so obtained
was washed with diethyl ether and then crystallized from
methanol to give pure product 5a.
Power level 450 W, Irradiation time 5 9 4 min, solvent
for TLC CHCl3/MeOH (9.2:0.8), Yield (88%), mp 208°C,
IR (KBr) mmax: 3341 (NH), 1671 (–C=N–), 1588 and 1573
(Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d (ppm): 3.876
(s, 6H, OCH3 ? OCH3), 6.917–6.966 (q, 2H, Ar), 7.399–
7.415 (d, 1H, J = 8 Hz, Ar),7.488–7.503 (d, 1H, J = 7.5 Hz,
Furan-2-yl methylene-(3-imidazol-1-yl-propyl)-amine
(3h) Power level 450 W, Irradiation time 3 9 3 min,
solvent for TLC CHCl3/MeOH (9.2:0.8), Yield 79%,
123

3626
Med Chem Res (2012) 21:3620–3628
Ar), 7.599 (s, 2H, Ar), 9.088–9.136 (2s looks like a doublet,
2H, –CH= ? –CH=),9.902(s, 1H, –OH, exch),10.155(s, 1H,
–OH, exch), 13.901 (s, 1H, -NH-, exch) 13C NMR (125 MHz,
DMSO-d6) d : 55.5 (C), 109.9 (C), 110.5 (C), 110.7 (C), 115.4
(C), 115.5 (C), 126.1 (C), 128.8 (C), 148.0 (C), 148.1 (C),
150.5 (C), 152.9 (C) and 191.0 (C) GC–MS m/z 367 (M?,
2.15%) Anal. calcd. For C18H17N5O4 C 58.85; H 4.63; N
19.07 Found C 58.60; H 4.60; N 19.28.
3.834 (s, 6H, 2 9 OCH3), 6.852–6.870 (d, 2H, J = 9 Hz,
Ar), 6.940–6.964 (dd, 2H, J = 3 Hz, 6 Hz, Ar), 7.429–
7.486 (d, 2H, J = 3.5 Hz, Ar), 8.643 (s, 2H, 2 9 –CH=)
13C NMR (125 MHz, DMSO-d6) d: 27.6 (C), 52.8 (C),
55.3 (C), 55.5 (C), 56.1 (C), 58.9 (C), 110.2 (C), 113.3 (C),
117.9 (C), 124.4 (C), 152.7 (C), 153.1 (C) and 155.8
(C) GC–MS m/z 496 (M?, 0.50%) Anal. calcd. For
C28H40N4O4 C 67.74; H 8.06; N 11.29 Found C 67.95; H
8.31; N 11.01.
4-(3-(4-(3-(4-hydroxy-3-methoxy benzylideneamine) pro-
pyl) piperazin-1-yl)-propylimino)-methyl)-2-methoxy phe-
nol (5b) Power level 300 W, Irradiation time 3 9 3 min,
solvent for TLC CHCl3/MeOH (9.5:0.5), Yield 79%, mp
196–198°C, IR (KBr) mmax: 3500 (–OH), 1648 (–C=N–),
N3, N5-bis (furan-2-yl methylene)-1H-1,2,4-triazole-3,5-
diamine (5e) Grinding by hand at room temperature,
solvent for TLC CHCl3/MeOH (9.5:0.5), Yield 77%, mp
180–182°C, IR (KBr) mmax: 3321 (NH), 1658 (–C=N–),
1596 and 1515 (Ar) cm-1. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 6.725 (s, 2H, Ar), 7.221 (s, 2H, Ar), 7.969 (s, 2H,
1
1586 and 1517 (Ar) cm-1. H NMR (500 MHz, CDCl3) d
(ppm): 1.880–1.938 (m, 4H, 2 9 CH2), 2.434–2.525
(t ? bs, 12H, 6 9 CH2), 3.617–3.644 (t, 4H, J = 7 Hz,
2 9 CH2), 3.970 (s, 6H, 2 9 -OCH3), 6.939–6.956 (d, 2H,
J = 8.5 Hz, Ar), 7.089–7.108 (dd, 2H, J = 1.5 Hz, 8 Hz,
Ar), 7.431 (s, 2H, Ar), 8.188 (s, 2H, 2 9 –CH=) 13C NMR
(125 MHz, DMSO-d6) d: 27.8 (C), 52.8 (C), 55.4 (C), 55.5
(C), 55.7 (C), 58.3 (C), 109.7 (C), 110.4 (C), 115.2 (C),
115.4 (C), 122.6 (C), 127.6 (C), 128.2 (C), 147.9 (C), 148.3
(C), 153.8 (C), 160.3 (C) and 190.9(C), GC–MS m/z 468
(M?, 2.96%) Anal. calcd. For C26H36N4O4 C 66.66; H
7.69; N 11.96 Found C 61.02; H 7.75; N 12.08.
Ar), 8.762 (s, 2H, 2 9 CH=), 11.967 (s, 1H, NH, exch) 13
C
NMR (125 MHz, DMSO-d6) d: 25.1 (C), 66.9 (C), 112.7
(C), 112.9 (C), 113.1 (C), 117.8 (C), 146.8 (C), 148.7 (C),
149.2 (C), 151.1 (C) and 151.7 (C) GC–MS m/z 255 (M?,
4.67%) Anal. calcd. For C12H9N5O2 C 56.47; H 3.52; N
27.45 Found C 56.50; H 3.60; N 27.52.
Furan-2-yl
methylene-[3-(4-(3-(furan-2-yl
methylene)
amino) propyl)-piperazin-1-yl) propyl] amine (5f) Grind-
ing by hand at room temperature, solvent for TLC CHCl3/
MeOH (9.2:0.8), Yield 87%, liquid, IR (KBr) mmax: 1634
N3,N5-bis(2,5-dimethoxy benzyl diene)-1H-1,2,4-triazole-
3,5-diamine (5c) Power level 600 W, Irradiation time
5 9 4 min, solvent for TLC CHCl3/MeOH (9.2:0.8), Yield
80%, mp 122°C, IR (KBr) mmax: 1607 (–C=N–), 1498 and
1426 (Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d (ppm):
3.803–3.919 (d, 12H, 4 9 OCH3), 7.173 (s, 4H, Ar), 7.579
(s, 2H, Ar), 9.540 (s, 2H, 2 9 –CH=), 14.182 (s, 1H, N,
exch) 13C NMR (125 MHz, DMSO-d6) d: 55.4 (C), 55.5
(C), 56.2(C), 109.4 (C), 109.5 (C), 113.6 (C), 119.8 (C),
124.1 (C), 153.2 (C), 154.0 (C), 156.2 (C), 156.4 (C) and
163.9 (C) Anal. calcd. For C20H21N4O5 C 60.75; H 5.31; N
17.72 Found C 61.08; H 5.35; N 17.80.
(–C=N–), 1442 (Ar) cm-1. H NMR (500 MHz, CDCl3)
1
d (ppm): 1.884–1.942 (m, 4H, 2 9 CH2), 2.374–2.490 (m,
12H, 6 9 CH2), 3.608–3.635 (t, 4H, J = 6.5 Hz,
2 9 CH2), 6.477–6.487 (q, 2H, J = 2 Hz, 3.5 Hz, Ar),
6.734–6.741 (d, 2H, J = 3.5 Hz, Ar), 7.520 (d, 2H,
J = 1 Hz, Ar), 8.099 (s, 2H, 2 9 –CH=) 13C NMR
(125 MHz, DMSO-d6) d: 27.3 (C), 52.4(C), 55.2 (C), 58.3
(C), 78.8 (C), 99.5 (C), 111.4 (C), 112.5 (C), 113.3 (C),
144.6 (C), 148.8 (C), 149.3 (C), 151.0 (C), 152.1 (C) and
177.9 (C) Anal. calcd. For C20H28N4O2 C 67.41; H 7.86; N
15.73 Found C 67.50; H 8.03; N 15.80.
Pharmacology
3,5-Dimethoxybenzylidene-[3-(4-(3-(2,5-dimethoxy-benzyl-
idene amino)-propyl) piperazin-1-yl)-propyl) amine (5d) 2,5
Dimethoxy benzaldehyde (332 mg, 2 mmol) and 1,4-bis
(3-aminopropyl) piperazine (0.20 ml, 1 mmol) were taken
together and grinded for 30 min in a small pastel mortar.
Solid product so obtained was crystallized from chloroform
to give pure product 5d.
Anti-inflammatory activity (Winter et al., 1962)
Paw oedema inhibition test was used on albino rats of
Charles Foster adopting the method of Winter et al.,
(1962). Group of five animals of both sexes (body weight
120–160 g), excluding pregnant females, were given a dose
of test compound. Thirty minutes later, 0.20 ml of 1%
freshly prepared carrageenan suspension in 0.9% NaCl
solution was injected subcutaneously into the planter apo-
neurosis of the hind paw, and the volume was measured by
a water plethysmometer apparatus and then measured again
1–3 h later.
Grinding by hand at room temperature, solvent for TLC
CHCl3/MeOH (9.2:0.8), Yield (83%), mp 100°C, IR (KBr)
1
m
(500 MHz, CDCl3)
max: 1628 (–C=N–), 1499 and 1464 (Ar) cm-1. H NMR
d (ppm): 1.875–1.932 (m, 4H,
2 9 CH2), 2.346–2.518 (m, 12H, 6 9 CH2), 3.643–3.669
(t, 4H, J = 6.5 Hz, 2 9 CH2), 3.817 (s, 6H, 2 9 OCH3),
123

Med Chem Res (2012) 21:3620–3628
3627
The mean increase of paw volume at each interval was
compared with that of control group (five rats treated with
carrageenan but not with test compound) at the same
intervals, and percent inhibition value calculated by the
formula given below.
stirred for 10 min using a mechanical stirrer. The optical
density (OD) was recorded on ELISA reader at 540 nm.
Acknowledgments We thank the technical staff of Chemistry
Department, IIT Roorkee, for their assistance in spectroscopic studies
and elemental analysis and to Mr. Rakesh Kumar (Integral Biosci-
ences Ltd. Noida) for helping to use microwave reactor. One of the
authors Ms. Surbhi Arya (JRF-NET) thanks to CSIR, New Delhi, for
financial assistance.
% anti - inflamatory activity ¼ ½1 ꢁ Dt=Dcꢂ ꢃ 100
Dt and Dc are paw volumes of oedema in tested and control
groups, respectively.
In vitro cytotoxicity against human cancer cell lines
(Skehan et al., 1990; Monks et al., 1991)
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