Synthesis, characterization and their anticonvulsant, anti-inflammatory studies of some novel chromeno oxadiazoles

Article abstract of DOI:10.1007/s00044-012-0103-1

In this study, a series of new 1,2,4-oxadiazole derivatives containing 3,4-dihydro-2H-chromen-2-amine moiety were synthesized by efficient microwave reaction of 2-amino-N′-hydroxychroman-3-carboxamidine and suitable aldehyde. Structures of all the synthesized compounds were confirmed by spectral studies and C, H, N analyses. Newly synthesized compounds were screened for their anticonvulsant and anti-inflammatory properties. Few of the compounds exhibited excellent anticonvulsant activity as compared to the standard drug Diazepam. Also compounds have exhibited moderate anti-inflammatory activity as compared to the standard drug Diclofenac sodium.

Full text of DOI:10.1007/s00044-012-0103-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0103-1
ORIGINAL RESEARCH
Synthesis, characterization and their anticonvulsant,
anti-inflammatory studies of some novel chromeno oxadiazoles
•
S. R. Ubaradka Arun M. Isloor Prakash Shetty
•
•
•
Prashanth Shetty Nishitha A. Isloor
Received: 7 June 2011 / Accepted: 22 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract In this study, a series of new 1,2,4-oxadiazole
derivatives containing 3,4-dihydro-2H-chromen-2-amine
moiety were synthesized by efficient microwave reaction of
2-amino-N0-hydroxychroman-3-carboxamidine and suit-
able aldehyde. Structures of all the synthesized compounds
were confirmed by spectral studies and C, H, N analyses.
Newly synthesized compounds were screened for their
anticonvulsant and anti-inflammatory properties. Few of the
compounds exhibited excellent anticonvulsant activity as
compared to the standard drug Diazepam. Also compounds
have exhibited moderate anti-inflammatory activity as
compared to the standard drug Diclofenac sodium.
Introduction
Nitrogen–oxygen containing heterocycles are of synthetic
interest because they constitute an important class of nat-
ural and synthetic products, many of which exhibit useful
biological activities (Vu et al., 1999). The interest in five-
membered systems containing one oxygen and two nitro-
gen atoms (positions 1, 2, and 4) stems from the occurrence
of saturated and partially saturated 1,2,4-oxadiazoles in
biologically active compounds and natural products (Orlek
et al., 1991; Ankersen et al., 1997).
1,2,4-Oxadiazoles have recently received considerable
attention by synthetic chemists as heterocyclic amide and
ester bioisosteres. Bioisosteric replacement of the amide
moiety represents an area that is currently a center of focus
because of its implications in peptide chemistry and the
development of peptidomimetics (Kaboudin and Navaee,
2003; Andersen et al., 1994). Furthermore, derivatives con-
taining 1,2,4-oxadiazole ring systems have been employed
as antirhinovirals, tyrosine kinase inhibitors, serotoninergic
(5-HT3) antagonists, dopamine receptor (D4) ligands, anti-
inflammatory agents, antitumor agents, monoamine oxidase
inhibitors, coronary artery dilators, anesthetic agents, muscle
relaxants, antischistosomal agents, and aldose reductase
inhibitors (Caliendo et al., 2001). In our recent paper (Isloor
et al., 2010), 1,2,4-oxadiazole derivatives have showed
significant antimicrobial properties.
Keywords Chromeno oxadiazole ꢀ
Anticonvulsant activity ꢀ Anti-inflammatory activity
S. R. Ubaradka
Department of Chemistry, Manipal
Institute of Technology, Manipal, India
A. M. Isloor (&)
Medicinal Chemistry Laboratory, Department of
Chemistry, National Institute of Technology Karnataka,
Surathkal, Mangalore 575 025, India
e-mail: isloor@yahoo.com
Prakash Shetty
Department of Printing, Manipal
Institute of Technology, Manipal, India
Compounds comprising a coumarin (2-oxo-2H-1-benz-
opyran) backbone have a wide range of biological activities
(Kalluraya et al., 2000, 2001). Thus, among the natural and
synthetic coumarin derivatives, there are compounds pos-
sessing antimicrobial (Isloor et al., 2010; Maxwell, 1993),
antitumor (Dexeus et al., 1990), anti-HIV (Zembower et al.,
1997), and other (Maxwell, 1993) activities. Combination
of chromene and oxadiazoles may further enhance the
Prashanth Shetty
Department of Pharmacology, Nitte Gulabi Shetty
Memorial College of Pharmacology, Deralakatte,
Mangalore 574 160, India
N. A. Isloor
Biotechnology Division, Department of Chemical Engineering,
National Institute of Technology Karnataka,
Surathkal, Mangalore 575 025, India
123

Med Chem Res
biological activity. Keeping in view of these observations
and in continuation of our research on biologically active
heterocycles, we hereby report the synthesis of some novel
1,2,4-oxadiazoles containing 3,4-dihydro-2H-chromen-2-
amine containing moieties and their pharmacological
evaluation.
observed directly. PTZ solution was prepared by dissolving
in distilled water and the test compounds were suspended in
carboxymethylcellulose sodium (CMC 1 %) and tween 80
(5 %). The test compounds (25 mg/kg) were injected orally
to groups of 06 mice 30 min before PTZ injection. PTZ-
induced convulsions and mortality were evaluated for
30 min after drug injection based on seizure latency of
tonic–clonic convulsions. Control groups received vehicle
including water with CMC/tween 80. The anticonvulsant
activity of the compounds was compared with diazepam as
standard anticonvulsant at the dose of 2 mg/kg, by injecting
intraperitoneally. As per the acute toxicity study (OECD
425), the dose of 25 mg/kg bw has been selected.
Chemistry
The general strategy used for the synthesis of 3,(1,2,4-oxa-
diazol-3-yl)-3,4-dihydro-2H-chromen-2-amine is outlined
in Scheme 1. Compound 1 was prepared by following the
reported procedure (Evdokimov et al., 2007). Subsequent
reduction of 1 using sodium borohydride in alcohol medium
gave compound 2 in high yield. Amidoxime 3 was prepared
by treating compound 2 with hydroxylamine hydrochloride
in the presence of base. Further, 1,2,4-oxadiazole was pre-
pared by using method reported in (Adib et al., 2006). The
structure of 4a was confirmed based on the elemental anal-
yses and spectral data. The efficiency of the first reaction
prompted us to extend this procedure to synthesize series of
compounds (4a–n) using microwave reactor (Scheme 1).
Anti-inflammatory activity
Screening of anti-inflammatory drugs by carrageenan-
induced paw edema method (Maria et al., 2008;
Hu et al., 2008)
Edema was induced in the left hind paw of Wistar rats
(200–250 g) by the sub-plantar injection of 0.1 mL of 1 %
carrageenan in distilled water. Both sexes were used. Each
group composed of 6 animals. The animals which were
bred in our laboratory were housed under standard condi-
tions and received a diet of commercial food pellets and
water ad libitum during the maintenance but they were
entirely fasted during the experiment period. Our studies
were conducted in accordance with recognized guidelines
on animal experimentation.
Pharmacology
Anticonvulsant activity
Male albino mice weighting 25–35 g were used for phar-
macological study. Animals were allowed free access to
food and water except during the experiment (Singh et al.,
1978; Srivastava et al., 1979) and housed at controlled room
temperature with 12 h light and 12 h dark cycle. Animals
were placed individually in glass cylinder (25 cm width,
25 cm length) and allowed to habituate for 30 min before
the drug administration. For induction of convulsions,
pentylenetetrazole (PTZ, Sigma, 80 mg/kg) was injected
intraperitoneally. Immediately after PTZ injection, each
animal was placed into the cylinder and its behavior was
The test compounds were given intraperitoneally 30 min
after carrageenan injection. The difference in the paw
volume of the injected and the control were compared for
each animal and expressed as the difference of final paw
volume to initial paw volume.
Statistical analysis
All experimental groups were composed of 6 animals. Data
obtained from animal experiments were expressed as
Scheme 1 Synthetic route for
the chromeno oxadiazoles
O
H
N
N
CN
CN
OH
Ethanol/Triethylamine
NaBH4/Ethanol
+
O
(1)
NH
O
NH
2
(2)
OH
N
O
O
N
R
NH
2
2
NH2OH.HCl/TEA/MeOH
R
H
N
O
(3)
NH
microwave, 5min
O
(4 a-n)
N
R
123

Med Chem Res
mean standard error (SEM). The statistical significance
of difference between groups were assessed by means of
analysis of variance (ANOVA) followed by Dunnet’s test.
4m have showed 100 % protection as compared to the
standard drug Diazepam. All these molecules have chro-
mene ring along with oxadiazoles with different sub-
stitutions, which has accounted for their significant
anticonvulsant activity. Similarly, compounds 4h and 4k
have showed moderate anticonvulsant activity. The results
have been presented in Table 2.
Result and discussion
Formation of 3,4-dihydro-2H-chromen-2-amine 1,2,4-oxa-
diazole derivatives was confirmed by recording their IR, 1H
NMR and mass spectra. IR spectrum of oxadiazole 4a
showed absorption at 3,006 cm-1 which is due to the
aromatic stretching. An absorption band at 1,699 cm-1 is
due to the C=N group, band at 1,057 cm-1 is due to
stretching of oxadiazole. The 1H NMR spectrum of 4a
showed multiplet in the region of d, 7.03–7.14, d, 7.5 is due
to aromatic proton. The mass spectrum of 4a showed
molecular ion peak at m/z 450 and 452 which is in agree-
ment with the molecular formula C24H17Cl2N3O2. Simi-
larly, the spectral values for all the compounds and C, H, N
analyses are given in the ‘‘Experimental’’.
Conclusion
A series of novel chromeno oxadiazoles were synthesized
by microwave reaction in reasonably good yield. They
were characterized by H NMR, 13C NMR, mass spec-
1
trometry, IR studies, and elemental analyses. Few of the
selected compounds were screened for their possible anti-
convulsant and anti-inflammatory studies using Diazepam
and Diclofenac sodium as standards, respectively. Few of
the tested compounds exhibited excellent anticonvulsant
activity as compared to the standard drug Diazepam. Also
compounds have exhibited moderate anti-inflammatory
activity as compared to the standard drug Diclofenac
sodium.
Anti-inflammatory activity screening was carried out by
paw edema method using Wistar rats. Anti-inflammatory
activity revealed that the most of the tested compounds were
moderately active. Compounds 4a, 4g, 4k, and 4n have
showed % inhibition of 37, 40.9, 42.5, and 37.0, as compared
to the standard drug Diclofenac sodium, which showed
percentage of inhibition at 80.7. However, remaining com-
pounds have showed poor anti-inflammatory activity. The
presence of chromene ring in association with oxadiazole
and other substitutions has accounted for the anti-inflam-
matory activity. The results of the anti-inflammatory studies
have been presented in Table 1.
From the anticonvulsant study, it was clear that most of
the compounds showed percentage inhibition of 100 % as
compared to the standard drug. The presence of the chro-
mene ring in association with the oxadizole has accounted
for the biological activity.
Experimental
Further anticonvulsant activity of test compounds revealed
that most of the tested compounds showed excellent anti-
convulsant activity against the male albino mice. Eight of
the tested compounds, namely 4a, 4b, 4c, 4d, 4e, 4g, 4l, and
Melting points were determined by open capillary method
and were uncorrected. The IR spectra (In KBr pellets) were
1
recorded on a Shimadzu FT-IR 157 spectrophotometer. H
NMR spectra were recorded on a Perkin–Elmer EM 300 MHz
Table 1 Anti-inflammatory activity of test compounds by Carrageenan-induced paw odema test
Treatment
Dose (mg/kg) Initial paw volume (ml) (b) Paw volume after 3 h (ml) (a) Edema volume (a - b) Percentage inhibition
Control
Vehicle
0.93 0.01
0.80 0.04
0.93 0.08
1.00 0.04
0.93 0.01
0.83 0.09
0.93 0.02
0.85 0.09
0.90 0.04
0.80 0.01
0.98 0.09
2.20 0.04
1.05 0.02
1.73 0.01
1.93 0.06
1.85 0.08
1.70 0.02
1.90 0.04
1.60 0.09
1.63 0.01
1.85 0.04
1.78 0.02
1.27 0.02
0.25 0.04
0.80 0.09
0.93 0.02
0.92 0.01
0.87 0.04
0.97 0.08
0.75 0.04
0.73 0.02
1.05 0.08
0.80 0.01
Diclofenac 10
80.4**
37.0
4a
4b
4c
4d
4f
20
20
20
20
20
20
20
20
20
26.8
27.5
31.5
23.6
4g
4k
4m
4n
40.9*
42.5*
17.3
37.0
* p \ 0.05, ** p \ 0.01 compared to control
123

Med Chem Res
Table 2 Anticonvulsant studies: PTZ-induced convulsions
Treatment
Dose (mg/kg)
No. of animals
used
No. of animals
survived
Onset of clonic
convulsions (s)
Mortality
(%)
(%)
Protection
Control
–
06
06
00
06
61
100
0
0
Standard
(Diazepam)
02
Absent
100
4a
4b
4c
4d
4e
4g
4h
4k
4l
25
25
25
25
25
25
25
25
25
25
06
06
06
06
06
06
06
06
06
06
06
06
06
06
06
06
04
04
06
06
226
218
325
158
101
60
0
0
100
100
100
100
100
100
66.6
66.6
100
100
0
0
0
0
128
80
33.3
33.3
0
104
201
4m
0
* p \ 0.05, ** p \ 0.01 compared to control
spectrometer using TMS as internal standard. The mass
spectra were recorded on a JEOL JMS-D 300 spectrometer
operating at 70 eV. Purity of the compounds was checked
by TLC silica-coated plates obtained from Merck.
microwave for 5 min. The completion of reaction was
monitored by TLC and mass analysis of crude reaction
mixture. The reaction mixture was diluted with diethyl ether
to get desired compound as a solid, which was recrystalised
using ethanol.
Preparation of 2-amino-N0-hydroxychroman-3-
carboxamidine (3)
N-(2-chlorobenzylidene)-3-(5-(2-chlorophenyl)-1,2,4-
oxadiazol-3-yl)-3,4-dihydro-2H-chromen-2-amine (4a)
To stirred solution of 2-amino-3,4-dihydro-2H-chromene-
3-carbonitrile 2 (10 g, 0.05 mol) in methanol (100 mL)
was added hydroxylamine hydrochloride (7.8 g, 0.1 mol),
and triethylamine (6.9 g, 0.06 mol) at 0 °C. Reaction
mixture was heated to reflux for 8 h, mass analysis of
reaction mixture confirms completion of reaction. Reaction
mixture was cooled to room temperature, diluted with
water (100 mL), solid separated was filtered, dried to get
pure compound as yellow solid. Yield 11.4 g, 96 %, m.p:
187–190 °C, IR (cm-1); 3416 (O–H), 3386 (N–H), 3003
(C–H), 1699 (C=N), 1284 (C–O). 1H NMR (300 MHz,
DMSO-d6) d (ppm): 2.5 (m, 2H, CH2), 3.5 (m, 1H, CH),
4.8 (m, 1H, CH), 5.9 (bs, 2H, NH2), 7.18–7.21 (m, 1H,
Ar–H), 7.24–7.29 (m, 1H, Ar–H), 7.55–7.61 (m, 2H,
Ar–H), 9.63 (s, 2H, NH2). MS: m/z = 208.1 (M?1). Anal.
calcd. for C10H13N3O2: C, 57.96; H, 6.32; N, 20.28. Found:
C, 57.95; H, 6.38; N, 22.33 %.
Yield 85 %, m.p:150–152 °C, IR (cm-1) 3006 (C–H),
1699 (C=N), 1284 (C–O). H NMR (300 MHz, CDCl3) d
1
(ppm): 2.59 (m, 2H, CH2), 3.3 (m, 1H, CH), 4.8 (m, 1H,
CH), 6.31 (d, 1H, Ar–H, J = 8 Hz), 6.76–6.80 (m, 1H,
Ar–H), 6.88 (d, 1H, Ar–H, J = 8 Hz), 6.96 (m, 1H, Ar–H),
7.03–7.14 (m, 3H, Ar–H), 7.15 (m, 2H, Ar–H), 7.34–7.29
(m, 1H, Ar–H), 7.58–7.61 (m, 2H, Ar–H), 8.97 (s, 1H,
CH). 13C NMR (300 MHz, CDCl3) d (ppm): 176.2, 173.2,
159.5, 155.6, 141.3, 137.8, 135.0, 134.8, 133.5, 131.2,
129.4, 129.1, 128.8, 128.4, 127.5, 126.7, 124.5, 120.5,
98.2, 47.4, 28.3. MS: m/z = 450 (M?1), 452 (M?2). Anal.
calcd. for C24H17Cl2N3O2: C, 64.01; H, 3.81; N, 9.33.
Found: C, 64.11; H, 3.91; N, 9.38.
N-(4-chlorobenzylidene)-3-(5-(4-chlorophenyl)-1,2,4-
oxadiazol-3-yl)-3,4-dihydro-2H-chromen-2-amine (4b)
Yield 88 %, m.p:145–147 °C, IR (cm-1) 3013 (C–H), 1689
(C=N), 1413 (C=C), 1284 (C–O). 1H NMR (300 MHz,
CDCl3) d (ppm): 2.58 (m, 2H, CH2), 3.3 (m, 1H, CH), 4.8
(m, 1H, CH), 6.69 (m, 1H, Ar–H), 6.91 (d, 1H, Ar–H,
J = 7.6 Hz), 7.0 (t, 1H, Ar–H, J = 7.6 Hz), 7.19 (d, 1H,
Ar–H, J = 7.6 Hz), 7.47–7.50 (m, 4H, Ar–H), 7.8 (d, 2H,
Ar–H, J = 8.4 Hz), 7.90 (d, 2H, Ar–H, J = 9.2 Hz), 8.97
General procedure for the synthesis of 3-(1,2,4-
oxadiazol-3-yl)-3,4-dihydro-2H-chromen-2-amine
derivatives (4a–n)
A mixture of 2-amino-N0-hydroxychroman-3-carboxamidine
3 (2.4 mmol) and aldehyde (6 mmol) were irradiated in
123

Med Chem Res
3,4-Dihydro-N-(3-phenylallylidene)-3-(5-styryl-1,2,4-
oxadiazol-3-yl)-2H-chromen-2-amine (4f)
(s, 1H, CH). MS: m/z = 450 (M?1), 452 (M?2). Anal.
calcd. for C24H17Cl2N3O2: C, 64.01; H, 3.81; N, 9.33.
Found: C, 64.08; H, 3.84; N, 9.34.
Yield 78 %, m.p: 160–162 °C, IR (cm-1) 2996 (C–H), 1656
(C=N), 1478 (C=C), 1352 (C–N), 1281 (C–O). H NMR
1
N-(2-hydroxybenzylidene)-3-(5-(2-hydroxyphenyl)-
1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-chromen-
2-amine (4c)
(300 MHz, CDCl3) d (ppm): 2.88 (m, 1H, CH2), 3.01 (m, 1H,
CH2), 3.68 (m, 1H, CH), 4.46 (m, 1H, CH), 5.8 (m, 1H,CH),
6.70 (m, 2H, Ar–H, CH), 6.84–6.99 (m, 3H, Ar–H,CH),
7.15–7.30 (m, 10H, Ar–H), 8.5 (s, 1H, CH). MS: m/z = 434.2
(M?1). Anal. calcd. for C28H23N3O2: C, 77.58; H, 5.35; N,
9.69. Found: C, 77.55; H, 5.36; N, 9.59.
Yield 90 %, m.p:130–132 °C, IR (cm-1) 3002 (C–H), 1656
(C=N), 1470 (C=C), 1350 (C–N), 1284 (C–O). H NMR
1
(300 MHz, CDCl3) d (ppm): 2.90 (m, 1H, CH2), 3.07 (m, 1H,
CH2), 3.68 (m, 1H, CH), 4.96 (m, 1H, CH), 6.73 (t, 1H, Ar–H,
J = 7.6 Hz), 6.80 (d, 1H, Ar–H, J = 8 Hz), 6.96–7.05
(m, 5H, Ar–H), 7.15 (d, 1H, Ar–H, J = 7.8 Hz), 7.44–7.53
(m, 2H, Ar–H), 7.54–7.55 (m, 1H, Ar–H), 7.60–7.62 (m, 1H,
Ar–H), 9.0 (s, 1H, CH), 9.07 (bs, 1H, –OH). 13C NMR
(300 MHz, CDCl3) d (ppm): 176.2, 173.2, 159.5, 155.6,
141.3, 137.8, 135.0, 134.8, 133.5, 131.2, 129.4, 129.1, 128.8,
128.4, 127.5, 126.7, 124.5, 120.5, 98.2, 48.0.4, 28.3. MS:
m/z = 414.1 (M?1). Anal. calcd. for C24H19N3O4: C, 69.72;
H, 4.63; N, 10.16. Found: C, 69.75; H, 4.53; N, 10.14.
N-(3-nitrobenzylidene)-3,4-dihydro-3-(5-
(3-nitrophenyl)-1,2,4-oxadiazol-3-yl)-2H-chromen-
2-amine (4g)
Yield 87 %, m.p: 168–170 °C, IR (cm-1) 3012 (C–H),
1648 (C=N), 1537 (N–O), 1358 (N–O), 1490 (C=C), 1330
(C–N), 1274 (C–O). 1H NMR (300 MHz, CDCl3) d (ppm):
2.60 (m, 1H, CH2), 3.17 (m, 1H, CH2), 3.58 (m, 1H, CH),
5.06 (m, 1H, CH), 6.76 (t, 1H, Ar–H, J = 7.6 Hz), 6.85 (d,
1H, Ar–H, J = 8 Hz), 6.96–7.25 (m, 5H, Ar–H), 7.35 (d,
1H, Ar–H, J = 7.8 Hz), 7.44–7.53 (m, 2H, Ar–H),
7.54–7.55 (m, 1H, Ar–H), 7.60–7.62 (m, 1H, Ar–H), 9.1 (s,
1H, CH). MS: m/z = 472.2 (M?1). Anal. calcd. for
C24H17N5O6: C, 61.15; H, 3.63; N, 14.86. Found: C, 61.08;
H, 3.65; N, 14.81.
N-(3,4-dimethoxybenzylidene)-3,4-dihydro-3-(5-(3,4-
dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2H-chromen-2-
amine (4d)
Yield 93 %, m.p: 141–143 °C, IR (cm-1) 3012 (C–H),
1658 (C=N), 1440 (C=C), 1346 (C–N), 1293 (C–O). H
1
N-(5-bromo-2-fluorobenzylidene)-3-(5-(5-bromo-2-
fluorophenyl)-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-
chromen-2-amine (4h)
NMR (300 MHz, CDCl3) d (ppm): 2.59 (m, 1H, CH2), 2.79
(m, 1H, CH2), 3.5 (m, 1H, CH), 3.84 (s, 6H, 2–OCH3), 4.9
(m, 1H, CH), 6.65–6.75 (m, 3H, Ar–H), 6.98–7.11 (m, 4H,
Ar–H),7.47–7.56 (m, 3H, Ar–H), 9.02 (s, 1H, CH). 13C
NMR (300 MHz, CDCl3) d (ppm): 176.1, 172.7, 161.8,
156.2, 154.5, 153.8, 153.5, 153.1, 133.8, 131.0, 128.2,
126.3, 124.1, 122.0, 121.5, 121.8, 120.8, 118.2, 117.8,
116.2, 115.3, 97.1, 57.3, 47.8, 27.3. MS: m/z = 502.2
(M?1). Anal. calcd. for C28H27N3O6: C, 67.05; H, 5.43; N,
8.38. Found: C, 67.12; H, 5.38; N, 8.38.
Yield 93 %, m.p: 134–136 °C, IR (cm-1) 2996 (C–H),
1664 (C=N), 1419 (C=C), 1328 (C–F), 1276 (C–O). H
1
NMR (300 MHz, CDCl3) d (ppm): 2.52 (m, 1H, CH2), 3.2
(m, 1H, CH), 3.8 (m, 1H, CH), 4.84 (m, 1H, CH), 6.34 (m,
1H, Ar–H), 6.47 (m, 1H, Ar–H), 6.80 (t, 1H, Ar–H,
J = 7.2 Hz), 6.88–6.96 (m, 2H, Ar–H), 7.02–7.15 (m, 5H,
Ar–H), 8.91 (s, 1H, CH). 13C NMR (300 MHz, CDCl3) d
(ppm): 176.5, 173.8, 160.9, 159.7, 158.4, 155.6, 136.2,
135.0, 134.9, 133.7, 129.9, 128.1, 127.3, 126.8, 126.5,
122.6, 122.0, 121.5, 121.2, 117.1, 97.9, 47.5, 27.3. MS:
m/z = 476 (M?1). Anal. calcd. for C24H15Br2F2N3O2: C,
50.11; H, 2.63; N, 7.3. Found: C, 50.17; H, 2.55; N, 7.28.
N-(4-fluorobenzylidene)-3-(5-(4-fluorophenyl)-1,2,4-
oxadiazol-3-yl)-3,4-dihydro-2H-chromen-2-amine (4e)
Yield 93 %, m.p: 154–157 °C, IR (cm-1) 3010 (C–H), 1654
(C=N), 1432 (C=C), 1340 (C–F), 1284 (C–O). H NMR
1
(300 MHz, CDCl3) d (ppm): 2.58 (m, 2H, CH2), 3.3 (m, 1H,
CH), 4.8 (m, 1H, CH), 6.69 (m, 1H, Ar–H), 6.91 (d, 1H,
Ar–H, J = 7.6 Hz), 7.0 (t, 1H, Ar–H, J = 7.6 Hz),
7.19–7.29 (m, 5H, Ar–H), 7.47–7.50 (m, 4H, Ar–H), 8.97 (s,
1H, CH). 13C NMR (300 MHz, CDCl3) d (ppm): 175.9,
172.8, 166.2, 162.9, 161.4, 156.6, 136.5, 131.1, 130.2, 129.3,
128.0, 126.7, 122.6, 117.3, 116.0, 115.5, 97.6, 47.7, 27.9.
MS: m/z = 418 (M?1). Anal. calcd. for C24H17F2N3O2: C,
69.06; H, 4.11; N, 10.07. Found: C, 69.02; H, 4.13; N, 9.97.
N-benzylidene-3,4-dihydro-3-(5-phenyl-1,2,4-
oxadiazol-3-yl)-2H-chromen-2-amine (4i)
Yield 95 %, m.p: 140–142 °C, IR (cm-1) 3000 (C–H),
1
1699 (C=N), 1284 (C–O). H NMR (300 MHz, CDCl3) d
(ppm): 2.59 (m, 2H, CH2), 3.2 (m, 1H, CH), 4.7 (m, 1H,
CH), 6.31 (d, 1H, Ar–H, J = 8 Hz), 6.76–6.80 (m, 1H,
Ar–H), 6.88 (d, 1H, Ar–H, J = 8 Hz), 6.96 (m, 1H, Ar–H),
123

Med Chem Res
3,4-Dihydro-3-(5-(thiazol-2-yl)-1,2,4-oxadiazol-3-yl)-
N-((thiazol-2-yl) methylene)-2H-chromen-2-amine (4m)
7.03–7.14 (m, 5H, Ar–H), 7.15 (m, 2H, Ar–H), 7.34–7.39
(m, 1H, Ar–H), 7.58–7.61 (m, 2H, Ar–H), 8.92 (s, 1H,
CH). 13C NMR (300 MHz, CDCl3) d (ppm): 176.2, 172.8,
150.9, 155.8, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1,
127.1, 126.0, 121.5, 116.2, 98.0, 47.4, 27.2. MS:
m/z = 382.2 (M?1). Anal. calcd. for C24H19N3O2: C,
75.57; H, 5.02; N, 11.02. Found: C, 75.59; H, 5.02; N, 11.12.
Yield 70 %, m.p: 136–138 °C, IR (cm-1) 2994 (C–H),
1
1680 (C=N), 1283 (C–O). H NMR (300 MHz, CDCl3) d
(ppm): 2.56 (m, 2H, CH2), 3.15 (m, 1H, CH), 4.28 (m, 1H,
CH), 6.61 (d, 1H, Ar–H, J = 8 Hz), 6.76–6.80 (m, 1H,
Ar–H), 6.88 (d, 1H, Ar–H, J = 8 Hz), 6.96 (m, 1H, Ar–H),
7.34–7.42 (m, 2H, Ar–H),8.24–8.16 (m, 2H, Ar–H), 9.2 (s,
1H, CH). 13C NMR (300 MHz, CDCl3) d (ppm): 173.2,
165.7, 158.9, 157.6, 155.6, 143.8, 131.2, 127.4, 126.0,
121.5, 119.8, 115.5, 97.8, 47.6, 27.3. MS: m/z = 394.2
(M?1). Anal. calcd. for C18H13N5O2S2: C, 54.67; H, 3.31;
N, 17.71. Found: C, 54.66; H, 3.38; N, 17.63.
3,4-Dihydro-3-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)-
N-((thiophen-2-yl)methylene)-2H-chromen-2-amine (4j)
Yield 73 %, m.p: 126–128 °C, IR (cm-1) 2990 (C–H), 1675
(C=N), 1286 (C–O). 1H NMR (300 MHz, CDCl3) d (ppm):
2.51 (m, 2H, CH2), 3.0 (m, 1H, CH), 4.2 (m, 1H, CH),
6.76–6.80 (m, 2H, Ar–H), 6.88–6.98 (m, 3H, Ar–H,), 6.96
(m, 2H, Ar–H), 7.13–7.24 (m, 3H, Ar–H), 8.92 (s, 1H, CH).
MS: m/z = 394.2 (M?1). Anal. calcd. for C20H15N3O2S2:
C, 61.05; H, 3.84; N, 10.68. Found: C, 61.25; H, 3.80; N,
10.69.
N-(4-fluoro-3-phenoxybenzylidene)-3-(5-(4-fluoro-3-
phenoxyphenyl)-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-
chromen-2-amine (4n)
Yield 91 %, m.p: 158–161 °C, IR (cm-1) 3010 (C–H), 1688
(C=N), 1289 (C–O). 1H NMR (300 MHz, CDCl3) d (ppm):
2.59 (m, 2H, CH2), 3.2 (m, 1H, CH), 4.7 (m, 1H, CH), 6.31
(d, 1H, Ar–H, J = 8 Hz), 6.76–6.80 (m, 1H, Ar–H), 6.88 (d,
1H, Ar–H, J = 8 Hz), 6.96 (m, 1H, Ar–H), 7.03–7.14 (m, 5H,
Ar–H), 7.15 (m, 3H, Ar–H), 7.34–7.39 (m, 4H, Ar–H),
7.58–7.61 (m, 4H, Ar–H), 8.92 (s, 1H, CH). MS: m/z = 382.2
(M?1). Anal. calcd. for C36H25F2N3O4: C, 71.87; H, 4.19; N,
6.98. Found: C, 71.80; H, 4.23; N, 6.70.
N-(4-hydroxy-3-methoxybenzylidene)-3-(5-(4-hydroxy-
3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)-3,4-dihydro-
2H-chromen-2-amine (4k)
Yield 85 %, m.p: 172–174 °C, IR (cm-1) 2994 (C–H),
1660 (C=N), 1420 (C=C), 1328 (C–O). 1H NMR
(300 MHz, CDCl3) d (ppm): 2.48 (m, 1H, CH2), 2.96 (m,
1H, CH), 3.88 (m, 1H, CH),3.93 (s, 6H, CH3), 4.94 (m,
1H, CH), 6.65 (m, 1H, Ar–H), 6.77 (m, 2H, Ar–H),
6.80–6.90 (m, 3H, Ar–H), 6.98–7.06 (m, 2H, Ar–H),
7.15–7.24 (m, 2H, Ar–H), 8.91 (s, 1H, CH), 9.6 (bs, 1H,
–OH). 13C NMR (300 MHz, CDCl3) d (ppm): 176.2,
173.2, 161.5, 156.1, 153.4, 149.7, 148.8, 129.4, 128.1,
126.0, 124.1, 123.2, 123.0, 120.5, 118.4, 117.8, 116.1,
115.5, 98.1, 47.9, 27.3. MS: m/z = 474.1 (M?1). Anal.
calcd. for C26H23N3O6: C, 65.95; H, 4.90; N, 8.87. Found:
C, 65.99; H, 4.80; N, 8.97.
Acknowledgments AMI is thankful to ‘‘Department of Atomic
Energy, Board for Research in Nuclear Sciences, Government of
India’’ for Young Scientist award.
References
Adib M, Jahromi AH, Tavoosi N, Mahdavi M, Bijanzadeh HR (2006)
Microwave-assisted efficient, one-pot three-component synthesis
of 3,5-disubstituted 1,2,4-oxadiazoles under solvent-free condi-
tions. Tetrahedron Lett 47:2965–2967
Andersen KE, Lundt BF, Jørgensen AS, Braestrup
C (1994)
N-(4-bromobenzylidene)-3-(5-(4-bromophenyl)-1,2,4-
oxadiazol-3-yl)-3,4-dihydro-2H-chromen-2-amine (4l)
Oxadiazoles as bioisosteric transformations of carboxylic func-
tionalities. Part I. Eur J Med Chem 29:393–399
Ankersen M, Peschke B, Hansen BS, Hansen TK (1997) Investigation
of bioisosters of the growth hormone secretagogue L-692,429.
Bioorg Med Chem Lett 7:1293–1298
Yield 94 %, m.p: 151–154 °C, IR (cm-1) 3015 (C–H), 1689
(C=N), 1412 (C=C), 1290 (C–O). 1H NMR (300 MHz,
CDCl3) d (ppm):2.56(m, 2H, CH2), 3.32(m, 1H, CH), 4.9 (m,
1H, CH), 6.71(m, 1H, Ar–H), 6.91(d, 1H, Ar–H, J =7.6 Hz),
7.0 (t, 1H, Ar–H, J = 7.6 Hz), 7.19 (d, 1H, Ar–H,
J = 7.6 Hz), 7.47–7.50 (m, 4H, Ar–H), 7.8 (d, 2H, Ar–H,
J = 8.4 Hz), 7.90 (d, 2H, Ar–H, J = 9.2 Hz), 8.93 (s, 1H,
CH). MS: m/z = 540 (M?1), 542 (M?2). Anal. calcd. for
C24H17Br2N3O2: C, 53.46; H, 3.18; N, 7.79. Found: C, 53.41;
H, 3.12; N, 7.84.
Caliendo G, Fiorino F, Perissutti E, Severino B, Gessi S, Cattabriga E,
Borea PA, Santagada
V (2001) Synthesis by microwave
irradiation and binding properties of novel 5-HT(1A) receptor
ligands. Eur J Med Chem 36(11–12):873–886
Dexeus FH, Logothetis CJ, Sella A, Fitz K, Amato R, Reuben JM,
Dozier N (1990) Phase II study of coumarin and cimetidine in
patients with metastatic renal cell carcinoma. J Clin Oncol
8:325–329
Evdokimov NM, Kireev AS, Yakovenko AA, Yu M, Antipin, Igor V,
Magedov, Kornienko A (2007) One-step synthesis of heterocy-
clic privileged medicinal scaffolds by a multicomponent reaction
123

Med Chem Res
of malononitrile with aldehydes and thiols. J Org Chem
72:3443–3453
Maxwell A (1993) The interaction between coumarin drugs and DNA
gyrase. Mol Microbiol 9:681–686
Hu X, Jin H, Xu W, Zhang W, Liu X, Yan S, Chen M, Li J, Zang W
(2008) Anti-inflammatory and analgesic effect of Daphne retusa
Hemsl. J Ethnopharmacol 120(1):118–122
Isloor AM, Kalluraya B, Pai KSR (2010) Synthesis, characterization
and biological activities of some new benzo[b]thiophene deriv-
atives. Eur J Med Chem 45:825–830
Kaboudin B, Navaee K (2003) One-pot synthesis of 1,2,4-oxadiazoles
media by microwave irradiation under solvent-free condition.
Heterocycles 60:2287–2292
Kalluraya B, Vishwanatha P, Isloor AM, Rai GR, Kotian M (2000)
Synthesis and biological activity of 6-substituted-3-[2-(-5-
Orlek BS, Blaney FE, Brown F, Clark MSG, Hadley MS, Hatcher J,
Riley GJ, Rosenberg HE, Wadsworth HJ, Wyman P (1991)
Comparison of azabicyclic esters and oxadiazoles as ligands for
the muscarinic receptor. J Med Chem 34(9):2726–2735
Singh SP, Pandey BR, Kumar S, Parmar SS (1978) Anticonvulsant
activity and inhibition of respiration in rat brain homogenates by
substituted trimethoxybenzamides. J Pharm Sci 67:1682–1685
Srivastava VK, Pandey BR, Gupta RC, Kishor K (1979) New CNS-
active 3-methyl-4-substituted methyl-delta 2-isoxazolin-5-ones.
Pharmazie 34:638–639
Vu CB, Corpuz EG, Merry TJ, Pradeepan SG, Bartlett C, Bohacek
RS, Botfield MC, Eyermann CJ, Lynch BA, MacNeil IA, Ram
MK, Schravendijk MR, Violette S, Sawyer TK (1999) Discovery
of potent and selective SH2 inhibitors of the tyrosine kinase
ZAP-70. J Med Chem 42(20):4088–4098
substituted-2-furfurylidenehydrazino)-4-thiazolyl]
Boll Chim Farm 139(6):263–266
coumarins.
Kalluraya B, Isloor AM, Shenoy S (2001) Synthesis and Biological
Activity of 6-substituted-3-[4-(3-substituted pyrazolidene)
hydrazino-4-thiazolyl] coumarins. Indian J Heterocycl Chem
11:159–162
Maria K, Dimitra HL, Maria G (2008) Synthesis and anti-inflamma-
tory activity of chalcones and related Mannich bases. Med Chem
4:586–596
Zembower DE, Liao S, Flavin MT, Xu ZQ, Stup TL, Buckheit RW,
Khilevich A, Mar AA, Sheinkman AK (1997) Structural
analogues of the calanolide anti-HIV agents, modification of
the trans-10,11-dimethyldihydropyran-12-ol ring (ring C). J Med
Chem 40:1005–1017
123