A facile synthesis, anti-inflammatory and analgesic activity of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,3′-indoline]-2′,4, 9-triones

Article abstract of DOI:10.1016/j.bmcl.2013.04.053

A new series of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,3′- indoline]-2′,4,9-triones (14) were synthesized by reaction of 4-amino-3-methyl-5-styrylisoxazole 10 with chloroacetic acid followed by a three component reaction with substituted isatins 12 and 1,4-naphthoquinone 13 using Ceric ammonium nitrate (CAN) catalyst under aerial oxidation condition. Structures of these compounds were established on the basis of IR, ¹H NMR, ¹³C NMR and mass spectral data. The title compounds 14a-j were evaluated for their anti-inflammatory and analgesic activity. Compounds 14d, 14e and 14f exhibited potent anti-inflammatory and analgesic activity as that of standard drugs.

Full text of DOI:10.1016/j.bmcl.2013.04.053

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3954–3958
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A facile synthesis, anti-inflammatory and analgesic activity
of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,30-indoline]-20,
4,9-triones
a
a
a
b
E. Rajanarendar a, , S. Ramakrishna , K. Govardhan Reddy , D. Nagaraju , Y. N. Reddy
⇑
a Department of Chemistry, Kakatiya University, Warangal, 506 009 AP, India
b Department of Pharmacology and Toxicology, Kakatiya University, Warangal, 506 009 AP, India
a r t i c l e i n f o
a b s t r a c t
A new series of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,30-indoline]-20,4,9-triones (14) were syn-
thesized by reaction of 4-amino-3-methyl-5-styrylisoxazole 10 with chloroacetic acid followed by a three
component reaction with substituted isatins 12 and 1,4-naphthoquinone 13 using Ceric ammonium
nitrate (CAN) catalyst under aerial oxidation condition. Structures of these compounds were established
on the basis of IR, 1H NMR, 13C NMR and mass spectral data. The title compounds 14a–j were evaluated
for their anti-inflammatory and analgesic activity. Compounds 14d, 14e and 14f exhibited potent anti-
inflammatory and analgesic activity as that of standard drugs.
Article history:
Received 7 January 2013
Revised 17 April 2013
Accepted 19 April 2013
Available online 30 April 2013
Keywords:
Isoxazolyl-2,3-dihydrospiro[benzo[f
]isoindole-1,30-indoline]-20,4,9-triones
Multi-component reaction
Ceric ammonium nitrate
Anti-inflammatory activity
Analgesic activity
Ó 2013 Elsevier Ltd. All rights reserved.
Exploring novel pharmacological agents with minimum num-
ber of synthetic steps and in less time is a major challenge to the
chemists. Besides, chemists are facing another challenge for the
past two decades, namely, that of developing new transformations
that are not only efficient, selective, and high yielding but also
environmentally benign.
The spirooxindole system is the core structure of many pharma-
cological agents and natural alkaloids.1–3 Naturally occurring
spirooxindole alkaloids (Fig. 1), such as spirotryprostatin A (1), a
natural product isolated from the fermentation of broth Aspergillus
fumigates, has been identified as a novel inhibitor of microtubule
assembly.4 Alstonisine (2) is a useful bioactive natural product. Mit-
raphylline (3) isolated from Uncaria tomentosa possesses anti-tumor
activity against human brain cancer cell lines.5 Horsfiline (4)6–11
isolated from Horsfieldia superba and elacomine (5)12 isolated from
Eleagnus commutata find use as indigenous medicine.
Various spiro ring systems have been reported in spirooxindole
natural products, for example, alstonisine (2) fused with pyrroli-
dine13 and tabernoxidine (6) fused with piperidine.14 Spirocyclic
isoxazoles such as aerothionin (7), aerophobin-1 (8), and zamamist-
atin (9) are biologically active alkaloids.15 The synthesis of spiroox-
indoles via cycloaddition of azomethine ylides to naphthoquinones
was reported in the literature.16 The development of new methods
for the synthesis of spirooxindoles is still required due to the im-
mense interest of this system from synthetic and biological stand-
points. As a part of our ongoing research in development of new
biologically active isoxazole derivatives17 from readily available
starting materials, we envisaged a multi-component reaction for
the synthesis of title compounds based on the biological activity
of spirooxindole moiety. Herein, we report the synthesis of isoxaz-
olyl-2,3-dihydrospiro [benzo[f]isoindole-1,30-indoline]-20,4,9-tri-
ones from 2-(3-methyl-5-styrylisoxazol-4-ylamino) acetic acids
and their anti-inflammatory and analgesic activities.
The reaction of substituted 4-amino-3-methyl-5-styrylisoxazole
10 with chloroacetic acid in dichloromethane (DCM), led to the for-
mation of 2-(3-methyl-5-styrylisoxazol-4-ylamino)acetic acids 11,
in65–78%yields.18 TheIRspectraof11a–gshowedabsorptionbands
around 1700–1720 cmꢀ1 and 3250–3270 cmꢀ1 for carboxyl group,
and 3315–3350 cmꢀ1 for amino group. 1H NMR spectra of com-
pounds 11a–g exhibited three singlets at d 4.11, 8.35 and 10.73
due to methylene, NH and OH protons respectively. 13C NMR spectra
of 11a–g showed a peak at d 48.32 due to methylene carbon. Data
from the elemental analyses and ESI mass spectra further confirmed
the assigned structures of 11a–g. The three component one-pot
reaction was first explored by interaction of 2-(3-methyl-5-sty-
rylisoxazol-4-ylamino)acetic acid 11, with isatin 12 and 1,4-naph-
thoquinone 13 in presence of 10 mol % of CAN at ambient
temperature in ethanol (15 mL) for 30 min under aerial oxidation
condition. The reaction afforded isoxazolyl-2,3-dihydrospi-
⇑
Corresponding author. Tel.: +91 870 2456363; fax: +91 870 2438800.
E-mail address: rajanarendareligeti@gmail.com (E. Rajanarendar).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.04.053

E. Rajanarendar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3954–3958
3955
H3C
O
O
O
H
H
O
H
H
N
CO2CH3
CO2CH3
N
HN
NH
H
H
N
N
MeO
H
H
O
O
O
N
H
O
N
O
N
H
Alstonisine
(2)
Horsfiline
(4)
Mitraphylline
(3)
Spirotryprostatin A
(1)
O
O
N
NH
OH
(CH )
NH
N
NH
2
n
N
HO
O
O
MeO
HO
Br
O
OH
CO2CH3
N
H
O
N
Br
H
Br
Br
OMe
OMe
Elacomine
(5)
Tabernoxidine
(6)
Aerothionin
(7)
O
Br
H
HO
N
N
O
O
HN
OMe
Br
HO
Br
H
Br
Br
N
MeO
NH
Br
N
O
OMe
OH
Aerophobin-1
(8)
Zamamistatin
(9)
Figure 1. Structures of biologically active spirooxindole alkaloids and spirocyclic isoxazoles as design templates.
ro[benzo[f]isoindole-1,30-indoline]-20,4,9-trione 14a in excellent
yield.19 When the same reaction was carried out in the absence of
CAN, the reaction required refluxing condition, longer reaction time,
and the product yield is moderate. Hence, CAN is essential for the
enhancement of the reaction rate, and to increase the product yield.
It has been found that this three-component process works well for
any tested combination of 2-(3-methyl-5-styrylisoxazol-4-ylami-
no)acetic acids, substituted isatins and 1,4-naphthoquinone in eth-
anol using CAN as catalyst under aerial oxidation condition. By
adopting similar procedure, ten new derivatives of 14a–j have been
synthesized by a one-pot three-component reaction. The IR spectra
of 14a–j showed absorption bands around 1685, 1645 cmꢀ1 due to
carbonyl functional groups and 3265 cmꢀ1 due to amino functional
group. The 1H NMR spectra of title compounds 14a–j displayed two
singlets at d 4.16 and 8.04 due to pyrrolidine methylene protons and
NH protons respectively, where as aromatic protons resonated be-
tween d 7.01 and 7.53 as multiplet. In 13C NMR, the peak at d
79.86 ppm corresponds to the spiro carbon and the peak at d
168.43 belongs to amide carbonyl carbon. The peaks at d 183.53
and 183.59 confirmed the presence of quinone carbonyl carbons.
Data from the elemental analyses and ESI mass spectra further con-
firmed the assigned structures of 14a–j. The structure of the prod-
ucts was elucidated with the help of IR, 1H NMR, 13C NMR and
mass spectral data (Scheme 1).
ammonium nitrate (CAN) may be activating the double bond of
quinone ring by forming a complex, thereby the reaction is facili-
tated and also it enhances the reaction rate (Scheme 2).
Anti-inflammatory analyses
Anti-inflammatory activity was determined by carrageenan in-
duced paw edema method.20 Wistar rats of either sex weighing
150–200 g were divided into 6 groups (n = 6) and they were fasted
18 h before the experiment with water ad libitum. Group-I re-
ceived 1% sodium CMC (negative control), Group-II received ibu-
profen at a dose of 100 mg/kg (positive control) and Group-III to
VI were given the compounds 14a–j (100 mg/kg). All the com-
pounds 14a–j were given in oral route. After 30 min, 0.1 mL of
1% carrageenan suspension in normal saline was injected into the
subplantar region of the left hind paw of each rat to induce edema.
The edema volumes of the injected paw measured with the help of
plethysmograph at the interval of 0, 1, 2, 4 and 6 h. The difference
between the paw volumes of treated animals were compared with
that of the control group and the mean edema volume was calcu-
lated. Percentage inhibition was calculated as per the formula,
%inhibition = [(Vo ꢀ Vt)/Vo] ꢁ 100, where Vo = volume of the paw
control at time t, Vt = volume of the paw of drug treated at time t.
The plausible mechanism involves the 1,3-dipolar cycloaddition
of azomethine ylide A, generated in situ via decarboxylative con-
densation of isatin 12 with isoxazole acetic acid 11 to 1,4-naphtho-
quinone 13 activated by CAN, followed by dehydrogenation under
aerial oxidation condition affords the title compound 14. Ceric
Analgesic analyses
The analgesic activity was determined by acetic acid induced
writhing.21 Swiss albino mice (n = 6) of either sex selected by

3956
E. Rajanarendar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3954–3958
O
H
H3C
NH2
H3C
N
OH
(i)
N
N
O
O
Ar
Ar
10
11
O
R
O
+
O
N
H
(ii)
O
12
13
H
O
N
O
R
N
H3C
O
N
O
Ar
14
11a, Ar = C6H5
11b, Ar = 4-CH3C6H4
14a, Ar = C6H5
14b, Ar = 4-CH3C6H4
R = H
R = H
11c, Ar = 4-CH3OC6H4 14c, Ar = 4-CH3OC6H4 R = H
11d, Ar = 4-ClC6H4
11e, Ar = 2,4-Cl2C6H3
11f, Ar = 2,6-Cl2C6H3
11g, Ar = 2-OHC6H4
14d, Ar = 4-ClC6H4
14e, Ar = 2,4-Cl2C6H3
14f, Ar = 2,6-Cl2C6H3
14g, Ar = 2-OHC6H4
14h, Ar = C6H5
R = H
R = H
R = H
R = H
R = Cl
R = OCH3
R = CH3
14i, Ar = C6H5
14j, Ar = C6H5
Scheme 1. Synthesis of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,30-indoline]-20,4,9-triones (14a–j). Reagents and conditions: (i) chloroacetic acid (1 mmol),
dichloromethane, 0 °C, stirring, 2 h; (ii) ethanol, CAN (10 mol %), rt, stirring, 30 min, O2 (air).
random sampling technique were used for the study and divided
into 6 groups. The animals were fasted 18 h before the experiment
with water ad libitum. Diclofenac (50 mg/kg) was administered as
standard drug for comparison. The test compounds 14a–j (50 mg/
kg) were administered orally 30 min. after the administration of
compounds. All the mice were given 1.0% v/v solution of acetic
acid, ip the dose being 1 mL/100 g of the mice and the writhings
produced in these animals were counted for 20 min. The no. of wri-
things produced in the treated groups was compared with those in
the control group. Percentage inhibition was calculated as per the
formula, % inhibition = [(Average writhes in control ꢀ Average
writhes in test)/Average writhes in control] ꢁ 100.
ibuprofen. The anti-inflammatory activity data (Table 1) indicated
that all the compounds 14a–j exhibited significant activity by
decreasing the paw volume that was produced by carrageenan.
Among all the compounds tested, it is interesting to note that
the compounds 14d, 14e and 14f showed better anti-inflamma-
tory activity, may be due to the presence of chloro substitution
on the benzene ring. The presence of electron donating methyl
and methoxy groups on benzene ring (14i and 14j) did not influ-
ence the activity much.
The analgesic activity of the newly synthesized compounds
14a–j were determined in vivo by acetic acid induced writhing
method21 in mice at a dose of 50 mg/kg body weight. All the com-
pounds 14a–j produced significant activity when compared to
standard diclofenac. Compounds 14d, 14e and 14f showed more
significant activity compared to other test compounds (Table 2).
These compounds 14d, 14e and 14f decreased the number of
writhings produced in mice to a remarkable extent. This may be
due to the presence of chloro substituent in these compounds.
The anti-inflammatory activity of the title compounds, 14a–j
were evaluated by carrageenan-induced paw edema method in
rats20 at a dose of 100 mg/kg body weight using ibuprofen as a
reference drug. Results were expressed as a mean S.E. The
anti-inflammatory properties were recorded at successive
intervals of 0, 1, 2, 4 and 6 h and compared with that of standard

E. Rajanarendar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3954–3958
3957
4
+
H
N
4
.
+
Ce
.
O
.........Ce
O
.
.
R
O
O
O
NH
H
N
R
H3C
R
OH
O
+
O
-H2O
-CO2
+N
N
H3C
H3C
O
N
+
O
O
N
N
N
13
O
H
O
Ar
Ar
Ar
11
12
A
B
4
+
Ce
H
N
H
N
O
O
O
O
R
O2
air
R
N
N
H3C
H3C
O
N
O
N
O
O
Ar
Ar
C
14
Scheme 2. Plausible mechanism for the formation of isoxazolyl-2,3-dihydrospiro[benzo[f] isoindole-1,30-indoline]-20,4,9-triones
Table 1
Table 2
Anti-inflammatory activity of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,30-ind-
oline]-20,4,9-trionesa (14a–j)
Analgesic activity of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,30-indoline]-
20,4,9-triones (14a–j)
Groupb
Paw volume (mL of Hg)c
Animal groupa
No. of writhingsb
% inhibition
0 h
1 h
2 h 4 h
6 h
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
Control
Diclofenac
30 1.31⁄
34 1.50⁄⁄
22.43 1.41
26.27 2.00
19.58 1.60
50.41 1.31
44.80 2.15
48.30 1.50
20.40 1.50
16.51 1.50
18.42 2.05
19.50 1.80
—
14a
14b
14c
14d
14e
14f
14g
14h
14i
0.37 0.01 0.75 0.03 0.84 0.08ns 0.75 0.06⁄⁄ 0.60 0.03⁄⁄
0.34 0.03 0.70 0.05 0.80 0.05ns 0.69 0.03⁄⁄ 0.54 0.01⁄⁄
0.36 0.03 0.80 0.01 0.91 0.04ns 0.65 0.02⁄⁄ 0.60 0.03⁄⁄
31.1 1.36⁄⁄⁄
21.5 2.40
20.4 1.54⁄⁄⁄
22.88 1.50⁄⁄⁄
33.61 1.48⁄
34.61 1.83⁄
27 1.38⁄
0.27 0.04 0.54 0.1 0.69 0.03
0.25 0.08 0.57 0.06 0.71 0.03
0.22 0.02 0.54 0.08 0.70 0.03
0.65 0.03⁄⁄ 0.41 0.05⁄⁄⁄
0.54 0.02
0.32 0.01⁄⁄⁄
0.67 0.03⁄⁄ 0.40 0.03⁄⁄⁄
0.31 0.03 0.78 0.02 0.81 0.03ns 0.80 0.04⁄⁄ 0.52 0.02⁄⁄
0.40 0.01 0.82 0.04 0.83 0.02ns 0.82 0.03
0.63 0.03⁄⁄
29 1.94⁄
0.34 0.04 0.73 0.01 0.91 0.05ns 0.81 0.03⁄⁄ 0.60 0.01⁄⁄
41 1.25
14j
Control
0.33 0.08 0.77 0.02 0.89 0.03ns 0.83 0.01⁄⁄ 0.55 0.05⁄⁄
19 1.23⁄⁄⁄
53.65 1.92
0.36 0.3 0.90 0.05 1.07 0.08
1.2 0.05
0.96 0.03
Ibuprofen 0.30 0.5 0.66 0.03⁄ 0.70 0.05⁄⁄⁄ 0.60 0.05⁄⁄⁄ 0.40 0.05⁄⁄⁄
Statistically significant compound to respective control value ⁄P <0.05, ⁄⁄P <0.01,
⁄⁄⁄P <0.001.
Statistically significant compound to respective control value ⁄P <0. 05, ⁄⁄P <0.01,
a
Dose levels: test compound (50 mg/kg b.wt) Diclofenac (50 mg/kg).
Values are expressed as mean S.E.
⁄⁄⁄P <0.001.
b
nsNonsignificant, compared to control.
a
n = 6, number of animals used in each group.
Dose levels: test compound (100 mg/kg b.wt) Ibuprofen (100 mg/kg b.wt).
Values are expressed as mean S.E.
b
c
evaluated for their anti-inflammatory and analgesic activity.
Compounds 14d, 14e and 14f are proved to possess remarkable
anti-inflammatory and analgesic activity.
Rests of the compounds (14a, 14b, 14c, 14g, 14h, 14i and 14j) are
Acknowledgments
moderately active.
In conclusion, we reported
a simple and efficient multi-
The authors are thankful to the Head, Department of Chemistry,
Kakatiya University, Warangal for providing the facilities, the
Director, Indian Institute of Chemical Technology, Hyderabad for
recording 1H NMR, 13C NMR and Mass Spectra. Financial assistance
from the UGC SAP (phase-1)-DRS programme, New Delhi, India, is
greatly acknowledged.
component protocol for the synthesis of isoxazolyl-2,3-dihydrospi-
ro[benzo[f]isoindole-1,30-indoline]-20,4,9-triones, using inexpen-
sive and commercially available materials with potent medicinal
properties. The newly synthesized novel isoxazolyl-2,3-dihydro-
spiro[benzo[f]isoindole-1,30-indoline]-20,4,9-triones 14a–j were

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E. Rajanarendar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3954–3958
16. Chen, H.; Wang, S.-Y.; Xu, X.-P.; Ji, S.-J. Synth. Commun. 2011, 41, 3280; (b)
Supplementary data
Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal, P. T. Eur. J. Med.
Chem. 2012, 51, 79.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.04.
053.
17. (a) Rajanarendar, E.; Raju, S.; Nagi Reddy, M.; Ramakrishna, S.; Hari Kiran, L.;
Ram Narasimha Reddy, A.; Narasimha Reddy, Y. Eur. J. Med. Chem. 2012, 50,
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Rajanarendar, E.; Nagi Reddy, M.; Rama Murthy, K.; Surendar, P.; Reddy, R. N.;
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