Efficient entry to diversely functionalized spirooxindoles from isatin and their biological activity

Article abstract of DOI:10.1007/s00044-012-0249-x

A collection of structurally complex and chemically diverse small molecules is a useful tool to explore cell circuitry. In this article, we have reported the two step synthesis of diverse spirooxindoles. The key reaction to assemble the spirooxindole core

Full text of DOI:10.1007/s00044-012-0249-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0249-x
ORIGINAL RESEARCH
Efficient entry to diversely functionalized spirooxindoles
from isatin and their biological activity
•
Mazaahir Kidwai Arti Jain Vishal Nemaysh
•
•
•
Rakesh Kumar Pratibha Mehta Luthra
Received: 10 March 2012 / Accepted: 14 September 2012
Ó Springer Science+Business Media New York 2012
Abstract A collection of structurally complex and chem-
ically diverse small molecules is a useful tool to explore cell
circuitry. In this article, we have reported the two step syn-
thesis of diverse spirooxindoles. The key reaction to
assemble the spirooxindole core is a Lewis acid catalyzed
three component coupling. The final library of compounds
was then analyzed for their cytotoxic activity against U87
human glioma cells. It is noteworthy to mention that this is
the first report on the pharmaceutical evaluation of such
compounds. Although the activity is moderate, it opens the
door for new chemical modifications of spirooxindoles.
Introduction
In recent years, the trend in combinatorial library design
has shifted to include target class focusing along with
diversity and drug likeness criteria. A goal of chemical
genetics is to find small molecules that modulate the
individual functions of gene products with high potency
and specificity (Schreiber, 2000).
Molecules bearing the spirooxindole moiety are widely
found in nature (Williams and Cox, 2003; Galliford and
Scheidt, 2007; Cui et al., 1996a, b; Kang et al., 2002;
Rahman et al., 1987). Among the oxygen-containing het-
erocycles fused with spirooxindole ring system, 4H-
chromenes are of particular utility as they belong to
‘‘privileged medicinal scaffolds,’’ (Evans et al., 1988;
Patchett and Nargund, 2000; DeSimone et al., 2004;
Skommer et al., 2006; Bonsignore et al., 1993; Konkoy
et al., 2000). But Spiro[indole-chromene] unit is an
unprivileged heterocyclic motif because this unit is not
involved in the core of a large family of alkaloid natu-
ral products. Recently, Nandakumar et al. (2010) have
explored the antimicrobial activity of 20-(indol-3-yl)-2-
oxospiro(indoline-3,40-pyran)derivatives. But no report is
available for the pharmacological evaluation of Spir-
o[indole-pyranopyrimindines] and Spiro[indol-pyranopy-
razoles]. This is very unfortunate as pyran nucleus has been
found to be associated with a group of biological activities.
(Kulkarni and Kaul, 1980).
Keywords Diversified series of spirooxindoles ꢀ
Novel compounds ꢀ Green methodology ꢀ
Two step multicomponent reaction ꢀ
Pharmacological activity
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-012-0249-x) contains supplementary
material, which is available to authorized users.
Present Address:
M. Kidwai (&)
Jiwaji University, Gwalior, M.P., India
e-mail: kidwai.chemistry@gmail.com
Heterocycles containing the pyrazole ring are important
targets in synthetic and medicinal chemistry because this
fragment is a key moiety in numerous biologically active
compounds (Elguero et al., 2002; Penning et al., 1997).
Furthermore, it has been reported that sharing of the indole
3-carbon atom in the formation of spiro-indoline deriva-
tives highly enhances biological activity (Joshi et al.,
M. Kidwai ꢀ A. Jain
Green Chemistry Research Laboratory, Department of
Chemistry, University of Delhi, New Delhi 110007, India
V. Nemaysh ꢀ R. Kumar ꢀ P. M. Luthra
Neuropharmaceuticals Research Laboratory,
Dr. B. R. Ambedkar Center for Biomedical Research,
University of Delhi, New Delhi 110007, India
123

Med Chem Res
1988). Our laboratory has been interested in exploring
diversity oriented synthesis (DOS), especially using
MCR’s as well as to find space for the new biological
active motifs (Kidwai et al., 2012a, b).
2020. Due to the lack of tumor-specific anticancer agents,
the discovery and development of new types of highly
selective anticancer agents is still a very urgent topic.
Herein, we present our contribution to concise construction
of novel spirooxindoles and their evaluation for cytotoxic
activity.
The interaction of organic compounds with proteins is
an extremely important biochemical problem with many
interesting facets. One of these is the extent to which drugs
or metabolically necessary compounds will be restricted in
their movements in the cell or intercellular fluids such as
blood. Such restriction of movement will depend on how
firmly they are bound to the protein with which they come
into contact (Hansch et al., 1965). One of the most
important forces holding proteins and small organic mol-
ecules together appears to be termed as hydrophobic
bonding (Kauzmann, 1959). Nature has provided effective
examples via natural products, which in turn have stimu-
lated the development of target oriented synthesis (TOS). A
number of biologically active compounds have been iso-
lated from plants and marine sponges, which contained a
lipophilic (hydrophobic) moiety in the form of alkyl/alke-
nyl chain attached to either benzene or heterocyclic skel-
eton (Jain et al., 2005; Kubo et al., 1993). Hence, our
objective is to check the synthesized compounds bearing
additional alkyl chain and then to check its viability as
biologically active compounds.
Results and discussion
Chemistry
It has been suggested that aliphatic chain reduces the
polarity of the whole compound. This leads to an increase
in lipophilicity of the molecule, which in turn, favors its
permeation through the lipoid layer of the membrane; this
enables the compound to cross the bacterial membrane/any
other more effectively thereby increasing the biological
activity of the compounds.
On the basis of the above hypothesis, our first task was
to attach an aliphatic chain on the nitrogen of isatin.
A literature survey has revealed that the reaction of
isatin with dibromoalkanes proceeds in hazardous organic
solvent like acetonitrile/DMF in the presence of K2CO3
(Marina et al., 2010). In order to maintain our goal to
explore environmentally benign protocols, we used PEG-
400 as solvent with K2CO3 for preparing the bromoalkyl
isatin.
The development of a facile procedure for the synthesis
of heterocyclic compounds is a major challenge of modern
heterocyclic chemistry in the view of the environmental,
practical, and hence economic issues. Replacement of
volatile organic solvents with environmental benign sol-
vents has received considerable attention in organic syn-
thesis (Sheldon, 2005). Several solvent systems, including
water (Cornils and Herrmann, 1998), supercritical fluids
(Leitner, 2002), ionic liquids (Sheldon, 2001), and soluble
polymers (Haimov and Neumann, 2002; Chandrasekhar
et al., 2002) have been exploited over the several years as
alternative reaction media.
First of all, 1-(2-bromoethyl)-indole-2,3-dione was
synthesized via isatin alkylation with excess of dibromo-
ethane in PEG 400 at room temperature in the presence of
potassium carbonate. Excellent yield of product (80 %)
was obtained by stirring the reaction mixture for 2 h
(Scheme 1).
The structure of products 3a–e were confirmed by spectral
studies as exemplified for compound 3a as follows: the 1H
Table 1 Effect of solvents on the synthesis of bromoalkylisatins
Cancer is one of the most devastating disease causing
more than 10 million new cases every year worldwide. The
global burden of cancer is continuously increasing day by
day. In the year 2000, 5.3 million men and 4.7 million
women developed a malignant tumor and 6.2 million died
from the disease. The number of new cases is expected to
grow by 50 % over the next 20 years to reach 15 million by
Solvents
Time (h)
Yield (%)a
Ethanol
Acetonitrile
DMF
3
70
80
80
55
50
48
80
80
65
50
2
2
Dioxane
THF
4
5
Toluene
PEG-200
PEG-400
PEG-600
PEG-800
5
O
O
N
Br
n
Br
2(a-e)
2
O
O
2
K2CO3
rt, 2h
N
H
PEG-400,
,
3
n
1
3(a-e)
3.5
Br
n= 1, 2, 3, 5, 9
Reaction condition: isatin (1 mmol), dibromoethane (excess); solvent;
catalyst K2CO3; room temperature
Scheme 1 Synthesis of bromoalkylisatin using K2CO3 in PEG-400 at
room temperature
a
Isolated yields
123

Med Chem Res
solvent ether, since PEG is immiscible with solvent ether.
To the recovered crude PEG (&3 ml), distilled ethanol
(10 ml) was added and passed through a very short pad of
silica gel and activated charcoal. The colorless organic
layer was evaporated under reduced pressure. PEG-400
was further dried under high vacuum overnight and used
for the next run. The recovered PEG-400 was reused up to
three cycles with a little loss of reactivity (Table 3).
PEGs could be regarded as open-chain crown ethers as
they are able to form complexes with alkaline and alkaline-
earth cations in protic and aprotic solvents (Yanagida et al.,
1978). We postulated that in the PEG/K2CO3 system,
the CO32- anion could be brought into solution through the
coordination of the cationic center of K2CO3 with the
Table 2 Optimization of concentration of K2CO3 for the synthesis
bromoethylisatin
Entry
K2CO3 (mol%)
Time (h)
Yield (%)a
1
2
3
4
3
5
4
4
2
2
70
72
80
82
10
15
Reactions were performed with isatin (0.01 mmol), dibromoethane
(excess), and K2CO3 (9 mol%) in PEG-400 (3 ml) by stirring the
mixture at room temperature
a
Isolated yield
Table 3 PEG 400 recycling studies
oxygen atom of PEG (Wang et al., 2007). Thus, the reac-
2-
Catalyst recycle
Yield (%)a
Fresh
80
2
3
4
tion of the CO3
anion with isatin was elevated by
enhancing the nucleophilicity of nitrogen for addition to
dibromoalkanes.
80
78
77
Reactions were performed with isatin (0.01 mmol), dibromoethane
(excess), and K2CO3 (10 mol%) in PEG-400 (3 ml) by stirring the
mixture at room temperature
The reaction of isatin with an equimolar amount of
dimedone and malononitrile as a model reaction was
examined to establish the feasibility of the strategy and
optimization of the reaction conditions. It is well known that
the choice of an appropriate reaction medium is of crucial
importance for successful synthesis. So to begin with, the
model reaction was done in water without any catalyst at
100 °C. Even after 6 h only 40 % product was formed. In
recent times, the usage of molecular iodine has received
considerable attention as an inexpensive, nontoxic, water
soluble, readily available catalyst with high tolerance to air
and moisture for various organic synthesis (Togo and Lida,
2006). The key reaction to assemble the spirooxindole core
is a Lewis acid variant of three component coupling. Hence
we tried the same reaction with I2 in water at 50 °C. To our
delight, deep red violet color of the 3-cyanomethylene
oxindole formed immediately after the addition of the cat-
alyst. A colorless product separated out only after 1 h of
stirring, which suggested that conjugated oxindolidine sys-
tem was converted to unconjugated oxindoles (Scheme 2).
We proposed the following possible mechanism to
account for the formation of 6. The process represents a
typical cascade reaction in which the isatin 1 first con-
denses with malononitrile 5 to afford isatylidene malono-
nitrile derivative (1a). This step can be regarded as a fast
knoevenagel addition. Then (1a) undergoes Michael addi-
tion with dimedone 4 to give the intermediate (1b)
a
Isolated yield
NMR spectrum peaks at d 3.59 and 4.75 reveals the presence
of two methylene groups. Absence of peak at d 8.56 shows
the removal of N–H by CH2CH2Br. The nature of reaction
media has an important role in the alkylation process in the
presence of K2CO3 (10 mol%). The yields of products were
excellent in polar solvents, such as PEG, CH3OH, DMF, and
CH3CN, whereas the yields were much lower in less-polar
solvents such as toluene, THF, and dioxane. We have also
tried various PEGs with different molecular weights. As the
molecular weight of PEGs increases, viscosity also increa-
ses, which led to the highly viscous reaction mixture thus
giving low yields of products (Table 1).
Catalyst concentration plays a major role in the opti-
mization of the product yield. By increasing the molar
concentration of potassium carbonate from 5 to 15 mol%,
it was observed that increased loading of the catalyst from
10 to 15 mol% gave almost the same yield of the product.
But when we used 2–8 mol% of the catalyst, low yield was
obtained. 10 mol% of potassium carbonate (K2CO3) was
the suitable choice for an optimum yield of the products
(Table 2).
In order to test the solubility and reusability of PEG-400
as a solvent, the reaction mixture was extracted with
Scheme 2 Synthesis of
spirooxindole using equimolar
each of isatin, dimedone, and
O
O
I
CN
2/Water
NH2
CN
+
O
+
O
malononitrile at 50 °C
O
O
CN
5
N
H
50°C
1
4
O
6
N
H
123

Med Chem Res
I2
OH
O
O
OH
C NH
CN
O
N
4
I2
N
/water
CN
CN
5
HO
C
O
CN
O
+
O
N
H
CN
O
O
50°C
1
N
H
N
H
N
H
1b
1a
H
O
O
NH
CN
NH2
O
O
CN
O
O
N
N
H
H
6
Scheme 3 Plausible mechanism for the I2 catalyzed synthesis of spirooxindoles
Scheme 4 Diversity-generating
synthesis scheme using
multicomponent reaction
Ph
H2N
O
Ph
N
O
N
N
X1
NC
N
(13)
O
N
R
14(a-g)
O
H2N
HN
O
H
N
X2
N
H
O
X1
NC
O
8(j-k)
NH
O
2
8j = X2 = O
8k = X2 = S
O
CN
X
X1
N
+
R
I2
9(a-g);9 : X2= O
19(a-g);10:X2=S
O
CN
(5)
Water
N
R
R
H2N
R
O
1(a-g)
X1
NC
R
O
O
4(h-i)
R
O
O
a=R=X1=H
4h = R=CH3
4i = R = H
N
b=R=H, X1=Br
R
c=R=CH2CH2Br, X1=H
6(a-g);6:R=CH3
7(a-g);7:R=H
d=R=CH2CH2CH2Br, X1=H
e=R=CH2(CH2)3Br, X1=H
f=R=CH2(CH2)5Br, X1=H
g=CH2(CH2)9Br, X1=H
OH
H2N
O
O
(11)
O
X1
NC
O
O
O
N
R
12(a-g)
123

Med Chem Res
10 carbon atoms was quite high as compared to others.
These results indicated that the presence of lipophilic
moiety often enhanced the biological activity of the com-
pounds. Compounds 6g and 3b showed even far better
activity than the standard used and hence could be used for
the industrial purpose.
Table 4 Screening of compounds for cytotoxic activity on U87
human glioma cells
Compounds MTT
IC50
Compounds MTT
IC50
Compounds MTT
IC50
(lg/ml)
(lg/ml)
(lg/ml)
6a
78
14c
6d
78
12f
14f
6g
156
7a
156
312
39
312
624
312
624
156
78
78
2.5
39
39
39
39
19
4.9
2.5
19
19
19
19
4.9
9a
7d
Conclusion
10a
12a
14a
6b
9d
7g
78
10d
12d
14d
6e
9g
In conclusion, we have developed a simple and an efficient
two step procedure for the synthesis of library of new series
of spirooxindole derivatives. A privileged medicinal scaf-
fold has been synthesized through three component reactions
of structurally diverse isatins with malononitrile and barbi-
turic acid/thiobarbituric acid/dimedone/1,3-cyclohexanedi-
one, 4-hydroxycoumarin/1-phenyl-3-methyl-pyrazolin-5-
one. It is a good attempt for the biological activity evaluation
of spirooxindoles. Further studies to delineate the scope and
limitations of the present methodology and skeleton modi-
fication for activity enhancement are under process.
156
156
312
78
10g
12g
14g
3a
7b
156
78
9b
7e
10b
12b
14b
6c
156
78
9e
312
78
3b
3c
10e
12e
14e
6f
156
78
78
3d
3e
39
7c
78
78
3f
9c
78
7f
78
3g
10c
12c
78
9f
78
78
10f
78
Standard used is Carmustine (BCNU) with IC50 value is 3.9 lg/ml
for MTT
Experimental
General
followed by cycloaddition and dehydration to form the
desired product (6) (Scheme 3).
Some chemicals were purchased from Sigma-Aldrich and
Lancaster and were used as such. All reactions and purity
of products were monitored by thin layer chromatography
(TLC) using aluminum plates coated with silica gel
(Merck) employing ethylacetate and hexane (3:7). IR
spectra were recorded on Perkin-Elmer FTIR-1710 spec-
In order to further explore the potential of present pro-
tocol for heterocyclic compound synthesis, and to form a
huge library of diversified compounds for their biological
evaluation, we investigated one pot reactions involving
1,3-cyclohexanedione, 4-hydroxy coumarin, barbituric
acid, thiobarbituric acid, and 1-phenyl-3-methyl-2-pyr-
azolin-5-one as active methylene compounds in place of
dimedone. Moreover, 5-bromoisatin and different bro-
moalkyl isatins were also tried with the above-listed active
methylene compounds (Scheme 4).
1
trophotometer using Nujol film and KBr pellet. H NMR
and 13C NMR spectra were recorded on a JEOL JNMECX
400P FT NMR system using TMS as an internal standard.
The chemical shift values are recorded on d scale. Ele-
mental analysis was performed on a Hereaus CHN rapid
analyzer. ESI-MS mass spectra were recorded on a Waters
LCT Micromass. The melting point of the compounds was
measured through a Thomas-Hoover melting point appa-
ratus and are uncorrected.
The common spectral features in all these compounds
are the presence of cyano group and amino group; in the IR
spectrum, the stretching frequency appeared in the range of
2,100–2,300 cm-1. Stretching frequency in the range of
3,100–3,400 cm-1 corresponds to –NH2 functional group.
1
In the H NMR, a broad singlet for NH2 appears in the
Synthesis of products (3a–e)
range of 10–12 ppm. A characterization peak in the range
of 90–100 ppm corresponding to cyano group attached
carbon comes in 13C NMR.
Potassium carbonate (10 mol%) was added to a stirred
solution of 1H-indole-2,3-dione (1 mmol) in 3 ml PEG-
400, then dibromo-alkane (2 mmol) was added. The mix-
ture was then stirred at room temperature until the reaction
was complete. The completion of the reaction was moni-
tored through TLC. Later, distilled water (50 ml) was
added to the reaction mixture and the product was extracted
with diethyl ether (3 9 5 ml). The combined organic layer
All the synthesized compounds were screened for their
in vitro MTT cell line activity.
Hence we have investigated the cytotoxic effects of all
the synthesized compounds on U87 human glioma cells.
Inspection of data in Table 4 revealed that the relative
anticancer activity of compounds having alkyl chain with
123

Med Chem Res
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In a 50 ml round bottom flask, appropriate active methy-
lene compound (0.01 mol), isatin/bromo isatin/N-alkyl
isatin (0.01 mol), and malononitrile (0.01 mol) in 3 ml
water. To this, iodine (10 mol%) was added, mixed, and
stirred at 40 °C. The progress of reaction was monitored by
TLC. The reaction mixture was treated with aqueous
Na2S2O3 solution. The solid product separated out was
filtered, then washed with water and dried. The crude
product thus obtained was subjected to purification by
column chromatography on silica gel (60–120 mesh size)
using ethylacetate in petroleum ether (10:90) as eluent to
yield pure product. The structures of all products were
1
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versity of Delhi for providing financial assistance.
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