Chapter V 143 6.0 CHAPTER V SPIROOXINDOLES 6.1 INTRODUCTION The indole template is generally recognized as a privileged structure in medicinal chemistry (Houlihan et al., 1992). Indole itself has been found to possess fungicidal, bactericidal, antidepressant, anticonvulsant and analgesic activities (Kant et al., 2005). In particular, oxindoles are important constituents of natural indole alkaloids as well as drugs under development and also in the clinical trial (Jossang et al., 1991; Zhang and Zhang, 2002; Akai, et al., 2004). For example, the oxindole motif is present in the anti-Parkinson’s drug ropinirole (Nagata et al., 2001), in non-opioid nociceptin receptor ligands and in the growth hormone secretagogues. In addition, the oxindole moiety constitutes a key structural element in several natural products including the antiobiotic speradin (Tsuda et al., 2003) and the cytostatin welwistatin (Zhang and Smith, 1996). 3,3-Diaryloxindoles have shown to possess mechanism- specific anti-proliferative, antibacterial, anti-protozoal and anti-inflammatory activities. These compounds have also been used as laxatives and lead compounds for Ca 2+ -depletion-mediated inhibition of translation initiation. 6.1.1 Biological Importance N H O N N O H H O O OH N H O O N Cl H H S ropinirole speradine A welwistatin
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Chapter V
143
6.0 CHAPTER V SPIROOXINDOLES 6.1 INTRODUCTION The indole template is generally recognized as a privileged structure in medicinal
chemistry (Houlihan et al., 1992). Indole itself has been found to possess fungicidal, bactericidal,
antidepressant, anticonvulsant and analgesic activities (Kant et al., 2005).
In particular, oxindoles are important constituents of natural indole alkaloids as well as
drugs under development and also in the clinical trial (Jossang et al., 1991; Zhang and Zhang,
2002; Akai, et al., 2004). For example, the oxindole motif is present in the anti-Parkinson’s drug
ropinirole (Nagata et al., 2001), in non-opioid nociceptin receptor ligands and in the growth
hormone secretagogues. In addition, the oxindole moiety constitutes a key structural element in
several natural products including the antiobiotic speradin (Tsuda et al., 2003) and the cytostatin
welwistatin (Zhang and Smith, 1996). 3,3-Diaryloxindoles have shown to possess mechanism-
specific anti-proliferative, antibacterial, anti-protozoal and anti-inflammatory activities. These
compounds have also been used as laxatives and lead compounds for Ca2+-depletion-mediated
inhibition of translation initiation.
6.1.1 Biological Importance
NH
O
N
NO
H
H
O
O
OH
NH
OO
N
Cl
HH
S
ropinirole speradine A welwistatin
Chapter V
144
6.1.1.1 Indoles
Bajji et al. (1994) reported the biological activity of substituted 3-(4’-oxothiazolidine-2’-
aryl/ alkyl imino) indoles. All the thioureas were screened for antibacterial activity against S.
aureus, B. cirroflagelosus, S. typhi and P. fluorescence at 10 mg/ml and 13 mg/ml concentration.
Antifungal activity against A. niger and C. albicans were also assessed. Only some of the
compounds were active against organisms tested at both the doses. Some of the compounds were
screened for anti-inflammatory and anticonvulsant activities. None of the compounds showed
noteworthy anti-inflammatory and anticonvulsant activity.
Sarangapani et al. (2001) reported the CNS activity of 2 substituted-[1,3,4]oxadiazilo-
[5,6-b]indoles. The compounds exhibited reduction in the locomotor activity and potentiation of
pentobarbital sodium induced sleeping time in experimental animals at 100 mg/kg dose. Ashok
kumar et al. (2004) reported the anti-inflammatory, analgesic and cox II inhibitory activities of
indolyl pyrazolines. All the compounds were found to possess better anti-inflammatory,
analgesic and cox II inhibitory activities. Saundane et al. (1998) reported the analgesic, anti-
inflammatory, oxytocic, anthelmintic and antimicrobial activities of indoloisoquinoline
derivatives. Some of the compounds exhibited analgesic, anti-inflammatory, anthelmintic,
antibacterial and antifungal activity against S. citrus, P. aeruginosa, P. vulgaris, E. coli, C.
albicans and A. niger.
6.1.1.2 Spirooxindoles
The indole moiety is probably the most well known heterocycle, a common and
important feature of a variety of natural products and medicinal agents. Compounds carrying the
indole residue exhibiting antibacterial and antifungal activities have been extensively reported.
Chapter V
145
Spiro[indole-thiazolidinones] are one of the most studied classes of 3-spiroindole derivatives due
Chapter V
146
to a wide variety of bioactivity associated with them and are used in pharmaceuticals because of
Chapter V
147
their anti-inflammatory (Rovnyak et al., 1978), fungistatic (Dandia et al., 2004) and
Chapter V
148
bacteriostatic activities ( Ali and Alam, 1994). Dandia et al. (2006) reported the series of
Chapter V
149
benzindozolyl/triazolyl spiro[indole-thiazolidinone as potent antifungal agent against
Chapter V
150
Rhizoctonia solani, Fusarium oxysporum and Collectotrichum capsici by poison plate technique
in 1000 and 500 ppm concentrations and pot trial method. All compounds have shown good
activity against these pathogen. Incorporation of triazole ring enhances the activity of
compounds as compared parent skeleton. Oxindoles that incorporate a quaternary stereogenic
centre at C3 are attractive targets in organic synthesis because of their significant biological
activities as well as wide-ranging utility as synthetic intermediates for alkaloids, drug candidates
and clinical pharmaceuticals (Marti and Carreira, 2003; Dounay et al., 2003). Spirocyclic
compounds are systems containing one carbon atom common to two rings and are structurally
quite interesting (Heathcock et al., 1983; Sannigrahi, 1999). They represent an important class of
naturally occurring substances characterized by highly pronounced biological properties. The
spirooxindole framework represents yet another important structural organization present in a
number of bioactive natural products such as coerulescine, horsfiline, welwitindolinone A,
spirotryprostatin A, elacomine, alstonisine, etc (Chang et al., 2005; Baran and Richter, 2005).
Spirotryprostatin A, a natural alkaloid isolated from the fermentation broth of Aspergillus
fumigatus, has been identified as a novel inhibitor of microtubule assembly, and pteropodine and
N
NH
Me
OMeO
NH
NH
OOH
NH
O
N
N
O
O HH
MeO
NH
NO
O
HH
H
H CO2Me
Me
N
NH
Me
O
NH
O
H
Cl
CN
horsfiline elacomine
spirotryprostatin A alstonisine
coerulescine
welwitindolinone A
Chapter V
151
isopteropodine have shown to modulate the function of muscarinic serotonin receptors (Cui et
al., 1996).
Benzopyrans and their derivatives occupy an important place in the realm of natural and
synthetic organic chemistry because of their biological and pharmacological properties such as
anti-sterility and anticancer agents. In addition, polyfunctionalized benzopyrans constitute a
structural unit of a number of natural products and because of the inherent reactivity of the
inbuilt pyran ring are versatile synthons. Moreover, they can
also be employed as cosmetics and pigments and utilized as potential biodegradable
agrochemicals. These findings stimulated the interest in the synthesis of heterocyclic derivatives
of these ring systems for their great importance.
Fused chromenes have been found to have a wide spectrum of activities such as
antimicrobial (Smith et al, 1998) antiviral (Hiramoto et al, 1997), mutagenicity (Dell et al,
1993), anti-proliferative (Bianchi and Tava, 1987), sex pheromone (Mohr et al, 1975), anti-
tumor (Elagamay and El-Taweel, 1990) and central nervous system activities
( Ballini et al, 2001).
6.1.2 Synthetic approaches
Padwa et al. (England et al., 2007) reported the synthesis of substituted spirooxindoles
from 3-hydroxysubstituted 1,3-dihydroindol-2-one by addition of various π-nucleophiles
followed by intramolecular cyclization.
Chapter V
152
NH
O
ORBF3.OEt2
NH
O
A simple and one-pot protocol for the synthesis of indene-spirooxindole derivatives via
TiCl4 mediated reaction between 1,1-diarylethylenes and isatin derivatives involving
construction of two carbon-carbon bonds through tandem Prins and intramolecular Friedel-Crafts
reaction has been described (Basaviah and Reddy, 2007).
NO
OR'
R R'' R''
TiCl4CH2Cl2, rt N
R'
R
R''R''
O+
Reaction of indole amides with tributylstannane gave spiroindolenines which were
readily converted into spiropyrrolidinyloxindoles (Hilton et al., 2000).
N
N
O
R
CH3
CN
Ph
N
N
R
O
CH3
CN
PhN
N
R
O
CH3
O
Ph
Bu3SnH KOtBu, O2, THF
200C, 1h
Miyamoto et al. (2006) reported a highly diastereoselective one-pot synthesis of
spirocyclic oxindoles through intramolecular Ullman coupling and Claisen
rearrangement.
Chapter V
153
N
OH
R
CH3
CuCl
NO
CH3
NO
CH3
2-amino pyridine
NaOMe, DME, MeOH1000C, 10 min
1500C, 8h
DME
R = H, I, OMe Diastereomeric three-, four-, five- and six-membered spirocycloalkyloxindoles were
successfully synthesized in a rapid and convenient manner from readily accessible starting
materials in moderate to high yields via a one-pot base-mediated double alkylation strategy
(Morales-Rios et al., 2007).
NO
CH3
CN
NCH3
O
BrCN
n
NaH, DMF
NO
H
CH3
CN
n
NO
CH3
HNC
n (CH2)nBr2
n=1-4 +
The spirooxindole ring system of citrinadin A was synthesized with excellent control
over the absolute stereochemistry at the spirocenter involving a novel diastereo selective
DMDO-mediated oxidative rearrangement employing an 8-phenylmenthol chiral auxiliary on the
indole ring (Pettersson et al., 2007).
N
OXc
DMDO
acetoneO
O
N
OXc
O silica
CH2Cl2, rt
OO
NO
OXc
00C
Xc = (-)-8-phenylmenthol
An efficient method was developed for the asymmetric synthesis of 2’-alkyl-4’-aryl-1H-
spiro[indole-3,3’-pyrrolidin-2-ones] which are potential inhibitors of the p53-MDM2 interaction
(Ding et al., 2005).
Chapter V
154
NH
O
ArRCHO
NH
OO Ph
Ph
NH
NH
ArR
O
O
NMe2
RR
+
An electrochemically induced catalytic multicomponent transformation of cyclic 1,3-
diketones, isatin and malononitrile in an undivided cell in the presence of NaBr as an electrolyte
results in the formation of spirooxindoles with fused functionalized 5,6,7,8-tetrahydro-4H-
chromene system (Elinson et al., 2007).
Zhu et al. (2007) carried out a simple and efficient one-pot method for the synthesis of
biologically important spirooxindoles by the reaction of isatin, activated methylene reagent and
1,3-dicarbonyl compounds in aqueous medium.
N
O
OR'
X
CN
O
O
R
O
N O XNH2
O
R'
R+ +H2O, TEBA
60oC
Shanmugam et al. (2006) reported a facile, high yield stereoselective synthesis of
functionalized diastereomeric 3-spirocyclopropane-2-indolones from the isomerized bromo
derivative of Baylis-Hillman adducts of isatin by reductive cyclization with NaBH4.
N
O
OR
R' CN
CN O
O
R''R''
O
N ONH2
O
R
CN
R'
R''R''
+ +electrolysis,0.1 F/mol
R'''OH, NaBr
Chapter V
155
N OR'
OH
RHBr, silica gel
N OR'
Br
RN OR'
BrR
RN OR'
HR
N OR'
H
MW, 750W+
+
NaBH4
THF, 0.5h
Z Z
Z
Z
Z
Nair et al. (2005) reported the synthesis of spirooxadiazolines from the reaction of N-
substituted isatins with the zwitterionic intermediate generated from dialkyl azodicarboxylate
and triphenylphosphine.
NO
O
R
R' NN
CO2R''
R''2OCPPh3
DME, Arrt
O
NN
NO
R
R'R''2OC
OR''
+ +
A novel regioselective synthesis of a number of functionalized 3-spiropyrrolizidine and
3-spiropyrroline oxindoles from Baylis Hillman adducts of isatin via [3+2] cycloaddition of
azomethine ylides in excellent yields has been reported (Shanmugam et al., 2007).
N OR'
OH
NO
O
R''
NH
CO2H
N OR''
N N
O
R'OH
+ +montmorillonite K 10
MeOH, reflux, 0.5h
Z
Z
A microwave-assisted three-component regioselective one-pot cyclocondensation method
has been developed for the synthesis of novel spiro[indole-thiazolidinones] using an
environmentally benign procedure at atmospheric pressure in open vessel (Dandia et al., 2006).
Chapter V
156
NH
O
OX HetNH2 SH
R
CO2HX
SN
NH
OHet
OR
+ +MW
One-pot synthesis of spiro[cyclohexane-1,3’-indoline]-2’,4-diones starting from
Danishefsky’s diene and 3-chloromethylene-2-indolones is described (Beccalli et al., 2003)
N O
H
Cl
CO2Et
OSiMe3
OMeN OCO2Et
OSiMe3Cl
OMe
p-TSAreflux
N OCO2Et
O
H2, Pd/C
AcOEtN OCO2Et
O
+toluene
reflux
Spiro dihydrofuran oxindole derivatives were prepared via (3+2) oxidative cycloaddition
of 1,3-dicarbonyl compounds to 3-(phenyl-2-oxoethylidene)-1-methyloxindole and 3-
benzylidene-1-methyloxindole derivatives mediated by CAN (Savitha et al., 2007).
NO
CH3
O
R' R
O
OR''
R''O
N
O
OR''
R''
O
CH3
R
R'CAN/NaHCO3+CH3CN, OoC
Chapter V
157
6.2 OBJECTIVES
Compounds carrying the indole residue, exhibiting antibacterial and antifungal activities,
have been extensively reported. Further more, it has been reported that sharing of the indole3–
carbon atom in the formation of spiroindoline derivatives highly enhances biological activity.
Spiroindolines are used in pharmaceuticals because of their anti-inflammatory, fungistatic,
bacteriostatic and anticonvulsant activities. The extensive literature survey revealed that the
presence of two or more different heterocyclic moieties in a single molecule often enhances the
biocidal profile. Hence the present study was designed with the following objectives.
To synthesize and characterize a few substituted spirooxindole derivatives of
biocidal interest
To study the possible antibacterial, antifungal and antiviral activities of the
added and stirred at reflux for about 1.5 h. On completion, the reaction mixture was poured into
crushed ice and the precipitate formed was filtered, dried and purified by column
chromatography to afford the pure product in 70 % yield. This procedure was followed for the
synthesis of all the spirooxindoles (4a-i).
6.3.3 Antibacterial activity
Anti-bacterial study was carried out for the synthesized spirooxindoles (4a-i) by disc
diffusion method against ATCC gram positive and gram negative bacterial strains at 1000 µg,
500 µg and 100 µg concentrations.
6.3.3.1 Materials requirement
• The gram positive organism used for this study was Staphylococcus aureus and the gram
negative organism was and Klebsiella pneumoniae (The strains were received from
Department of Veterinary Microbiology, Madras Veterinary College, Chennai-600 007).
Chapter V
160
• The medium Tryptose Soy Agar (TSA) powder (HiMedia, Mumbai) was used at 4 g /100
ml to prepare solid agar plates and was used for both Gram positive and Gram negative
bacteria.
6.3.3.2 Method The same procedure was followed as given in chapter -1.Students‘t’ test was used for
statistical analysis. P values < 0.001 and <0.01 were considered to be statistically significant.
6.3.4 Antifungal activity
The in vitro anti-fungal activity of the spirooxindoles(4a-i) were studied
against Candida albicans using disc diffusion method at 1000 µg, 500 µg and 100 µg
concentrations.
6.3.4.1 Materials requirement
• The ATCC strain of Candida albicans was used for the anti-fungal study. (The strain was
received from Department of Veterinary Microbiology, Madras Veterinary College,
Chennai-600 007)
• The medium of Sauboraud’s Dextrose Agar (HiMedia, Mumbai) was used at 6.5 g/100
ml concentration for preparing solid agar plates.
6.3.4.2 Method
The same procedure was followed as given in chapter -3.
6.3.5 Cytotoxic assay The same procedure was followed as given in chapter -4. 6.3.6 Antiviral assay The same procedure was followed as given in chapter -4. 6.4 SPECTRAL DATA