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Isatin Derivatives with Several Biological Activities

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Review Article

Isatin Derivatives with Several Biological Activities

AJMER SINGH GREWAL ∗
JCDM College of Pharmacy, Sirsa-125055, Haryana (India)

ABSTRACT
Isatin (2,3-dioxindole) is an important class of heterocyclic compounds, and is an indole derivative. Isatin
derivatives are synthetically important substrates, which can be used for the synthesis of a large variety of
heterocyclic compounds, and as raw material for drug synthesis. Recently, isatin derivatives have attracted strong
interest in organic and medicinal chemistry due to their potent biological and pharmacological activities. Isatin
and its derivatives possess numerous biological properties like antitumor, antimicrobial, anti-inflammatory,
analgesic, anti-mycobacterial, anticonvulsant, antiviral, anthelmintic, anti-HIV, antioxidant, CNS depressant
activities. The present review outlines some commonly used methods to synthesize the isatin moiety and its
derivatives, with advances in the use of isatin derivatives for its biological and pharmacological properties.

Key words: Isatin, Antibacterial, Anticancer, Antifungal, Anti-inflammatory.

INTRODUCTION enter into addition reactions at the C-O bond and into
condensation reactions. Through the primary amine
Isatin or 1H-indole-2,3-dione, is an indole derivative group, compounds of the isatin series are capable of
containing keto group at position 2 and 3 of the ring. entering into N-alkylation and N-acylation and into
Isatin ring system consists of pyrrole ring fused with Mannich and Michael reactions [5-9]. Literature surveys
benzene ring. Isatin was first synthesized by Erdman reveal that various derivatives of isatin possess diverse
and Laurent in 1841 by the oxidation of indigo with ni- activities such as antibacterial, antifungal, antiviral, an-
tric acid and chromic acids [1-3]. The compound is ti-HIV, anti-mycobacterial, anticancer, anti-inflammatory
found in many plants, such as Isatis tinctoria, Calanthe and anticonvulsant activities [10].
discolor and in Couroupita guianensis. Substituted isa-
tins are also found in plants, for example the melosatin GENERAL METHODS FOR SYNTHESIS OF
alkaloids (methoxy phenylpentyl isatins) in Melochia ISATINS
tomentosa. Isatin is also found in humans as it is a met-
abolic derivative of adrenaline [4]. Sandmeyer synthesis
The synthesis of isatin derivative involving the reaction
O of chloral hydrate, hydroxylamine, and a primary aryl
amine to give α-isonitrosoacetanilide and subsequent
O electrophilic cyclization in the presence of a strong acid
N such as concentrated sulfuric acid is generally known
H as the Sandmeyer isatin synthesis (Scheme 1). This
1H-indole-2,3-dione method is suitable for anilines with electron-
withdrawing substituents, such as 2-fluoroaniline [11-
Isatin is a versatile chemical building block, able to form 13].
a large number of heterocyclic molecules. Isatin is able
H
to participate in a broad range of synthetic reactions, NH2 Chloral hydrate NH O
H2SO4 N
leading to its extensive use as a precursor molecule in O
Hydroxyl amine
medicinal chemistry. The presence of several reaction N
centers in isatin and its derivatives render them capable OH O

of participating in a large number of reactions. The keto Scheme 1: Sandmeyer isatin synthesis
group at position 2 and particularly at position 3 can

∗ Address for correspondance

Ajmer Singh Grewal, JCDM College of Pharmacy, Sirsa-125055, Haryana (India)
E-mail address: ajmergrewal2007@gmail.com, Phone: +91 9416700430
Received: 19/10/2013, Revised: 11/11/2013, Accepted: 20/11/2013

International Journal of Pharmaceutical Research | January-March 2014 | Volume 6 | Issue 1 | 1

 Ajmer Singh Grewal / A mini review on isatin derivatives
Martinet isatin synthesis
The Martinet method (Scheme 2) for the synthesis of
isatins involves the reaction of an aminoaromatic com-
pound and either an oxomalonate ester or its hydrate in
the presence of an acid to yield a 3-(3-hydroxy-2-
oxindole) carboxylic acid derivative which after oxidative
decarboxylation yields the respective isatin [13-14].
H H
H3CO NH2 Oxomalonate ester
H3CO N H3CO
O O
H+ H3CO
H3CO
HO
COOR
Scheme 2: Martinet isatin synthesis
Stolle method
The most important alternative to Sandmeyer synthesis
is the method of Stolle (Scheme 3). In this method ani-
lines are reacted with oxalyl chloride to form an inter-
mediate chlorooxalylanilide which can be cyclized in the
presence of a Lewis acid, usually aluminium chloride to
give the corresponding isatin [15-16].
(COCl)2
H3CO NH2 H3CO
OCH3
Scheme 3: Stolle method for isatin synthesis
Gassman method
This method involves the formation and subsequent
oxidation of an intermediate 3-methylthio-2-oxindole to
give the corresponding substituted isatins (Scheme 4).
Two complementary methods for the synthesis of the 3-
methylthio-2-oxindoles were developed. When electron-
withdrawing groups are present, the oxindole derivative
can be synthesized via an N-chloroaniline intermediate,
which further reacts with a methylthioacetate ester to
furnish an azasulfonium salt. In the case of electron-
donating groups that destabilize the N-chloro intermedi-
ate, by reaction of the chlorosulfonium salt with appro-
priate aniline gives better yields of the 3-methylthio-2-
oxindoles [17].
SMe
N-Chlorosuccinimide
R R O R
NH2 N HgO/BF3
H H
Scheme 4: Gassman method for isatin synthesis
Metalation of anilide derivatives
A more recent method for the synthesis of isatins is
based upon the directed ortho-metalation of N-pivaloyl-
and N-(t-butoxycarbonyl)-anilines (Scheme 5). The cor-
responding dianions are treated with diethyl oxalate and
2 | International Journal of Pharmaceutical Research | January-March 2014 | Volume 6 | Issue 1
the isatins are obtained after deprotection and cyclisa-
tion of the intermediate α-ketoesters [18].
O
O
R
O
1) n-BuLi, THF; R HCl
N O
2) diethyl oxalate
N O
THF/∆
R
N
O
H O H
O H
OEt
Scheme 5: Metalation of anilide derivatives for
N isatin synthesis
- CO2 H3CO
O MEDICINAL IMPORTANCE OF ISATIN DE-
RIVATIVES
Isatin derivatives as anticonvulsants
A large number of derivatives of isatin have been re-
ported to possess anticonvulsant activity [19]. A number
of hydrazines, hydrazides, and related compounds were
condensed with isatin and substituted isatins, and anti-
convulsant activity of these compounds was reported
[20]. Various Schiff bases were prepared by reacting 5-
(un)-substituted isatin with some heterocyclic com-
pounds, and evaluated for anticonvulsant and neurotox-
ic properties. The compound, 3-(3',4'-dihydro-2'-
O methylmercapto -4'- oxoquinazolin- 3'- yl) iminoisatin
emerged as the most active analogue showing better
O activity than valproic acid. All the compounds showed
N lower neurotoxicity than phenytoin and carbamazepine
H
OCH3 [21]. Anticonvulsant activity of hydrazones, Schiff and
Mannich bases of isatin were evaluated by maximal
electroshock method (MES) and metrazol-induced con-
vulsions (MET). Eight compounds of the series exhibited
significant anticonvulsant activity. The compound, 3-(4-
chloro-phenylimino)-5-methyl-1,3-dihydro-indol-2-one
was found to be the most potent compound of the se-
ries. All the compounds showed lesser neurotoxicity
compared to phenytoin and greater protection than so-
dium valproate [22]. Schiff bases of N-methyl and N-
acetyl isatin derivatives with different aryl amines have
been synthesized and screened for anticonvulsant activ-
ities against MES and Met. N-methyl-5-bromo-3-(p-
chlorophenylimino)isatin exhibited better activity than
the standard drugs phenytoin, carbamazepine and
valproic acid [23].
Isatin derivatives as anti-HIV agents
The isatin derivatives N-methylisatin-beta-4':4'-
O
diethylthiosemicarbazone and N-allylisatin-beta-4':4'-
O diallylthiosemicarbazone inhibit the production of Hu-
N man Immunodeficiency virus (HIV) [24]. About 12 new
Mannich bases of isatin were synthesized and evaluated
against HIV-1 (IIIB) and HIV-2 (ROD) strains in MT-4
cells. In initial studies, one compound has shown max-
imum protection of 16 % in subtoxic concentration [25].
The Schiff bases and N-Mannich bases of 5-chloro and
5-bromo isatin derivatives were synthesized and
screened for anti-HIV activity. Among the compounds
tested 1-[N,N-dimethylaminomethyl]-5-bromo isatin-3-
 Ajmer Singh Grewal / A mini review on isatin derivatives
{1'-[4"-(p-chlorophenyl) thiazol-2"-yl] thiosemicarba-
zone} showed the most favourable antimicrobial activity
[26]. Isatin, its 5-chloro and 5-bromo derivatives were
added to 3-amino-2-methylmercapto quinazolin-4(3H)-
one to form Schiff bases and the N-Mannich bases of
these compounds were synthesized by reacting with
formaldehyde and several secondary amines [27]. On
the basis of pharmacophoric modelling studies of exist-
ing non-nucleoside reverse transcriptase inhibitors, a
series of isatin beta-thiosemicarbazone derivatives was
synthesized and evaluated for their anti-HIV activity.
Three compounds showed significant anti-HIV activity
[28]. An isatinimino lead compound as a novel non-
nucleoside reverse transcriptase inhibitor with antimy-
cobacterial properties for the effective treatment of AIDS
and AIDS-related tuberculosis was designed and among
the synthesized compounds, one emerged as the most
potent broad-spectrum chemotherapeutic agent active
against HIV and Mycobacterium tuberculosis [29]. New
bis-Schiff bases of isatin were prepared by condensa-
tion of isatin with primary aromatic amines and antibac-
terial, antifungal and antiviral activity was reported [30].
Isatin derivatives as anticancer agents
Isatin showed antioxidant activity and was cytotoxic to
the HL60 cells due to induction of apoptosis. The isatin
can be used as a prophylactic agent to prevent the free
radical-induced cancer and as a chemotherapeutic
agent to kill the cancer cells [31]. Novel isatin based
conjugates with thiazolidine and pyrazoline moieties
were synthesized and screened for antitumour activity.
The synthesized compounds were tested for their anti-
cancer activity in NCI60 cell lines [32]. A series of new
isatin-thiazoline and isatin-benzimidazole derivatives
were synthesized via condensation of isatin Mannich
bases with either 2-aminothiazoline or 2-
aminobenzimidazole. The anti-breast cancer activity of
some of the synthesized compounds was assessed in
the MCF-7 human breast cancer cell line [33]. New
2,3,5-trisubstituted 4-thiazolidinones bearing an isatin
fragment were synthesized and evaluated for the anti-
cancer activity. Among the synthesized compounds,
(5′Z)-5′- (benzylidene) -3′-(4- chlorophenyl) spiro [3H-
indole-3,2′-thia-zolidine]-2,4′(1H)-dione and (5′Z)-3′-(4-
chlorophenyl) -5′- [4- (1-methylethyl) -benzylidene]
spiro [3H-indole-3,2′-thiazolidine]-2,4′(1H)-dione were
superior in anticancer activity [34]. The recent FDA ap-
proval of the oxindole sunitinib malate, as a kinase in-
hibitor for the treatment of advanced renal carcinoma
and gastrointestinal stromal tumours, underscores the
increasing interest in isatins as a new class of antineo-
plastic agents. In addition to potent kinase inhibition,
the mechanism of action of other isatin derivatives in-
cludes the inhibition and/or modulation of proteases,
translation initiation, neo-vascularisation and tubulin
polymerisation [35].
Isatin derivative as antiviral agents
International Journal of Pharmaceutical Research | January-March 2014 | Volume 6 | Issue 1 | 3
A new series of isatin N-Mannich bases was synthe-
sized and evaluated for antiviral, antibacterial, and anti-
fungal activity [36]. New series of Mannich bases isatin-
beta-thiosemicarbazone derivatives was synthesized.
Three compounds among the synthesized series
showed protective effect on mice infected with vaccinia
virus [37]. A novel series of substituted isatin ribonucle-
osides were synthesized in good yields and evaluated
for antiviral activity. All the isatin derivatives tested did
not inhibit HIV-1 Reverse Transcriptase activity [38]. The
compound, 4-[(1,2-dihydro-2-oxo-3H-indol-3-
ylidene)amino]-N(4,6-dimethyl-2-pyrimidiny)benzene
sulphonamide and its derivatives were synthesized and
evaluated for antiviral activity against Pathogenic virus-
es such as Hepatitis C Virus (HCV) and SARS-CoV The 5-
fluoro derivative inhibited the HCV RNA synthesis at 6
μg/ml, without toxicity at a concentration up to 42
μg/ml [39]. New series of Schiff’s bases, hydrazones,
thiosemicarbazones, thiazoles, and thiocarbohydra-
zones of 5-fluoroisatin were synthesized by the reaction
of 5-fluoroisatin with primary amines, hydrazine hy-
drate, and thiocarbohydrazides. Some of the synthe-
sized compounds exhibited antiviral activity [40]. Isatin
derivatives were tested for antiviral activity against in-
fluenza A (H1N1, H3N2, and H5N1) and B viruses in
Madin Darby canine kidney cell culture. Fifty percent
effective concentration (EC50) values were determined
in cytopathic effect (CPE) inhibition assays quantified by
neutral red dye uptake. The basic molecule is amenable
to diverse chemical modifications, which may improve
water solubility and antiviral potency [41].
Isatin derivatives as antibacterial and anti-
fungal agents
Isatin and substituted Isatin were reacted with 4-amino-
N-carbamimidoyl benzene sulfonamide to form a series
of Schiff’s bases. The Mannich bases of these com-
pounds were synthesized by reacting them with formal-
dehyde and secondary amine (piperidine). The antimi-
crobial activity of the synthesized compounds was eval-
uated by tube dilution method. The synthesized com-
pounds showed better antibacterial activity than the
reference drugs [42]. New isatin-3-
isonicotinylhydrazones, isatinazine and its Mannich ba-
ses and spiro (indoline-3, 2'-thiadiazoline)-2-one have
been synthesized. These compounds have been
screened for their antibacterial activity against the
Gram-positive and Gram-negative bacteria [43]. Isatin-
derived Schiff bases have also been reported to possess
antibacterial activity [44]. Twenty-eight bacteria of clini-
cal interest were used in the studies performed by Pan-
deya and colleagues. One compound was notably more
than 1000-fold potent than sulphamethoxazole. Other
isatin-derived Schiff bases have been described in the
literature, but with no expressive antibacterial activities
[45].
Isatin derivatives as anti-tubercular agents
 Ajmer Singh Grewal / A mini review on isatin derivatives
Isatin derivatives are reported to show anti-tubercular
activities, accordingly, isatin is a versatile lead molecule
for designing of potential anti-tubercular agent. Some of
these derivatives are natural products, for example,
tryptanthrin, an alkaloid from the Chinese herb Stro-
bilanthes cusia showed potent activity against MTB
H37Rv (1mg/l) [46]. An isatinimino lead compound was
designed as a novel non-nucleoside reverse transcrip-
tase inhibitor with antimycobacterial properties for the
effective treatment of AIDS and AIDS-related tuberculo-
sis [29]. Schiff bases of nalidixic acid carbohydrazide
and isatin derivatives were synthesized. Anti-TB activity
of the synthesized derivatives was investigated against
four Mycobacterium strains: Mycobacterium intercellu-
lari, Mycobacterium xenopi, Mycobacterium cheleneo
and Mycobacterium smegmatis. Modest anti-TB activity
was observed within the investigated compounds [47].
Isatin derivatives with antiglycation activity
Schiff bases of isatin were synthesized and tested for
their antiglycation potential. One compound showed
77% inhibition, which is an excellent antiglycation activ-
ity, if compared with standard aminoguanidine having
85.69% inhibition [48]. Bis-Schiff bases of isatin were
synthesized and their in vitro antiglycation potential was
evaluated. One compound showed an excellent anti-
glycation activity better than the standard (rutin). This
study has identified a series of potential molecules as
antiglycation agents [49]. A series of N-aroylated isatins
was synthesized and evaluated for their antiglycation
activity [50].
Isatin derivatives with anti-inflammatory
and analgesic activity
Recent literature survey reveals that isatin derivatives
exhibit anti-inflammatory and analgesic activities [51].
Schiff bases of isatin with aminothiazole, its N-mannich
bases and Spiro isatin derivatives were synthesized.
Anti-inflammatory activity was tested by carragenin-
induced rat paw edema and compounds were evaluated
for analgesic action by the acetic acid-induced writhing
method [52]. A series of novel Schiff bases of isatin
were synthesized by condensation of imesatin with dif-
ferent aromatic aldehydes and screened for the analge-
sic activity by the tail-immersion method. Compounds
containing electron-donating groups exhibit better anal-
gesic activity than the electron-withdrawing groups
[53]. Novel schiff bases were synthesized by condensa-
tion of 5-subsituted imesatin with different substituted
aromatic aldehydes and evaluated for analgesic activity
(Tail-immersion method), anti-inflammatory activity
(carrageenan-induced paw oedema method) and anti-
bacterial activity (paper disc diffusion technique) [54]. A
different series of isatin derivatives such as Isatin-3-
[N2-(2-benzalaminothiazol-4-yl)]hydrazones were taken
and their anti-inflammatory, analgesic and antipyretic
activity was evaluated in animal models using indo-
4 | International Journal of Pharmaceutical Research | January-March 2014 | Volume 6 | Issue 1
methacin as a standard [55].
Isatin derivatives with antimalarial activity
The synthesis of a novel series of thiolactone-isatin hy-
brids led to the discovery of tetracyclic by-products
which displayed superior antiplasmodial activity. This
series reported antimalarial activity against the chloro-
quine-resistant strain of Plasmodium falciparum [56]. A
new series of 1H-1,2,3-triazole tethered 7-
chloroquinoline-isatin hybrids was synthesized and
evaluated for antimalarial activity. Activity against cul-
tured parasites was dependent on the C-5 substituent of
the isatin ring as well as the alkyl chain length between
the isatin and 7-chloroquinoline moieties. Compound
with an optimum alkyl chain length (n = 3) and a chloro
substituent at the C-5 position of the isatin ring, dis-
played the best activity among the tested compounds
against cultured W2-strain Plasmodium falciparum [57].
A new class of 4-aminoquinoline derivatives was syn-
thesized based on the natural product isatin scaffold
and evaluated for antimalarial activity against three
strains of the malaria parasite plasmodium falciparum.
These derivatives showed antiplasmodial IC50 values in
the ranges of 1.3-0.079 and 2.0-0.05 μM against a
chloroquine-sensitive and two resistant strains of P.
falciparum [58].
Isatin derivatives with antioxidant activity
Isatin was reported with antioxidant activity [31]. A new
series of 3,3-bis(4-amino-2,5-dimethoxyphenyl)-1, 3-
dihydroindol-3-one derivatives was synthesized based
on the reaction between isatin and 2,5-dimethoxyaniline
and evaluated for antioxidant activity [59]. A series of β-
Isatin aldehyde-N, N’-thiocarbohydrazone derivatives
were synthesized and assayed for their in vitro antimi-
crobial and antioxidant activity. Four compounds
showed most effective antioxidant activity against DPPH
and H2O2 scavenging activity [60]. A new series of bis-
isatin carbohydrazone derivatives was synthesized and
evaluated for their antimicrobial and antioxidant activi-
ties. The in vitro antioxidant activity was evaluated us-
ing 1,1-diphenyl-2-picryl-hydrazyl and hydrogen perox-
ide (H2O2), and the total antioxidant capacity by a phos-
phomolybdenum assay and their ability to chelate fer-
rous iron. In general, the derivatives were found to ex-
hibit antioxidant activity [61].
Isatin derivatives with anthelmintic activity
A new series of tetradentate Schiff bases was synthe-
sized and screened for anthelmintic activity against
earthworm (Peretima posthuma) using 5 μg/ml concen-
tration [62]. A series of novel isatin derivatives were
synthesized from different substituted chalconised in-
dole-2,3-dione prepared from the different chalconised
isatin. Some compounds reported anthelmintic activity
against Pheretima posthuma [63]. Various 3-(2-
hydrazino benzothiazoles)-substituted Indole-2-one de-
 Ajmer Singh Grewal / A mini review on isatin derivatives
rivatives were synthesized, and all the synthesized
compounds were screened for anthelmintic activity by
using Indian adult earthwarms (Pheretima postuma)
[64].
Isatin derivatives with antianxiety activity
Isatin derivative like Schiff bases of N-methyl and N-
acetyl isatin, spirobenzodiazepines, 5-hydroxy isatin
and isatinic acid act as antianxiety agents. A new series
of 5-hydroxy isatin derivatives was synthesized by the
hydroxylation of the aromatic ring in isatin and showed
mild antianxiety effect [2].
CONCLUSION
The isatin scaffold can be found in a broad range of
natural and synthetic compounds of medicinal im-
portance. Isatin and its derivatives showed diverse
pharmacological activities including anticonvulsant,
anti-HIV, anticancer, antiviral, antibacterial, antifungal,
anti-tubercular, antiglycation, anti-inflammatory, anal-
gesic, antimalarial, antioxidant, anthelmintic and anti-
anxiety activity.
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