Acta Pharm.

55 (2005) 27–46 Review article

Biological activities of isatin and its derivatives

SURENDRA NATH PANDEYA1* Isatin is an endogenous compound identified in humans

SIVAKUMAR SMITHA2
that possesses a wide range of biological activities. Isatin
MAYANK JYOTI2
SESHAIAH KRISHNAN SRIDHAR3 has anxiogenic, sedative, anticonvulsant activities and
acts as a potent antagonist on atrial natriuretic peptide
1 Department of Pharmaceutics, Institute receptors in vitro. A series of p-substituted isatin semicar-
of Technology, Banaras Hindu University bazones have shown anticonvulsant activity in MES,
Varanasi–221 005, India scPTZ and scSTY tests. Various isatin-N-Mannich bases
of isatin-3-thiosemicarbazones have shown antiviral and
2Department of Pharmaceutical Sciences tuberculostatic activity. Methisazone is an effective com-
Faculty of Health and Medical Sciences pound against variola and vaccinia viruses. The N-dime-
Allahabad Agricultural Institute–DU thyl and morpholino derivative of 5-methyl isatin and tri-
Allahabad–211 007, India methoprim exhibited an EC50 of more than 4.3 and 17.7
mg mL–1, respectively. Isatin (3-o-nitrophenyl) hydrazone
3 C. L. Baid Mehta College of Pharmacy has shown activity against Walker carcinoma-256. Vari-
Jothi Nagar, Thorapakkam, ous substituted indolinones showed antitubercular acti-
Chennai–600 096, India vity against M. tuberculosis H37Rv with MIC ranging from
10–20 mg mL–1. Isatin derivatives of Mannich bases had
fibrinolytic, muscle relaxant, antiallergic, immunosup-
pressant, and antithrombotic activity. Isatin showed car-
dioinhibitory effect on frog heart, and hypotensive, re-
spiratory depression and antidiuretic effects.
Received July 2, 2003 Keywords: isatin, Mannich bases, semicarbazones, anti-
Accepted January 25, 2005 convulsant, antimicrobial, antitubercular effects

Isatin (2,3-dioxindole) is an endogenous compound identified in humans, and its ef-

fect has been studied in a variety of systems. Biological properties of isatin include a
range of actions in the brain and offer protection against certain types of infections.

CNS ACTIVITIES

CNS depressant activities. – Isatin has a range of actions such as CNS-MAO inhibi-
tion, anticonvulsant and anxiogenic activities. Its effect as a mono amino-oxidase (MAO)
inhibitor is the most potent in vitro action recorded to date. It is a selective MAO B inhi-

* Correspondence, e-mail: [email protected]

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

bitor with an inhibitory concentration (IC50) of about 3 mg mL–1 (1). At higher concentra-
tions it inhibits a variety of other enzymes, such as alkaline phosphatases. In rodents, it
has been reported to act as an antiseizure agent and to potentiate the antiseizure action
of propranolol. Isatin has also been found to increase vigilence (2). At a low dose (15 mg
kg–1), it is anxiogenic and prolongs pentylenetetrazole (PTZ) induced seizures while at
higher dosage (80 mg kg–1) it becomes sedative and anticonvulsant and the brain 5-HT
levels are found to be significantly raised (3).

Anticonvulsant activity. – Bhattacharya and Chakraborti (4) reported isatin to be an

endogenous compound with anxiogenic properties, which occur within a narrow intra-
peritoneal (i.p.) dose range (15–20 mg kg–1). Higher doses exhibited a significant anti-
convulsant effect against both PTZ and 3 MPA (mercapto propionic acid) induced clonic
convulsions. Bhattacharya et al. (5) have found isatin to function as a potent antagonist
on anti-natriuretic peptide (ANP) receptors in vitro, and to inhibit anxiolytic, memory fa-
cilitating and diuretic actions of intracerebroventricularly administered ANP.
Li et al. (6) studied the inhibitory effect of isatin on amygdaloid kindling in rats, sei-
zure and anticonvulsant effect in convulsion models. Isatin (50–200 mg kg–1) given i.p.
significantly raised the focal after-discharge threshold (ADT), reduced the seizure sever-
ity and percentage of generalized seizure (p < 0.01) in kindled rats.
Pajouhesh et al. (7) synthesized a series of cyclohexane and other cyclic ketone de-
rivatives of isatin and screened them for anticonvulsant activity (Fig. 1). A considerable
number of analogues were active in pentylenetetrazole seizure threshold tests. However,
no consistent structure to activity pattern was recorded.

OH R = H, 1-CH2C6H5, 5-Br, 5-Cl, 5-CH3, 5-OCH3,

5-NO2, 6-Cl, 7-CH3, 4-Cl-7-CH3, 4-Cl-7-OCH3,
R
O O 5- Cl-7-CH3, 5-O-CH3- 6-Cl, 6-Cl-7-CH3
N
H

OH R1 R = H, 1-CH3, 5-Br, 5-NO2, 4-Cl-7-CH3;

R1 = 2-methyl cyclohexanone,
R 2-cyclohexyl cyclohexanone,
O O 3-methyl cyclohexanone
N
H

Fig. 1. Cyclic ketone derivatives of isatin.

Jain and Bansal (8) synthesized a series of condensed compounds by reacting a he-
terocyclic system like isatin/5-fluoroisatin with ethyl cyano acetate and substituted ke-
tones. The structure represented in Fig. 2 showed anticonvulsant activity in rats.
Blackburn et al. (9) reported that indoles, such as 1-[5-(2-thienyl methoxy-1H-indol-
3-yl) propan-2-amine, were used in the treatment and prevention of epilepsy and mi-
graine.

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

CH3

H5C6OC O
F
NH 2
COOC2H5
N O
H
Fig. 2. Heterocyclic derivatives of isatin.

Difabio et al. (10) synthesized substituted indole-2-carboxylates as in vivo potent an-

tagonists acting at the strychnine insensitive glycine binding site and evaluated their in
vitro potency to inhibit convulsions induced by N-methyl-D-aspartate (NMDA) in mice.
Olesen and Kanstrup (11) prepared pyrido[2,3-b]indoles to treat a disease in the CNS
via the metabotrophic glutamate receptor system. The title compounds are useful for tre-
ating diseases in the CNS such as epilepsy, senile dementia and Parkinsonism (Fig. 3).

R5 R4
6 R1 = H, C1–6 alkyl (CH3, C2H5, C3H7–C6H13);
R R3 C2–6 alkenyl (C2H4, C3H6 – C6H12), R2 = piperidino,
morpholino, etc.; R3 = H, COOH, CN, etc.;
R7 N N R2 R4 = H, C1–6 alkyl (CH3, C2H5, C3H7, etc.);
R1 R5 = R8 = H, NO2, NH2
R8
Fig. 3. Pyrido[2,3-b]indoles.

Sharaf (12) investigated pyrroloindoles and indolethiazepines for their anticonvul-

sant, analgesic, anti-inflammatory and ulcerogenic activities. All the compounds show-
ed potent anticonvulsant and analgesic activities.
Evanno et al. (13) synthesized 1H-pyrido[3,4-b]indole-4-carboxamide derivatives of
the structure presented in Fig. 4.

X = H, halo, alkyl, alkoxy, CF3, OCH3; R1 = H, alkyl,

NR3R4
O cyclopropyl, CH3; R2 = alkyl, phenyl alkyl, cyclo-
hexylmethyl, thienylmethyl; R3 = R4 = H, alkyl, 2-
X methoxy ethyl, OC2H5, carboxy alkyl, alkoxycarbo-
NR2 nylalkyl, phenyl alkyl, pyrrolidinyl, piperidinyl,
N1 morpholinyl, 4-methyl piperazinyl, azetidinyl, thia-
R O diazolinyl

Fig. 4. 1H-pyrido[3,4-b]indole-4-carboxamide derivatives.

The different substituted compounds (Fig. 4) were tested for their anxiolytic, hyp-
notic and anticonvulsant activities.
Jakobsen et al. (14) prepared thieno[2,3-b]indoles and pyrido[2, 3-b]indoles as anta-
gonists on the metabotropic glutamate receptor and therefore useful in treating CNS dis-
eases such as epilepsy, Parkinsonism and senile dementia (Fig. 5).

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

R5 R4 R3 R2
R1 = C1-6 alkyl optionally substituted with halogen
6 (CH3, C2H5, C3H7, etc.), C2-6 alkenyl (C2H4, C3H6,
R S etc.); R2 = COOH, CN, NO2; R3 = H, C1-6 alkyl CF3;
7 R4–R7 = H, NO2, NH2
R N
R

R6b R5b R4b R3b

R1b= H, alkyl C1–6 (CH3, C2H5, C3H7, etc.), C2–6 alke-
R 7b nyl (C2H4, C3H6, etc.) R2b = unsubstituted NH2; pi-
R2b
peridino, morpholino, R3b = H, COOH, CN; R4b = H,
N
C1–6 alkyl; R5b–R8b = H, NO2, NH2
R8b N
R1b
Fig. 5. Thieno[2,3-b]indoles and pyrido[2, 3-b]indoles.

Evanno et al. (15) synthesized 4-oxo-3,5–dihydro-4-H-pyridazano-4,5-b-indole-1-acet-

amide derivatives that can be used for treating diseases related to GABA aminergic (GABA
– gamma amino butyric acid) transmission disorders. The compounds also showed hyp-
notic and anticonvulsant activities in rats and mice. The structures of the compounds are
given in Fig. 6.

O OCH3
O
N R2 R3 F N
N N
N
X Y
O
O N
N
C2H 5
R1
O
N(CH3) 2
X = H, halo, CH3, OCH3, OCH2C6H5; Y = H, 1
F N
N
halo atom, CH3, OH, OCH3, NO2; R1 = H, C1-4
alkyl (CH3, C2H5, C3H7, etc.); R2R3 = H, C1-4
alkyl, CH2C6H5 or R2R3 = azetidine, pyrrolidinyl,
O
N 3-ethoxy pyrrolidinyl, piperidinyl, morpholinyl,
4-methyl piperazinyl, 1,3-thiadiazolinyl
C2H 5
Fig. 6. 4-Oxo-3,5–dihydro-4-H-pyridazano-4,5-b-indole-1-acetamide derivatives.

Karali et al. (16, 17) synthesized a series of 3-thiosemicarbazono-2-indolinones (Fig. 7).

Hydrazides (R = Br, Cl; R1 = OC2H5, N2H3) were prepared from the appropriate fur-
furyl dihydro triazolethiones. Subsequent treatment of 2-furoic hydrazide-2,3-indoline-
dione or 3-bromo-2,3-indolinedione furnished the corresponding 3-hydrazono-2(1H)in-
dolinones. Two of the new compounds showed anticonvulsant activity in preliminary
tests.

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

R2 O
N
1
R NNHC(S)NHR2 R1
NH
S
N O O
N

–
R R
R = H, COCH3; R1 = H, Br; R2 = CH3, C2H5, C6H5

Fig. 7. 3-Thiosemicarbazono-2-indolinones.

Reddy et al. (18) prepared indolinyl and tetrahydro quinolyl carboxamidines. N-(1-
napthyl)-1-indolinyl carboxamidine at 2 mg kg–1 i.p. caused 82% inhibition of seizures in
mice.
Gursoy and Karali (19) synthesized a new series of 3-aryloxyl, arylthioxy acetyl hy-
drazono-2-indolinones (Fig. 8) and 1-morpholino methyl-3-aryloxyl-aryl thioxy acetyl
hydrazono-2–indolinones.

R NHCOCH2XR1
X = O, S; R = H, Br; R1 = C6H5; 3-CH3C6H4, 4,5-di-
N O phenyl-(1H)-imidazol-2-yl
–

Fig. 8. 3-Aryloxyl, arylthioxy acetyl hydrazono-2-indolinones.

Anticonvulsant evaluation of these compounds revealed varying degrees of activity against

pentylenetetrazole induced seizures.
Popp and Donigan (20) synthesized three series of compounds, namely, 3-hydroxy-
-3-phenacyloxindoles (Fig. 9).

O
OH
R = H, 1-CH3, 1-CH2-C5H10N, 1-Br, 5-CH3, 5-NO2,
CH2 – C – Ar 7-CH3, 6-Cl; Ar = C6H5, 4-NO2-C6H4, 4-C5H10N,
R
O 4-CH3-C6H4, 4-CH3O-C6H5, 4-Cl-C6H4, 2-pyridyl,
N
3-indolyl ferrocenyl
–

H
O
CH – C – Ar
R = H, 5-Br, 5-CH3, 5-NO2, 5,7 (CH3)2; Ar = C6H5,
R
4-NO2-C6H4, 4-C5H10N, 4-CH3-C6H4, 4-CH3O-C6H4,
N O
4-Cl-C6H4, 2-pyridyl, 3-indolyl ferrocenyl
–

H
Fig. 9. 3-Phenacyclidine-2-indolinone and 3-phenacyl-2-indolinones.

3-Phenacyclidine-2-indolinone was active at both 100 and 300 mg kg–1 in the maxi-
mal electroshock seizure test.
Galambos (21) prepared racemic or optically active 3-spiroxindole derivatives (Fig. 10).

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

Z
X Z
W
W
H H X = H or halo, Z = CH, W = N
HN HN
O O

Fig. 10. 3-Spiroxindole derivatives.

The isatylidene derivative in Fig. 10. has antihypoxic activity, anticonvulsant activ-
ity and provides protection from pentylenetetrazole induced brain oedema.
Ghaney and El-Helby (22) synthesized new 1,3-dioxo-N-phenyl-2H-isoindole-2-ace-
tamides (Fig. 11) by condensation of chloroacetanilides with the potassium salt of 1H-
-isoindole-1,3-dione in DMF.

O R1
O R2
R1 = H, CH3, halo, OH; R2 = H, CH3, Br;
N CH2- C - NH R3 R3 = H, CH3, Br, Cl
O
Fig. 11. 1,3-Dioxo-N-phenyl-2H-isoindole-2-acetamides.

Preliminary pharmacological screening of some of the new compounds showed that

they could have marked anticonvulsant activity against pentylenetetrazole-induced con-
vulsions in frogs.
David et al. (23) have shown that 2-aminonapthyridine is prepared by ring cleavage
of 2-isoindolinyl napthyridine (Fig. 12).

N
N N Cl R = H, COOH
R CH(CH3)2
O
Fig. 12. 2-Isoindolinyl napthyridine derivatives.

These compounds have exhibited remarkable anxiolytic, hypnotic, anticonvulsant

and muscle relaxant properties.
Smith et al. (24) investigated the role of nitric oxide in epilepsy. The neuronal selec-
tive nitric oxide synthase inhibitor, 7-nitroindazole (7-NI), is an anticonvulsant. The ef-
fect of 7-NI in rodents with reflex epilepsy may result from arginine accumulation or a
reduction of nitric oxide or L-citrulline formation. Alabadi et al. (25) reported that 7-ni-
troindazole increases hippocampal extracellular glutamate concentration in status epi-
lepticus induced by kainic acid in rats.
Srivastava et al. (26) synthesized a series of compounds from carbazole, which on
condensation with chloroacetyl chloride in the presence of triethylamine afforded aze-

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

tidinones. Some of the compounds exhibited promising antibacterial, antifungal, anti-in-

flammatory and anticonvulsant activities (Fig. 13).

N
N N C6H5
CH2 N
S
O Cl
Fig. 13. Azetidinone derivatives of isatin.

Singh et al. (27) synthesized a series of isatin-based spiroazetidinones and screened

them for their anticonvulsant activity (Fig. 14).

C6 H 5
C6 H 5 O

NR R = 4-Cl-C6H4, napthyl

N O
COCH (C6H5)2
Fig. 14. Isatin-based spiroazetidinones.

Pandeya et al. (28) synthesized a series of p-nitrophenyl substituted semicarbazones

and their anticonvulsant activity was screened against maximal electroshock (MES), subcu-
taneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (scSTY) tests (Fig. 15).
All the compounds were active in scPTZ and MES tests. Two compounds were ac-
tive in the MES test at 100 mg kg–1.
Pandeya et al. (29) synthesized a series of N-methyl/acetyl-5-(un)substituted-isatin-
-3-semicarbazones (Fig. 15).
In this series, compounds with 4-bromo and 2-chloro substitution (R = 4-Br and
2-Cl) showed promising activity and were also active in MES, scPTZ and scSTY induced
tests.
Further, Pandeya et al. (30) synthesized halosubstituted isatin semicarbazones to stu-
dy the role of hydrogen bonding for anticonvulsant activity (Fig. 16).
Pandeya et al. (31) synthesized a series of p-nitrophenyl substituted semicarbazones
and phenoxyl/p-bromophenoxy acetyl hydrazones and their anticonvulsant activity was
screened against MES, ScPtz and ScSty (Fig. 17). Compounds with NHCO- group were
found to be the most active in all these tests. These compounds were also active in the
MES test after oral administration in rats. On the other hand, compounds with -OCH2
group were devoid of anticonvulsant activity. The studies revealed that the hydrogen-
-bonding domain in semicarbazones, adjacent to the lipophilic aryl ring, is essential for
the anticonvulsant activity.

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

R HN
NO2 HN
C=O
C=O

NH NH
R N R2 N

N O N O
H
R1
R = H, Cl, NO2 R = 2-Cl, 3-Cl, 4-Cl, 4-Br, 4-NO2, 4-SO2NH2
R1 = CH3, COCH3; R2 = H, NO2
Fig. 15. Semicarbazones isatine derivatives.

NNHC= O R1
R
N O
R2
R1=-CH 2O-C6H5, 1-CH2O-(4-Br)-C6H4, R2=COCH3, CH2C6H5, R=H, 4-Cl, 5-Cl, 6-Cl
Fig. 16. Halosubstituted isatin semicarbazones.

NHCONHR

O2N

N N

CH3
R= NC
CH3

O O

Fig. 17. p-Nitrophenyl substituted semicarbazones.

Pandeya et al. (32) had synthesized Schiff bases of N-methyl and N-acetyl isatin de-
rivatives with different aryl amines and screened them for anticonvulsant activity against
MES and scMet. N-methyl-5-bromo-3-(p-chlorophenylimino) isatin exhibited anticon-
vulsant activity in MES and scMet with LD50 > 600 mg kg–1, showing better activity than
the standard drugs such as phenytoin, carbamazepine and valproic acid (Fig. 18).
Anxiogenic and other CNS activities. – Palit et al. (33) studied the behavioral effects of
isatin, a putative biological factor in rhesus monkeys. Isatin, one of the constituents of
tribulin, a postulated endocoid marker of stress and anxiety, has been shown to induce

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

R N R2
R = Br, NO2; R1 = CH3, COCH3;
O R2 = NO2, COOH, OCH3, Cl, F
N
1
R
Fig. 18. Schiff bases of N-methyl and N-acetyl isatin derivatives.

anxiety in rodents. Medvedev et al. (34) studied a range of isatin analogues for their in
vitro inhibition of human MAO A and B. Most analogues were less potent than isatin.
Hydroxylation of the aromatic ring in isatin changed the inhibitory potency in favour of
MAO A, with 5-hydroxy isatin being a potent and selective MAO A inhibitor (IC50 8 mg
mL–1). Isatinic acid, which is formed reversibly from isatin in alkaline medium, showed
no inhibition (Fig. 19).

O
OH O
C - COOH

N O
H NH2

Fig. 19. 5-Hydroxy isatin and isatinic acid.

The QSAR (Quantitative Structure Activity Relationship) analysis revealed the re-
quirement of co-planar structure of substitutents at C2 and C3 for selective MAO A inhi-
bition. Hamaue et al. (35) have shown that isatin is an endogenous inhibitor of MAO and
that it has several physiological properties for stress and anxiety following extensive ex-
perimental and clinical investigations. Isatin has an inhibitory effect on acetylcholine es-
terase (AchE). This study elucidated the effect of isatin administered exogenously on the
acetylcholine and dopamine (DA) levels of brain tissues in rats. These results suggest
that endogenous isatin may play a role in regulating the brain levels of acetylcholine by
increasing the level of dopamine. Stress conditions, like acute food deprivation and acu-
te cold exposure, were found to markedly increase the urinary excretion of isatin, as re-
ported by Tozawa and Veki (36).
Sarangapani and Reddy (37) synthesized isatin N-(2-alkyl-benzoxazole-5-carbonyl)
hydrazones and screened them for analgesic, antidepressent and H1-antihistaminic ac-
tivities.
Kennis et al. (38) synthesized hexahydropyrido (4,3-b) indole derivatives.

S N CH3 H H
N
N CH2CH2 N
O H
Fig. 20. Hexahydropyrido (4,3-b) indole derivatives.

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

The compound displayed in Fig. 20. was found to have central dopamine and serotonin
antagonistic activity in the combined apomorphine, tryptamine and nor-epinephrine
test in rats.

CHEMOTHERAPEUTIC ACTIVITIES

Antimicrobial activity. – Varma and Nobles (39) investigated various isatin-N-Man-

nich bases of isatin-3-thiosemicarbazone derivatives against viral, fungal and bacterial
organisms (Fig. 21). Thiosemicarbazones of different carbonyl compounds have shown
antiviral and tuberculostatic activity. Three compounds from this series were toxic to
cancer cells and two compounds were active against Poliovirus type II, against Gram
positive bacteria, fungi and yeast. The same authors (39) synthesized isatin N-Mannich
bases of the structure showen in Fig. 21.

S
R NNHCNH2
R = H, CH3, Br; R1 = piperidino, morpholino,
diethylamino, 3-methyl piperidino
N O
CH2 NR1
Fig. 21. Isatin-3-thiosemicarbazone derivatives.

O
R R = H, Br; R1 = piperidino, morpholino,
N O N(C2H5)2 p-(propylbenzyl)-piperidino
CH2N R1

Fig. 22. Isatin N-Mannich bases.

Nine compounds showed activity against Polio II virus, one compound displayed activ-
ity against four different viruses, two compounds (R = H, R1 = p-propylbenzyl-piperi-
dino; R = Br, R1 = morpholino) showed activity against all four types of organisms (Gram
positive bacteria, Gram negative bacteria, acid fast bacteria, yeast and fungi).
Kupini} et al. (40) synthesized a congenic series of isatin N-Mannich bases and evalu-
ated their antimicrobial activities (Fig. 23).

R2
R3 R1 = H, CH 3, CH2N(CH2CH2OH)2, CH2N(CH2CH2Cl)2,
O CH2C4H8NO, CH2NC5H10; R2 = O, NNHCOCH3,
N NNHCH3, NNHCSNH2, NNHCOOH; R3 = H, NO2
R1
Fig. 23. Isatin N-Mannich bases.

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

Most of the above-synthesized compounds strongly inhibited Gram-negative bacteria

and fungi but only moderately inhibited the growth of Gram-positive bacteria. Three
compounds (R1 = H, R2 = NNHCOCH3, R3 = H; R1 = C2H-C4H8NO, R2 = NNHCSNH2,
R3 = H; R1 = H, R2 = NNHCOOH, R3 = H) were most active against the Gram-positive
bacterium Micrococcus flavus.
A series of 5-haloisatins were amino methylated in position 1 and hydrazino groups
were introduced in position 3 by Maysinger et al. (41). The synthesised N-Mannich bases
and hydrazones were tested against various bacteria and fungi. Halogen in position 5
and an amino moiety in position 1 showed better activity than unsubstituted isatin. The
most biologically active compound was found to be the di-i-propyl amino N-Mannich
base of 5-chloroisatin.
Daisley and Shah (42) investigated the antimicrobial and antifungal activities of a
series of 5-nitro-3-phenyl iminoindol-2-(3H)-ones and their 1-piperidino methyl analo-
gues (N-Mannich bases). Growth inhibition of Gram positive bacteria was observed
with little or no activity against Gram negative bacteria. Antifungal activity was absent.
Dilber et al. (43) synthesized many isatin and N-alkylisatin derivatives by the Re-
formatsky reaction (Fig. 24). The synthesized compounds were screened against Esche-
richia coli, Staphylococcus aureus and Saccharomyces cerevisiae. Two compounds were found
to be active against S. aureus and E. coli.

OH R2
C R3
COOR 4 R1 = H, CH3, C2H5; R2 = H, CH3; R3 = H, CH3;
O R4 = C2H5, 5-butyl, t-butyl
N
R1
Fig. 24. N-alkylisatin derivatives.

Pandeya and Sriram (44) synthesized Schiff bases of isatin and its derivatives with
trimethoprim and their N-Mannich bases (Fig. 25). All the synthesized compounds sho-
wed good activity against Vibrio cholerae, Shigella boydii, Enterobacter faecalis and Edward-
siella tarda with MIC (Minimum Inhibitory Concentration) in the range of 10–25 mg mL–1.
Some compounds were found to be active against Salmonella typhi and Vibrio cholerae
0139; two compounds inhibited HIV-1 (IIIB) with EC50 of 7.6 and 12.3 mg mL–1.
Pandeya et al. (45) synthesized Schiff bases of isatin and 5-methyl isatin with sul-
fodoxine (Fig. 25).
All the compounds showed notable activity when compared to sulphadoxine. The
piperidino methyl compounds were found to be the most active ones in the series. Six
compounds were active against Candida albicans, Candida neoformis, Histoplasma capsula-
tum, Microsporum audounii and Trichophyton mentagrophytes at a concentration of 100 mg
mL–1. The compound containing piperidino methyl group showed appreciable activity
(10%) against the HIV-2 (ROD) strain.
Mannich bases of ciprofloxacin and lomefloxacin were synthesized by Pandeya et al.
(46). Isatin Mannich bases of ciprofloxacin were equivalent or more potent than cipro-
floxacin against E. coli, V. cholerae, Staphylococcus epidermidis, Klebsiella pneumoniae and

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S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

OCH3
N
R N CH2 OCH3
N OCH3
N O

CH2 R1
1
R = N(CH3)2, N(C2H5)2, morpholino, piperidino, pyrrolidino, sulphamethoxazolo

N
R
N SO 2 NH N

H3CO OCH3
N O

CH2 R1
R = H, CH3; R1 = N (CH3)2, N(C2H5)2, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, pyrimethamine

Fig. 25. Schiff bases of isatinderivatives with trimetoprim and sulfodoxine.

Pseudomonos aeruginosa. Mannich bases of lomefloxacin were equipotent to those of lo-

mefloxacin (Fig. 26).
Pandeya et al. (47) reported the synthesis of N-[4-(4'-chlorophenyl) thiazol-2-yl] thio-
semicarbazide Schiff base of isatin and its 5-chloro and 5-bromo derivatives. N-Mannich
bases of these compounds were also synthesized. Antimicrobial activity of compounds
was tested against 28 pathogenic bacteria and 8 pathogenic fungi, and anti-HIV activity
against HIV-1 (IIIB) in MT-4 cells. 1-[N,N-dimethylaminomethyl]-5-bromoisatin-3-{1'-[4''-
-(p-chlorophenyl)thiazol-2''-yl]thiosemicarbazone} showed the most favourable activity.
The same group (48) reported the synthesis of N-(6-chlorobenzthiazol-2- yl) thiosemicar-
bazide Schiff base of isatin and its N-Mannich bases. Antimicrobial activity of the above
compound against 25 pathogenic bacteria was investigated. Results indicated that 1-[N,N-
dimethylaminomethyl] isatin-3-[1'-(6''-chlorobenzothiazol-2''-yl) thiosemicarbazone was
the most active among the synthesized compounds.
Synthesis, antimicrobial and anti-HIV evaluation of 3-amino-2-methyl mercapto qui-
nazolin-4-(3H)-one Schiff bases of 5-chloro, 5-bromo isatins and their N-Mannich bases

R O
O
R1
N O F COOH

CH2 N N

R2 R3
R = R1 = H, CH3; R2 = H, F; R3 = C2H5, cyclopropyl

Fig. 26. Isatin Mannich bases of ciprofloxacin and lomefloxacin.

38
S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

were reported by Pandeya et al. (49). 5-Chloro-3-(3',4'-dihydro-2'-methyl-mercapto-4-oxo-

quinazolin-3'-yl)-1-morpholino methyl imino isatin was reported to be the most active
antimicrobial agent among the compounds synthesized. None of them showed appre-
ciable anti-HIV activity.
Pandeya et al. (50) investigated antimicrobial and anti-HIV activity of 3-(4'-pyri-
dyl)-4-amino-5-mercapto-4-(H)-1,2,4-triazole Schiff base and N-Mannich bases of isatin.
Among the synthesized compounds, 1-(piperidino methyl)-3-bromo-[3’-(4''-pyridyl)-5'-
-mercapto-4'(H)-1',2',4'-triazol-4'-yl] imino isatin showed the most favourable antimicro-
bial activity. None of them showed appreciable anti-HIV activity.
Methisazone (N-methyl isatin-3-thiosemicarbazone) (Fig. 27) was found to be an ef-
fective compound against variola and vaccinia viruses (51).

NNHC NH2
S
N O

CH3
Fig. 27. Methisazone (N-methyl isatin-3-thiosemicarbazone).

As given by Teitz et al. (52), N-methyl isatin-b-4',4'-diethylthiosemicarbazone and

N-allyl-b-4',4'–diallyl thiosemicarbazone (Fig. 28) have shown inhibition of HIV by their
action on reverse transcriptase and viral structural proteins.

S S
C2H5 CH2CH = CH2
N NHC N N NHC N
C2H5 CH2CH = CH2

O N O
N
CH3 CH2 CH = CH2

Fig. 28. Isatin thiosemicarbazone derivatives.

Webber et al. (53) reported the design, synthesis and biological evaluation of reversi-
ble, non-peptidic inhibitors of human rhinovirus (HRV) 3 C protease (3CP). A novel se-
ries of isatins were designwed (Fig. 29).

R R = H, Cl, I, NO2, COOH, COCH3, CN, CONH2,

O CONHCH3, CON(CH3)2, CSNH2COCH3, OSCH3;
R1 = CH3, CH2-CH=CHC6H5, CH(CH2)3, C6H5,
N O CH2C6H5, CH2, CH2-b-naphthyl, CH2(4-CH3-C6H4),
1 CH2(3,4-(CH3)2-C6H3), CH2(3-OCH3-C6H4), CH2(3,5
R (OCH3)2-C6H3)

Fig. 29. Isatine derivatives – reversible inhibitors of rhinovirus 3CP.

39
S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

All the compounds were tested for inhibition of purified HRV-14 3CP. Three compounds
(R = CONH2, R1 = CH3 or CH2 = CHC6H5 or CH2(4-CH3-C6H4) were found to have ex-
cellent selectivity for HRV-14 3CP compared to other proteolytic enzymes, including
chymotrypsin and cathepsin B.
Britcher and Susan (54) synthesized 3-substituted heterocyclic inhibitors of HIV re-
verse transcriptase (Fig. 30).

O X
X = halo, NO2, cyano, C1-4 alkoxy or alkyl-
S amines, sulfonamido, C1-4 alkyl bearing 0-3
O
X Het halo, n = 0-5, Het = stable 4-6 membered un-
saturated mono cyclic heterocycle with 1-4 of
NH N, O, S and P

O C6H5
S N
O

N
NH H

Fig. 30. 3-Substituted heterocyclic inhibitors of HIV reverse transcriptase.

Optionally, oxidized at N and S and/or substituted, those indols and their pharma-
ceutically acceptable salts are useful as inhibitors of HIV reverse transcriptase, preven-
tion or treatment of HIV infection.
HIV protease inhibitors were disclosed by Vacca et al. (55) (Fig. 31).

O R1 R6 R3
N R5
R4
R2 R6
R1; R2 = H, alkyl, aryl, R3= unsubsti-
tuted benzyl, etc.; R4 = alkyl, amino,
N etc.; R5 = (hydroxyindanyl), amino,
OH C 6 H5
N H isoquinolyl), amino; R6 = hydroxy-
N N OH amino

CONHC(CH3)3

Fig. 31. HIV protease inhibitors.

Artico et al. (56) prepared 1H-pyrrol-1-yl and 1H-indol-1-yl aryl sulfones for treat-
ment of HIV-1 infections.

40
S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

Anticancer activity. – Popp and Pajouhesh (57) synthesized 3-o-nitrophenyl hydra-

zones of isatin by condensation of isatin with o-nitrophenyl hydrazine (Fig. 32). These
compounds were found to be active intramuscularly against Walker carcinoma-256 and
inactive against L-1210 lymphoid leukaemia.

N - NH R = H, 1-CH3, 1-COCH3, 4-CF3, 5-Br, 5-Cl, 5-F,

R 5-OCH3, 5-CH3, 5-NO2, 5-SO3H, 7-Cl, 7-CH3,
O NO2 4-Cl-7-OCH3, 6-Cl-5-OCH3, 4-Cl-7-CH3, 4,7-(Cl)2,
N
H 5,7-(Cl)2, 4,7-(CH3)2, 5,7-(CH3)2, 6,7-(CH3)2

Fig. 32. 3-o-Nitrophenyl hydrazones of isatin.

A novel series of 5-(2-oxo-3-indolinyl) thiazolidine-2,4-dione having positions 1 and

3 of the isatin and thiazolidine rings, respectively, substituted by various Mannich bases
were prepared by Eshba and Salama (58) (Fig. 33).

O CH3
N CH2 N
CH3
Br N
S O

N O

CH2 N CH3
CH3
Fig. 33. 5-(2-Oxo-3-indolinylidine) thiazolidine-2,4-dione.

Five compounds were evaluated for antileukaemic activity against p388 lymphocytic
leukaemia in the mice. The di-Mannich base with a dimethyl amino component exhib-
ited the highest activity of the tested compounds. Introduction of bromine into the aro-
matic moiety of the isatin ring at position 5 increased the activity among the parent mo-
lecule to a smaller extent.
Teitz et al. (59) studied the selective repression of V-alb coded protein (P120) on onco-
gene product associated with tyrosine kinase activity by N-methylisatin-4',4'-diethyl thio-
semicarbazone and N-allyl-isatin-4',4'-diallyl thiosemicarbazone. These compounds se-
lectively suppress the V-alb oncogene as well as moloney murine leukaemia virus (Fig. 28).
Broadbent et al. (60) reviewed the chemistry and pharmacology of indole-3-carbinol
and 3-methoxymethyl indole; they showed antimutagenic, anticarcinogenic properties
against a variety of classes of carcinogens and acted as anticancer agents against certain
common neoplasms.

MISCELLANEOUS ACTIVITIES

Antitubercular activity. – Ramachandran (61) synthesized 1-nonyl-7-phenyl-1H-in-

dol-2,3-dione and the MIC against Mycobacterium tuberculosis was £ 20 mg mL–1.

41
S. N. Pandeya et al.: Biological activities of isatin and its derivatives, Acta Pharm. 55 (2005) 27–46.

Varma and Pandeya (62) synthesized 3-[p-(p-(alkoxycarbonyl)-phenyl)carbamoyl)]

phenyl)imino-1-aminomethyl-2-indolinones and investigated their antitubercular activ-
ity against M. tuberculosis H37Rv (Fig. 34).

N CONH COOR

X = O, CH2
N O
R = CH3, C2H5, n-propyl, n-butyl
CH2 N X

Fig. 34. 3-[p-(p-(Alkoxycarbonyl)-phenyl)carbamoyl)] phenyl)imino-1-aminomethyl-2-indolinones.

Nine compounds have shown complete inhibition of the growth of M. tuberculosis

H37Rv with MIC ranging from 10 to 20 mg mL–1.
Collino and Volpe (63) synthesized Mannich bases of isatin with dipiperidine. The
synthesized compounds had fibrinolytic (5 mg kg–1 in mice), muscle relaxant, antialler-
gic, antihistaminic, immunosuppressant and antithrombotic activities.
Inhibitor of glucose, aminoacid uptake. – Gargari et al. (64) have shown that isatin com-
petitively inhibited (27–40%) Na+- dependent L-Lysine uptake in rat intestine. Isatin was
unaffected by SH group reacting agents. Isatin (1–10 mmol) inhibited Na+, K+- ATP-ase
in the intestine in vitro, but the drug had no effect on enzyme activity under in vivo con-
ditions.
Hota and Acharya et al. (65) studied the possible peripheral actions of isatin. The re-
sults showed spasmogenic responses of isatin on guinea pig, rat and rabbit ileum and
rat stomach fundus. Histamine induced bronchoconstriction could be antagonized by
isatin. Isatin had a cardioinhibitory effect on isolated frog heart, and hypotensive, respi-
ratory depressant and antidiuretic effects; it was devoid of any effect on inflammation
and gastric activities. However, the present results suggest a possible involvement of
heterogenic 5-HT3 receptor in GI smooth muscle.

CONCLUSIONS

Isatin molecule is the most versatile moiety having diverse types of biological acti-
vity; exploitation of this moiety in antiviral and anticonvulsant area will be especially
fruitful.

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S A @ E TA K

Farmakolo{ko djelovanje izatina i njegovih derivata

SURENDRA NATH PANDEYA, SIVAKUMAR SMITHA, MAYANK JYOTI i SESHAIAH KRISHNAN SRIDHAR

Izatin je endogeni spoj prisutan u organizmu ~ovjeka koji posjeduje niz farmako-
lo{kih u~inaka. Izatin djeluje kao antioksidans, sedativ i antikonvulziv. In vitro je sna`ni
antagonist na receptorima za natrijeve ione u atriju. Serija p-supstituiranih semikarba-
zona izatina pokazala je antikonvulzivno djelovanje u MES, scPTZ i scSTY testovima, a
N-Mannichove baze izatina i izatin-3-tiosemikarbazona virustatsko i tuberkulostatsko
djelovanje. Metisazon je u~inkovit protiv infekcija variola i vakcinia virusima. EC50 N-di-
metil i morfolino derivata 5-metilizatina i trimetoprima ve}i je od 4,3, odnosno 17,7 mg
mL–1. Izatin (3-o-nitrofenilhidrazon) inhibira rast tumorskih stanica Walker-256, a sups-
tituirani indolinoni su aktivni protiv M. tuberculosis H37Rv (MIC vrijednosti 10-20 mg
mL–1). Mannichove baze izatina su fibrinolitici, miorelaksansi, antihistaminici, imuno-
supresivi i antitrombotici, te djeluju protiv filarija. Izatin ima kardioinhibitorni u~inak
na srce `abe, a djeluje i kao hipotenziv, depresor respiracije i antidiuretik.

Klju~ne rije~i: izatin, Mannichove baze, semikarbazoni, antikonvulzivno, antimikrobno i tuberkulo-

statsko djelovanje

Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi-221 005

India

Department of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, Allahabad Agricultural
Institute-Du, Allahabad-211 007, India

C. L. Baid Mehta College of Pharmacy, Jothi Nagar, Thorapakkam, Chennai-600 096, India

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