Development of Isatin as CNS Agents: Anticonvulsant activity
©2014
Textbook
54 Pages
Summary
The present study was aimed at synthesizing isatin-5-sulphonamide derivatives are prepared by chlorosulphonation of isatin to prepare isatin-5-sulphonic acid chloride and it is subjected to reaction with different amines or anilines to form respective sulphonamide derivatives. The new compounds were characterized based on spectral (FT-IR, NMR and Mass) analysis. All the test compounds showed CNS depression while studying the gross behavioral changes. All the test compounds exhibited reduction in locomotor activity. Compound IIIf (R = p-toluidino) showed more reduction in the locomotor activity among all the test compounds. Compounds IIId, IIIc, IIIb, IIIa were next in the order of reduction of locomotor activity. The compounds were evaluated for anticonvulsant activity against maximum electric shock induced and Pentylenetetrazol (PTZ) induced seizures in mice using phenytoin as a standard.
Excerpt
Table Of Contents
2
A general observation reveals that the nature of final product always depends
on the experimental conditions and substituents on nitrogen atom which may affect
the electron density at
and carbonyl carbon atoms respectively
4
.
Synthesis of Isatins
The Sandmeyer methodology :
The method developed by Sandmeyer is the oldest and the most frequently
used for the synthesis of isatin. It consists of, reaction of aniline with chloral hydrate
and hydroxylamine hydrochloride in aqueous sodium sulfate to form an
isonitrosoacetanilide, which after isolation, when treated with concentrated sulfuric
acid, furnishes isatin (1) in >75% overall yield (Guo and Chen, 1986). This method is
applied mostly well to anilines with electron-withdrawing substituents, such as 2-
fluoroaniline
5
.
(1)
NH
2
Cl
3
CCH(O H)
2
NH
2
OH.HCl
Na
2
SO
4
N
H
O
NOH
1) H
2
SO
4
2) H
2
O
N
H
O
O
R
R
R
Scheme-1
In addition to the use of H
2
SO
4
for the cyclization step, isonitrosoacetanilides
is heated in BF
3
.Et
2
O at 90
o
C. After cooling the reaction mixture, addition of water
allows isolation of the respective isatins. This methodology has been proved to be
particularly effective for the preparation of benzo-oxygenated isatin derivatives
6,7
.
3
The Stolle Procedure
The most important alternative to Sandmeyer's procedure is the method of
Stolle. In this method anilines react with oxalyl chloride to form an intermediate
chloro-oxalylanilide which can be cyclized in the presence of a Lewis acid, usually
aluminium chloride or BF
3
.Et
2
O, although TiCl
4
has also been used to give the
corresponding isatin. This method has been used for the synthesis of 1-aryl
8
and
polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine
9
as
well as indoline
10
. In the case of dimethoxyanilines, spontaneous cyclization to yield
dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in
the synthesis of melosatin A (2), albeit in very low yield (Scheme-2).
AlCl
3
or BF
3
.Et
2
O
Melosatin A
MeO
OMe
N
O
O
H
(COCl)
2
MeO
OMe
NH
2
(2)
Scheme-2
The Martinet Isatin Synthesis
The Martinet procedure for the synthesis of indole-2,3-diones involves the
reaction of an aminoaromatic compound 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 (3). This
method was applied successfully for the synthesis of 5,6-dimethoxyisatin from 4-
aminoveratrole whereas the use of 2,4-dimethoxyaniline was less successful
11
(Scheme-3).
4
(3)
O
O
NH
2
O
O
N
H
O
HO
CO
2
R
O
O
N
H
O
O
HCl
-CO
2
Scheme-3
The Martinet procedure is readily applied to naphthylamines, thus yielding
benzoisatin derivatives
12
.
The Gassman Procedure
A fundamentally different and general procedure developed by Gassman is
another option for the synthesis of isatins
13
. This methodology consists in the
formation and subsequent oxidation of an intermediate 3-methylthio-2-oxindole to
give the corresponding substituted isatins (4) in 40-81% yield.
Two complementary methods for the synthesis of the 3-methylthio-2-
oxindoles were developed, and the methodology of choice is dependent upon the
electronic effect of substituents bonded to the aromatic ring. When electron-
withdrawing groups are present, the oxindole derivative can be synthesized via N-
chloroaniline intermediate, which further reacts with a methyl thioacetate ester to
furnish an azasulfonium salt (Method 1, Scheme 4). In the case of electron-donating
groups that destabilize the N-chloro intermediate, and thus give diminished yields of
the azasulfonium salt, a second method of generation of this salt, by reaction of the
5
chlorosulfonium salt with an appropriate aniline, gives better yield of the 3-
methylthio-2-oxindoles.
NH
2
X
1) tBuOCl
2) MeSCH
2
CO
2
Et
3) Et
3
N; 4) H
3
O
+
X
N
H
O
SMe
S
CO
2
Et
Cl
Cl
2) Et
3
N; 4) H
3
O
+
1)
Method 1
Method 2
NCS
N
H
O
Cl
SMe
X
HgO/BF
3
or
H
2
O / THF /
X
N
H
O
O
(4)
Scheme-4
6
Reactions of Isatin :
The reactive carbonyl group at position-3 undergoes typical reactions with the
ketonic reagents such as hydroxylamine
14
, phenyl hydrazine
15
and semicarbazide
16
.
The carbonyl group at position-2 is less active and has less ketonic character
compared with carbonyl group at C
3
.
[X = O, S]
Ar = H, alkyl, aryl, acyl
N
H
NNHCNH
2
O
X
N
H
NNHAr
O
N
H
NOH
O
NH
2
NHCNH
2
X
ArNHNH
2
NH
2
OH
N
H
O
O
(5)
(6)
(7)
(8)
Schiff Bases :
Isatin reacts with a variety of aromatic amines
17
in the presence of glacial
acetic acid to yield Schiff bases (9) (azomethines, imines, anils).
N
H
O
O
H
2
N
Ar
CH
3
COOH
N
H
N
O
Ar
Isatin-3-imine
(9)
7
Mannich Reaction
18
:
Isatin reacts with formaldehyde and a variety of amines in the Mannich
reaction to give their respective Mannich bases (10), in the absence of an amine, isatin
and substituted isatin with formaldehyde give hydroxymethyl isatins (11).
(11)
(10)
Mannich reaction
N
O
O
CH
2
OH
N
O
O
CH
2
N
R
R
N
O
O
H
HCHO
HCHO
HN
R
R
Other Reactions of Isatins
a) Electrophilic Substitution and Related Reactions :
Reaction of Isatin and haloisatins with chlorosulfonic acid gave 5-
chlorosulfonylisatin which were then converted into sulfonamides
19
.
Nitration of isatin
20
, 7-methyl isatin, 4,7-dimethyl isatin
21
and 1-ethyl isatin
22
leads to the introduction of the nitro group into the 5-position. Nitration of 5-methyl
isatin gave 5-methyl-7-nitro isatin
24
.
8
Pharmacology of Isatin
25
:
Isatins are endogeneous compounds identified in human and rat tissues. Isatin
is a well known pharmacological agent having a range of action in the brain and also
protective against certain types of infections.
Isatin contains indole nucleus as that of 5-HT transmitter and is expected to
have CNS activity.
Physiologically CNS is divided into following parts
26
:
Medulla oblongata
Pons
Midbrain
Thalamus
Gray and white matter
(Basal ganglia)
Brain stem
Cerebellum
Cerebrum
Spinal cord
Brain
CNS
9
The human brain has about 100 billion nerve cells, also called neurons.
Neurons carry signals around the brain and between the brain and the rest of the body.
Each neuron produces electrical signals, but chemicals called neurotransmitters are
responsible for spreading them
27
.
10
The important neurotransmitters of the central nervous system
28
Name Predominant
activity
-Aminobutyric acid (GABA)
Inhibitory
Glycine
Inhibitory
Aspartate
Excitatory
Acetylcholine
Inhibitory
Dopamine
Inhibitory
Norepinephrine
Inhibitory
Epinephrine
Complex
5-Hydroxytryptamine (5-HT)
Inhibitory
Histamine
Complex
The drug acting on CNS are divided into two types
29
:
CNS depressants
· General
Anaesthetics
·
Anxiolytic, sediative and hypnotic agents
· Antipsychotics
·
Anticonvulsant (or) antiepileptic drugs
Central Nervous System Stimulants
· Analeptics
· Methylxanthines
·
Central sympathomimetic agents (Psychomotor stimulants)
11
Mechanism of action of CNS Drugs
30
·
Intereference with the action-potential in the pre-synaptic fibre
Eg : sedative & hypnotic
·
Inteference with ion-channels in pre-or postsynpatic membrane.
Eg : General anaesthetics
·
Interference with the synthesis or storage of neurotransmitter.
Eg : Reserpine depletes NA
·
Intereference with the release or the metabolism of neurotransmitter
Eg : Antidepressants inhibit the enzyme MAO.
·
Blockade of the reuptake of the neurotransmitter. Eg : antidepressants inhibit
the reuptake of NA or 5-HT.
·
Stimulation or inhibition of specific receptors. Eg : Phenothiazine
EPILEPSY
Epilepsy, characterized by the periodic and unpredictable occurrence of
seizures is the most prevalent neurological disorder
31
. Approximately 1% of the
world's population has epilepsy, the second most common neurological disorder after
stroke. Although standard therapy permits control of seizures in 80% of these
patients, millons (500,000 people in the USA alone) has uncontrolled seizures
32
.
The term seizure refers to a transient alteration of behaviour due to the
disordered, synchronous and rhythmic firing of populations of brain neurons
33
. The
term epilepsy refers to a disorder of brain function characterized by the periodic and
unpredictable occurrence of seizures.
12
Seizures can be "nonepileptic" when evoked in a normal brain by treatments
such as electroshock or chemical convulsants or "epileptic" when occurring without
evident provocation.
Based on the type of behavior and brain activity, seizures are divided into two
broad categories, generalized and partial (also called local or focal)..These two
categories include many individual types, usually identified by the kind of behavior
the seizure produces.
Types of generalized seizures
34
Types of partial seizures
· Grandmal
seizures
· Simple partial seizures
· Absence
seizures
· Complex partial seizures
· Myoclonic
seizures
· Focal seizures
· Clonic seizures
· Tonic seizures
· Atonic seizures
Generalized seizures are produced by electrical impulses from throughout the
entire brain, whereas partial seizures are produced (at least initially) by electrical
impulses in a relatively small part of the brain
35
.
Generalized seizures
(produced by the entire brain)
Symptoms
1.Grandmal or generalized
tonic-clonic
Unconsciousness, convulsions, muscle rigidity
2.Absence
Brief loss of consciousness
3.Myoclonic
Sporadic (isolated), jerking movements
4.Clonic
Repetitive, jerking movements
5.Tonic
Muscle stiffness, rigidity
6.Atonic
Loss of muscle tone
13
Partial Seizures
(Produced by a small area of brain)
Symptoms
1.Simple
(awareness is retained)
a. Simple Motor
b. Simple sensory
c. Simple psychological
a. Jerking, muscle rigidity ,spasms, head-
turning
b .Unusual sensations affecting either the
vision, hearing, smell taste or touch.
c. Memory or emotional disturbances.
2.Complex (impairment of
Awareness)
Automatisms such as lip smacking, chewing,
fidgeting, walking, and other repetitive,
involuntary but coordinated movements.
3.Partaial seizure with secondary
Generalization
Symptoms that are initially associated with a
preservation of consciousness that than
evolves into a loss of consciousness and
convulsions.
ANTIEPILEPTICS AGENTS
36
.
Pharmacological agents in current clinical use inhibit seizures, and thus
referred to as antiseizure drugs . Wheather any of these agents has prophylactic value
in preventing development of epilepsy (epileptogenesis) is uncertain.
Accordingly antiepileptic may be classified as follows
37
:
1. Drugs inhibiting Na+ channels :
(a) Phenytoin, Fosphenytoin, Ethotoin, Mephenytoin
(b) Lamofrigine, Topiramate
(c) Carbamezepine
2. Drugs affecting Ca++ channels
(a) Flunarizine
(b) Ethosuccinimide, Phensuccinimide, Methsuccinimide
Details
- Pages
- Type of Edition
- Erstausgabe
- Year
- 2014
- ISBN (eBook)
- 9783954897797
- ISBN (Softcover)
- 9783954892792
- File size
- 1 MB
- Language
- English
- Publication date
- 2014 (May)
- Keywords
- development isatin agents anticonvulsant
