Abstract
We
report here novel Schiff bases of 5-substituted-1H Indole-2, 3 Dione comparing
modified with aromatic primary amine and hydrazine. A recombinant with Mannich
base has been synthesized. A structure of the synthesized compounds was
analyzed for structure confirmed by mass spectral data. Compound 1a-p has
screened for anti-convulsant activity, increased in latency time and reduction
in duration of convulsion and standard drug when compared, sodium valporate
300mg/kg. PTZ dose of 90mg/kg produced severe clonic convulsions in 88% of the
mice injected, with a mean onset time of 3.61 ± 0.5 min and 80% mortality.
Clonic convulsive activity lasted 2.3±0.45 min and has postictal period of
decreased motor activity and subsequently. Test result revealed that compounds
at dose of 300 mg/kg, the severity and duration of the convulsive episode
following PTZ has not observed.
Keywords: 1H Indole-2, 3 Diones; Schiffs base; Mannich
base; Anti-convulsant
Introduction
Epilepsy
has accepted group of disorders in which there are recurrent episodes of
altered cerebral function associated with paroxysmal excessive &
hypersynchronus discharge of cerebral neurons [1]. The clinical accompaniments
of those episodes seizures vary in manifestation from brief lapses of awareness
to prolonged bouts of unconsciousness incontinence. It has episode of
neurological dysfunction a seizure. Isatin (1H-indole-2, 3-dione) and scaffold
demonstrated a diverse array of biological activities. It has 5-halo
derivatives have reacted to form the Schiff’s base, Mannich bases to form C-N,
C=N bonds, from the spectral studies, Isatin undergo reaction at C-3 and N-1
position and showed the anti-convulsant activity.
R & D of Iso nitroso acetanilide (Scheme I)
In round bottom flask took 9g (0.05 moles) of chloral hydrate in 86 mL of water added mixture 7g of sodium sulfate and solution of 3.1g (0.03moles) of aniline (4-halo substituted derivatives) in 30mL of water containing 4-5 mL of HCl added (dissolved amines). Finally, the solution of hydroxylamine in 50 mL of water added in the flask. Heat the mixture at 45 0C to dissolved precipitate and then boiled the solution vigorously for 1-2 min. Cooled the solution to room temperature. The precipitate obtained has filtered off. The yield has 80% (Scheme 1).R & D of 5-Substituted-Indole-2, 3 Dione (Scheme I)
Heat
the 3 mL of concentrated Sulphuric-acid at 70 0C. To this added 1 g of iso
nitroso acetanilide with vigorous stirring. Heat the mixture to 80 0C for 1-2
min. Cool the mixture at room temperature. Added the 3-4 piece of ice or
crushed ice having volume 3-4 times greater than the mixture with vigorous
stirring, Yields was 72% melting point of different 5-substituted Isatin. 5-Cl-
Isatin- 254-256Co, 5 NO2-Isatin- 180-182 Co, 5-Fl-Isatin-224-226 Co,
5-I-Isatin-280-282 Co, 5-CH3-Isatin- 264-266 Co.
R & D of Schiff’s bases of different 5-substituted 1-H-indole
-2, 3-dione (Scheme II) (1a-p)
Equimolar
quantities (0.004 mol) of isatin/5-substituted isatin and the aromatic primary
amine/hydrazine has dissolved in 10 mL of warm ethanol and heated on a steam
bath for 20-40 min. standing for approximately 24 h at room temperature, the
crystalline product has separated by filtration, vacuum dried and
recrystallized from ethanol (Scheme 2).
R & D of different Mannich base from Schiff’s base of different 1-H-Indol -2, 3-Dione (Scheme II) (1a-p)
Molar
absolute (0.004 mol) of diphenyl amine in 10mL of ethanol has added to slurry
containing the appropriate isatin and aqueous formaldehyde solution dissolved
in 10mL of ethanol. The reaction mixture has magnetically stirred for 1 h at
room temperature and refrigerated for 48h. The product has separated by suction
filtration, vacuum dried and recrystallized from ethanol. Final compound with
their respective substitution of groups describe in Table 1 and physicochemical
data of synthesized more novel 5-substituted 1-H-Indole-2,3-Dione described in
Table 2.
Preparation of Solutions
The
PTZ solution (90 mg/kg) has prepared in saline solution. Sodium valporate
(300mg/kg), has used as standard drug. Various test compounds have suspended in
carboxy methyl cellulose (0.5%), suspensions have prepared freshly prior to the
dosing.
Selection of Animals
Albino
female mice of Wister strain weighing around 25- 35gm has collected and housed
at the animal house in groups of six animals per cage at standard laboratory
conditions at room temperature with 12:12 h light and dark cycle. All the animals
have fed on standard laboratory diet and free access of water. The scientific
animal ethical committee approved the present animal protocol [2]. The selected
animals have kept in the cages for a week prior to dosing for all the
limitations of the laboratory conditions.
Acute Toxicity Studies
LD50
of test compounds have performed as per the O.E.C.D guideline 423. Test
compounds have suspended in 0.5% CMC solution. The compounds have administered
orally at a dose level of 500,750 1000 and 1500 mg/kg body weight, to groups of
6 animals. After administration of test compounds, the mice have observed for
gross behavioral neurological autonomic and toxic effects (3). The
toxicological effects have observed in terms of mortality. No death occurred
within 24h of dose of 500 and 1000mg/kg but at a dose of 1500mg/kg 50%
mortality was observed. As dose was increased further up to 4000mg/kg, total
mortality was found. Hence 1000 mg/kg dose was considered as LD50. 1/10th of
the LD50 was considered as an effective dose i.e.150 mg/kg.tg
Evaluation of antiepileptic activity (PTZ model)
The
compounds synthesized in the present investigation has subjected to
pharmacological screening, to ascertain their anticonvulsant activity. The
anti-convulsant activity was evaluated by using PTZ induced convulsion mice
models [4,5]. In this method convulsion produce by intraperitoneal
administration of pentylinetetrazole (PTZ) solution prepared in saline (90mg/
kg, 10mL/kg) was recorded over a period of 30 min, after pentylinetetrazole
injection. The mice were treated orally with test (50,100,150,300mg/kg)
suspended in 0.5% CMC or standard drug (sodium valporate 300 mg/kg, diazepam
4mg/kg, phenytoin 30mg/ kg), 30 min before i.p. injection of
pentylinetetrazole. The time of convulsant recorded and permitted to express
the protection of mice. The evaluations of anti-convulsant of the compounds has
been listed in Table 3.
Statistical Analysis
All
the results have expressed as Mean + S.D and has subjected to student t-test
using Graph-pad prism 4 software. Values have considered as significant when
P< 0.05.
Results and Discussion
Synthesis
of 5-substituted-1H Indole-2, 3 Diones have done by extended Sandmeyer method
from Cl, NO2, I, CH3 and F aniline. The synthesized compounds have purified in
ethanol. All these spectral analysis data showed the authenticity of the
structure of the synthesized compounds. The mass spectra of compounds 1a-p
showed molecular ion peaks M+ at m/z corresponding to their respective
molecular masses, which agrees with their respective molecular formulas
recorded in the Table 4. Anticonvulsant activity of the compounds 1b, 1c, 1f,
1h, 1j, 1l, 1m, 1n, 1o, 1p has examined using PTZ induced convulsion mice
models. In this method convulsion produce by intraperitoneal administration of
pentylinetetrazole (PTZ) solution prepared in saline (90mg/ kg,10 mL/kg) has recorded
over a period of 30 min, after pentylinetetrazole injection. The mice have
treated orally with test (50,100,150,300mg/kg) suspended in 0.5% CMC or
standard drug (sod. valporate 300 mg/kg), 30 min before i.p. injection of
pentylinetetrazole. The time of convulsant recorded and permitted to express
the protection of mice. The evaluations of anti-convulsant of the compounds
have listed in Table 5.
Conclusion
It
can be concluded that the Schiff and N-Mannich base of 5-substituted-1H
Indole-2, 3 Diones has synthesized easily. The pharmacological screening has
done by pentylenetetrazole (PTZ) induced convulsion method, for this Sodium.
Valporate (300 mg/ kg) has used as reference standard. Test compound has given
to mice in different doses (50,100,150,300 mg/kg). The result suggested that
all the compounds possess good anti-convulsant activity with increased in
latency time and reduction in duration of convulsion as like the standard drug
when compared Table 3. All tested compound shows moderate effect at 150 mg/kg
dose and significantly effective at 300mg/kg dose. It concluded that the
synthesized Schiff and N-Mannich isatin derivatives have shown excellent
anti-convulsant activity.
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