international journal of innovative pharmaceutical...

RESEARCH ARTICLE Touseef Begum et.al / IJIPSR / 3 (4), 2015, 232-243

Department of Pharmaceutical Chemistry ISSN (online) 2347-2154

Available online: www.ijipsr.com April Issue 232

SYNTHESIS OF NEW 1-(1, 3-DIOXOISOINDOLIN-2-YL)-3-[(Z)-

SUBSTITUTED BENZYLIDENE] UREA AND THEIR

ANTICONVULSANT ACTIVITY

1Touseef Begum*,

2Shibeer A. Bhat,

2Suroor A. Khan,

1Ibn Sina National College for Medical Studies, Ghulail, Jeddah-21418, SAUDI ARABIA

2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi -

110062, INDIA

Corresponding Author

Dr.Touseef Begum

Assistant Professor

Ibn Sina National College for Medical Studies

Jeddah-21418, SAUDI ARABIA

Email: [email protected]

Mobile: +966504364909

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

A new series of 1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)-substitutedbenzylidene] urea 4 (4a- j) were synthesized by

the reaction of 1-(1,3-dioxoisoindolin-2-yl)urea with various substituted aromatic aldehydes. The structure of the

synthesized compounds was established by spectral data and elemental analysis. All the synthesized compounds

were evaluated for their anticonvulsant activity and neurotoxicity profile in two phases. Phase I included MES,

s.c. PTZ and neurotoxicity test, all the test compounds were administered at doses of 30, 100, and 300 mg/kg

body weight and the anticonvulsant activity was noted at 0.5 h and 4 h time intervals after the drug administration.

Phase II included quantification of the results obtained from phase I in terms of ED50, TD50 and protection

index. The anticonvulsant study revealed that compounds have selectivity for MES screen, the average protection

index values of the MES screen were 4 times the values generated in s.c. PTZ screen. Compound 4h displayed

ED50 values of 23.26 mg/kg and compound 4i displayed ED50 values of 24.32mg/kg in MES test. All the

compounds selected for phase II trial are active at similar concentration to phenytoin, at higher concentration to

carbamazepine and lower concentration then sodium valproate. All the compounds in phase two trial show low

toxicity with high protective index especially for MES screen. The results obtained justify the usage of these

compounds from their promising anticonvulsant activity with lesser neurotoxicity.

Keywords: Anticonvulsant, Epilepsy, Protective index, Neuroprotection.

mailto:[email protected]




INTRODUCTION

Epilepsy is a chronic brain disorder characterized by recurrent derangement of the nervous system

due to sudden excessive disorderly discharge from the cerebral neurons [1]. The long established

AEDs control seizures in 50% of patients developing partial seizures and in 60-70% of those

developing generalized seizures [2-4]. During past decade several new drugs were approved but

despite the advances in the new drug treatment of epilepsy, approved antiepileptic drugs have

dose-related toxicity and idiosyncratic side effects [5]. Thus the search for new anticonvulsant

drugs continues to be an active area of investigation in medicinal chemistry. In recent study 1-(4-

substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea and several new ureas

were synthesized and screened for anticonvulsant [6-8], CNS depressant and sedative-hypnotic

activity in the mice [9]. Several urea derivatives were prepared and tested for anticonvulsant

activity using by pentylenetetrazole-induced seizure (PTZ) and maximal electroshock seizure

(MES) tests [10]. In recent years Schiff bases, have gained much attention due to its wide

spectrum of biological activities like anticonvulsant [11], antifungal, antibacterial [12, 13],

antimalarial [14], antiproliferative, anti-inflammatory [15], antiviral, and antipyretic properties

[16 ]. Schiff bases were synthesized and showed very potent anticonvulsant activity [17, 18]. The

therapeutic importance of these Schiff bases are prompted us to synthesize new 1-(1, 3-

dioxoisoindolin-2-yl)-3-[(Z)-substituted benzylidene] urea using the modification of

isobenzofuran-1,3-dione heterocyclic ring to 1-(1, 3-dioxoisoindolin- 2-yl)- 3- [(Z)-substituted

benzylidene]urea and evaluated them for their anticonvulsant effect using MES[ 19, 20 ] and PTZ

methods[ 21 ]. They were also tested for their neurotoxicity effect by rotorod test [22].

MATERIALS AND METHODS

Chemical and instrumentations

Materials were procured from Sigma–Aldrich. Solvents were obtained from Merck (Darmstadt,

Germany). Melting points (m.p.) were determined in open capillary tubes on a Buchi digital

melting point apparatus and are uncorrected. IR spectra were recorded on KBr disks using Perkin

Elmer 881, FTIR spectrophotometer (νmax in cm-1

). 1H-NMR spectra were recorded on a Bruker

DRX-300 (300 MHz FT-NMR) spectrometer using tetramethylsilane [(CH3)4Si] as the internal

reference (chemical shifts in δ ppm).The splitting pattern abbreviations are as follows s,singlet;

d,doublet; dd,double doublet; t,triplet; q,quartet; m,multiplet; J,coupling constant. Spectral data

consistent with assigned structure. Elemental analysis were performed on a Perkin Elmer model




240 analyser (C, H, N) and found within the range of 0.4% of theoretical values. TLC data

were obtained using aluminium backed sheets with silica gel G254 using a) benzene: acetone (4:1)

and b) benzene: ethylacetate: acetone (10:5:1) as developing solvent systems and the spots were

developed by exposure to iodine vapors.

Synthesis

1-(1,3-dioxoisoindolin-2-yl)urea (3). An equimolar quantity of isobenzofuran-1, 3-dione (1)

14.8g (0.1mole) was refluxed with semicarbazide HCl (2) 11.5g (0.1mole) in 100 mL acetic acid

as a solvent for 4-6 h [23-25]. The reaction mixture was allowed to cool at room temperature .The

product is precipitated by adding cold water. The crude product is filtered, dried and recrystalised

from ethanol as white needles, 10.0 g (86 %), mp 278-280 °C; ir: CO of isoindolin 1669 1680,

CO of urea 1640.00, ArCH 3021.01, secondary amide- NH 3435.10 cm-1

; 1

H-nmr (DMSO-d6):

7.53-8.10 (m, 4H, Ar-H), 6.5 (br s,3H, NH). Anal.Calcd. for C9H7N3O3: C, 52.58; H, 3.56; N,

20.47; O, 23.40 Found C, 52.51; H, 3.46; N, 20.55; O, 23.50.

General procedure for the synthesis of 1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)-substituted

benzylidene] urea 4 (4a- j ). An equimolar quantity of 1-(1,3-dioxoisoindolin-2-yl)urea (3) 2.0 g

(0.01mole) was refluxed with appropriate aldehyde (0.01mole) in 25mL acetic acid for 8 h. The

reaction mixture was allowed to cool and the product was precipitated by adding cold water. The

crude product was filtered, dried and recrystalised from ethanol.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)-2,4-dichlorobenzylidene]urea (4a). This compound was

obtained as colorless needles, 2.3 g (62 %), mp 232-234 °C; ir: CO of isoindolin 1654.32,1670 ,

CN 1610.03, CO of urea 1634.25, CCl 1112, aliphatic CH 2981.05, Ar-CH 3050.03, secondary

amide-NH 3425.05 cm-1

; 1

H-nmr: 7.83-8.09 (m, 4H, Ar-H), 6.99 (d, 2H,J = 8.8Hz,H-3,5,

benzylidene), 7.48 (d, 1H, J = 8.8Hz,H-6, benzylidene), 8.25 (br s,1H, NH-C=O),8.50 (s, 1 H,

N=CH). Anal.Calcd. for C17H12Cl2N3O3: C, 53.12; H, 2.15; Cl, 18.99; N, 11.54; O, 14.21. Found

C, 53.10; H, 2.18; Cl, 18.92; N, 11.62; O, 14.19.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)- 2-chloro,4-nitrobenzylidene]urea (4b). This compound

was obtained as yellow needles, 2.65 g (70 %), mp 247-249 °C; ir (cm-1

): 1648.32,1660 (C=O of

isoindolin); 1612.03 (C=N); 1644.25 (C=O of urea ); 748 (C-Cl); 1524,1339 (NO2); 2970.20

(aliphatic - CH); 3110.03 (Ar-CH); 3375.16 (secondary amide- NH). 1

H-nmr (DMSO-d6): 7.79-

8.07 (m, 4H, Ar-H); 7.56 (d, 2H,J = 8.8Hz,H-3,5, benzylidene); 7.46 (d, 1H, J = 8.8Hz,H-6,

benzylidene); 8.19 (br s,1H, NH-C=O); 8.45 (s, 1 H, N=CH). Anal.Calcd. for C17H12ClN4O5: C,




51.63; H, 2.40; Cl, 9.52; N, 14.48; O, 21.98. Found C, 51.53; H, 2.50; Cl, 9.43; N, 14.58; O,

21.97.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)- 4-hydroxybenzylidene]urea (4c). This compound was

obtained as colorless crystals, 1.9 g (60 %), mp 235-237 °C; ir (cm-1

): 1638.12,1670 (C=O of

isoindolin); 1613.03 (C=N); 1654.25 (C=O of urea ); 3567 (Ar-OH); 2934.28 (aliphatic - CH);

3120.01 (Ar-CH); 3370.18 (secondary amide- NH). 1

H-nmr (DMSO-d6): 7.74-8.09 (m, 4H, Ar-

H); 7.32 (d, 2H,J = 8.8Hz,H-3,5, benzylidene); 7.40 (d, 2H, J = 8.8Hz,H-2,6, benzylidene); 8.10

(br s,1H, NH-C=O); 8.40 (s, 1 H, N=CH). Anal.Calcd. for C17H14N3O4: C, 62.12; H, 3.58; N,

13.61; O, 20.70. Found C, 62.14; H, 3.48; N, 13.71; O, 20.68.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)- 3,4-dimethoxybenzylidene]urea (4d). This compound was

obtained as colourless needle shaped crystals, 2.55 g (71 %), mp 264-266 °C; ir (cm-1

):

1637.12,1671 (C=O of isoindolin); 1612.04 (C=N); 1651.28 (C=O of urea); 1090(C-O-C);

2933.25 (aliphatic - CH); 3125.10 (Ar-CH); 3380.10 (secondary amide- NH). 1

H-nmr (DMSO-

d6): 3.88 ( s, 6H, 2xOCH3); 7.69-8.12 (m, 4H, Ar-H); 7.10 (d, 1H,J = 8.8Hz, H-5, benzylidene);

7.40 (d, 1H, J = 8.8 Hz, H-6, benzylidene); 7.55 (s, 1H, J = 8.8 Hz, H-2, benzylidene); 8.15 (br

s,1H, NH-C=O); 8.36 (s, 1 H, N=CH). Anal.Calcd. for C19H18N3O5: C, 62.01; H, 4.28; N, 11.87;

O, 21.85. Found C, 62.10; H, 4.20; N, 11.86; O, 21.87.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)- 3,4,5-trimethoxybenzylidene]urea (4e). This compound

was obtained as colorless needles, 2.92 g (75 %), mp 268-270 °C; ir (cm-1

): 1638.10,1671 (C=O

of isoindolin); 1615.10 (C=N); 1641.28 (C=O of urea ); 1098(C-O-C); 2934.16 (aliphatic - CH);


H-nmr (DMSO-d6): 3.88 ( s, 9H, 3xOCH3);

7.70-8.02 (m, 4H, Ar-H); 7.49 (s, 2H, H-2,6, benzylidene); 8.10 (br s,1H, NH-C=O); 8.40(s, 1 H,

N=CH). Anal.Calcd. for C20H20N3O6: C, 59.56; H, 4.68; N, 10.76; O, 25.04. Found C, 60.02; H,

4.48; N, 10.45; O, 25.09.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)- 3-methoxy-4hydroxybenzylidene]urea (4f). This

compound was obtained as colorless needles, 2.57 g (74 %), mp 255-257 °C; ir (cm-1

): 3445 (Ar-

OH); 3357.16 (secondary amide- NH); 1635.13,1665 (C=O of isoindolin); 1605.10 (C=N);

1645.30 (C=O of urea); 1076(C-O-C); 2924.19 (aliphatic - CH); 3120.11 (Ar-CH);. 1

H-nmr

(DMSO-d6): 3.83 (s, 3H, OCH3); 7.68-8.15 (m, 4H, Ar-H); 6.90 (d, 1H, J=8.4Hz, H-5,

benzylidene); .7.10 (d, 1H, J=8.4Hz, H-6, benzylidene); .7.39 (s, 1H, H-2, benzylidene); 8.01(br




s,1H, NH-C=O); 8.42(s, 1 H, N=CH);9.37(s,1H, OH). Anal.Calcd. for C18H16N3O5: C, 60.21; H,

3.96; N, 12.25; O, 23.59. Found C, 60.22; H, 3.95; N, 12.15; O, 23.70.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)-4-dimethlyaminobenzylidene]urea (4g). This compound

was obtained as colorless crystals, 2.45 g (71 %), mp 265-267 °C; ir (cm-1

): 3317.10 (secondary

amide- NH); 1634.12,1669 (C=O of isoindolin); 1605.10 (C=N); 1645.30 (C=O of urea); 2934.19

(aliphatic - CH); 3110.18 (Ar-CH);. 1

H-nmr (DMSO-d6): 2.32 (s, 6H, 2xCH3); 7.71-8.10 (m,

4H, Ar-H); 7..21 (d, 2H, J=8.8Hz, H-3,5, benzylidene); .7.57 (d, 2H, J=8.8,Hz, H-2,6,

benzylidene); 8.12(br s,1H, NH-C=O); 8.20 (s, 1 H, N=CH). Anal.Calcd. for C19H19N4O3: C,

64.35; H, 4.78; N, 16.35; O, 14.53. Found C, 64.31; H, 4.80; N, 15.95; O, 14.95.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)-benzylidene]urea (4h). This compound was obtained as

slight greyish prism shape crystals, 1.8 g (63 %), mp 210-212 °C; ir (cm-1

): 1653.10,1672 (C=O

of isoindolin); 1613.03 (C=N); 1638.34 (C=O of urea ); 2970.20 (aliphatic - CH); 3210.03 (Ar-

CH); 3425.11 (secondary amide- NH). 1

H-nmr (DMSO-d6): 7.73-8.12 (m, 4H, Ar-H); 7.13-7.3

(m, 5H, Ar-H, benzylidene) 8.10 (br s,1H, NH-C=O); 8.20 (s, 1 H, N=CH). Anal.Calcd. for

C16H11N3O3: C, 65.44; H, 3.87; N, 14.22; O, 16.50. Found C, 65.40; H, 3.92; N, 14.18; O, 16.51.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)- 2-chlorobenzylidene]urea (4i). This compound was

obtained as colorless needles, 2.1 g (65 %), mp 225--227 °C; ir (cm-1

): 1657.11,1670 (C=O of

isoindolin); 1615.01 (C=N); 1638.33 (C=O of urea ); 736 (C-Cl); 2960.10 (aliphatic - CH);


H-nmr (DMSO-d6): 7.77-8.10 (m, 4H, Ar-

H); 7.26-7.50 (m, 4H, H-3,4,5,6, Ar-H, benzylidene); 8.12 (br s,1H, NH-C=O); 8.40 (s, 1 H,

N=CH). Anal.Calcd. for C16H10ClN3O3: C, 58.60; H, 3.16; Cl, 10.71; N, 12.99; O, 14.54. Found

C, 58.58; H, 3.20; Cl, 10.70; N, 12.84; O, 14.67.

1-(1, 3-dioxoisoindolin-2-yl)-3-[(Z)- 4-chlorobenzylidene]urea (4j). This compound was

obtained as colorless needles, 2.0 g (63 %), mp 228--230 °C; ir (cm-1

): 1656.12,1668 (C=O of

isoindolin); 1625.20 (C=N); 1638.30 (C=O of urea ); 786 (C-Cl); 2962.12 (aliphatic - CH);


H-nmr (DMSO-d6): 7.78-8.09 (m, 4H, Ar-

H); 7.36 (d, 2H,J = 8.8Hz,H-3,5, benzylidene); 7.50 (d, 2H, J = 8.8Hz,H-2,6, benzylidene); 8.15

(br s,1H, NH-C=O); 8.46 (s, 1 H, N=CH). Anal.Calcd. for C16H10ClN3O3: C, 58.60; H, 3.16; Cl,

10.71; N, 12.99; O, 14.54. Found C, 58.57; H, 3.22; Cl, 10.69; N, 12.82; O, 14.69 .

Biological evaluation: Male albino mice (18-25 g) were obtained from animal house maintained

by the university. The animals were kept in colony cages at 252 oC, relative humidity maintained




between 45-55 oC under 12h light / dark cycles. All the animals were allowed to adapt to the

experimental surroundings. All the experimental procedures were carried out in accordance with

committee for the purpose of control and supervision of experiments on animals (CPCSEA)

guidelines. The study was reviewed and approved by the Institutional Animal Ethics Committee,

Jamia Hamdard, New Delhi, India.

The pharmacological evaluation of the synthesised compounds was carried out as per the

guidelines put forward by Anti epileptic Drug Development Program (ADD) [26-28]. The study

was divided into two phases which included.

Phase I:

a) The phase I involved invivo evaluation of the synthesised compounds in maximal electroshock

screen (MES); Electrical stimuli were applied via ear clip electrodes to swiss mice (20-26 g ) at

50mA, in a pulse of 35Hz for 400 ms according to the method of Swinyard [19]. Abolition of

tonic hind limb extension after drug treatment was considered as the end point of protection [20].

b) PTZ- Induced seizures in swiss mice (20-26 g) were pretreated with the drug or vehicle prior to

the subcutaneous administration of pentylenetetrazole (PTZ). For the systemic injections, all

compounds were given i.p. (0.1ml/10g of the body weight) as a freshly prepared solution in 50%

DMSO and 50% sterile normal saline (0.9 % NaCl). The convulsive dose of PTZ (85mg/kg) was

applied and the animals observed for a period of 30 min. A threshold convulsion was an episode

of clonic spasm lasting for at least 5 sec. The absence of this threshold convulsion over 30 min

period indicated that the tested substance has the ability to elevate seizure threshold [21].

c) Neurotoxicity evaluation /Motor coordination Test:

Male Swiss mice (20-26g) in groups of 10 mice were trained to do coordinated motor movements

continuously for 2 min on a rotorod 3 cm in diameter at 8 rpm. Impairment of the coordinated

motor movements was defined as the inability of the mice to remain on the rotorod for 2 min test

period [22].

Phase II:

The compounds which were screened in phase II of their invivo animal study are 4g, 4h, 4i, and

4j. These were evaluated for their median effective dose (ED50), median toxic dose (TD50) and

protection index (PI). The ED50 and TD50 values and their confidence limits were determined at

the time of peak effect for each compound by method reported previously [29].




RESULT AND DISCUSSION

O

O

NNH

2HN OO

O

O 2HN NH

O

NH2

N

O

ONH

O N

______R

a

b

1 2 3

4 (4a - j)

Scheme 1 : (a) acetic acid (b) aromatic aldehyde,dry ethanol

+

Chemistry

The synthetic route of compounds are outlined in Scheme 1. In the synthetic route, iso

benzofuran-1,3-dione 1 was reacted in acidic medium with semicarbazide 2 to give compound

1-(1,3-dioxoisoindolin-2-yl)urea 3, which was further reacted with different substituted aromatic

aldehydes to give 1- (1,3-dioxoisoindolin-2-yl) -3-(Z)-1-(substitutedbenzylidene)urea 4 (4a- j).

The yields of the compounds were good. The structure of the synthesized compounds was

established by elemental analysis, 1H NMR, mass and FT-IR spectral method. The results of

elemental analysis of the synthesized compounds were in all cases ± 0.4% of theoretical values.

Biological evaluation

All the synthesized compounds were evaluated for anticonvulsant and neurotoxicity profile in two

phases. Phase I included maximal electroshock screen (MES), subcutaneous pentylenetetrazole

screen (s.c.PTZ) and neurotoxicity screen (rotorod test) after intraperitoneal injection into mice

and the results are presented in tables 1. The Phase II included the quantification of some selected

compounds in terms of median effective dose (ED50), median toxic dose (TD50) and protection

index (PI). The results are summarized in table 2. The data in tables 1 indicates the evaluation of

all the molecules in MES, s.c.PTZ and neurotoxicity screens after ip injection in mice using doses

of 30,100 and 300mg/kg. The results showed the following pattern, the molecules show more

protection in the MES screen rather then s.c.PTZ which may be noted comparing not only the

percentage of the compounds which were active in both the screens but the fact that lower doses

were required to afford the protection in MES. The compounds which showed significant activity

(anticonvulsant and neurotoxicity) profile were selected and evaluated in Phase II. Quantitative

evaluation of the anticonvulsant and neurotoxicity of the compounds in Phase II confirmed the

selectivity in efficacy of these anticonvulsants in reducing seizures in MES screen rather than in




the s.c.PTZ screen. Furthermore, a comparison of the PI values revealed that higher figures were

always obtained from MES screening. The average PI values of the MES screens were 4 times the

values obtained from s.c.PTZ screens for ED50 figures. The comparison was made with three

reference drugs, phenytoin, carbamazepine and valproate in terms of the potency and PI values.

The ED50 values for compounds 4h (23.26 mg/kg), 4i (24.32 mg/kg), in MES screen, are similar

to phenytoin (23.2 mg/kg), but are greater then carbamazepine (3.57 mg/kg) and are considerably

lower then valproate (395 mg/kg) as reported in literature [30-32].

Table 1: Anticonvulsant and Neurotoxicity Screening: Phase I results for compounds 4

(4a - j)

Compound R Intraperitoneal injection in micea

MESb scPTZ

c NT

d

0.5h 4h 0.5h 4h 0.5h 4h

4a 2,4 –di -Cl 100 300 - - 30 30

4b 2,4 –di -NO2 100 100 100 - 30 30

4c 4-OH 100 100 100 - 30 30

4d 3,4 –di –OCH3 100 - 100 - 30 30

4e 3,4,5 –tri –OCH3 300 300 30 - 30 30

4f 3–OCH3-4-OH 300 300 100 - 30 30

4g 4-N (CH3)2 100 300 100 - 30 30

4h H 30 30 300 - 30 30

4i 2Cl 30 100 100 - 30 30

4j 4Cl 30 100 100 - 30 30

Phenytoin - 30 30 - - 100 100

Carbamazepine - 30 100 100 300

Sodium

valporate

- x x 300 x x x

a Number of animal used =4, doses of 30, 100, and 300 mg/kg were administered. The figure in

the table indicates the minimum dose whereby bioactivity was demonstrated in half or more of the

mice. The animals were examined at 0.5 and 4 h.Dash (-) indicates the absence of anticonvulsant

activity and neurotoxicity at the maximum dose administered (300 mg/kg). x – indicates not done,

b Maximal electroshock test,

c Subcutaneous pentylenetetrazole test,

d Neurotoxicity screening-

rotorod test, Reference drugs: phenytoin, carbamazepine and Sodium valporate.




Table 2: Protection against seizures induced in the MES and s.c.PTZ screens and also

Neurotoxicity by various compounds after intra peritoneal injection in mice

Compounds MES

screen

s.c PTZ

screen

Toxicity

screen

Protection Index (PI)

ED50

(mg/kg) ED50(mg/kg) TD50(mg/kg)

TD50/

ED50

TD50/

ED50

t h (95%Cl) t h (95%Cl) t h (95% Cl) MES s.c PTZ

4g 0.5

76.32

65.46-

82.52

0.5 84.60

52.12-88.42 0.5 >500 >6.55 >5.91

4h 0.5

23.26

21.02-

25.54

0.5 90.20

76.92-93.21 0.5 >500 >21.49 >5.54

4i 0.5

24.32

20.31-

27.76

0.5 86.11

72.04-95.21 0.5 >500 >20.55 >5.80

4j 0.5

28.92

23.06-

29.52

0.5 77.23

71.20-82.63 0.5 >500 >17.28 >6.47

CONCLUSION

The activity profile justifies the overall project which included the synthesis, anticonvulsant

activity and neurotoxicity profile assessment in Phase I of the study and determination of ED50,

TD50 and PI values of the compounds in Phase II study and concludes that there is a considerable

scope for structural variation in the development of new anticonvulsants.

ACKNOWLEDGEMENTS

The authors are thankful to Jamia Hamdard, New Delhi, India for providing the facilities to carry

out this research work. The authors are thankful to UGC ,New Delhi, India for providing financial

assistance Author are also thankful to Mrs. Shaukat Shah, University animal house in-charge for

providing animals for pharmacological activity and Faculty of Science Department of University

for generation of elemental analysis. The author are thankful to IIT Delhi for spectral analysis.

REFERENCES

1. Maiha BB, Magaji MG, Yaro AH, Hamza AH, Ahmed SJ, Magaj AR Anticonvulsant

studies on Cochlospermum tinctorium and Paullinia pinnata extracts in laboratory

animals.Nig. J. Pharm. Sci. 2009; 8: 102-108.

2. Lima JM.The new drugs and strategies to manage epilepsy. Curr. Pharmac. Design. 2000;

6: 873-878.




3. Berk M, Segal J, Janet L, Vorster M. Emerging options in the treatment of bipolar

disorders. Drugs. 2001; 61(10): 1407-1414.

4. Duncan JS. The promise of new antiepileptic drugs. Br. J. Clin. Pharmacol. 2002;

53(2):123-131.

5. Bordie MJ. Established anticonvulsants and treatment of refractory epilepsy. Lancet.

1990; 350-354.

6. Shimshoni JA, Bialer M, Wlodarczyk B, Finnell RH, Yagen B. Potent anticonvulsant urea

derivatives of constitutional isomers of valproic acid. J. Med. Chem. 2007; 50 (25): 6419-

6427.

7. Okada A, Noyori H, Yagen B, Shimshoni JA, Bialer M, Fujiwara M. Anticonvulsant

profile and teratogenic evaluation of potent new analogues of a valproic acid urea

derivative in NMRI mice. Birth Defects Res. B. Dev. Reprod. Toxicol. 2009; 86(5): 394-

401.

8. Nichols AC, Yielding KL. Anticonvulsant activity of 4-urea-5,7-dichlorokynurenic acid

derivatives that are antagonists at the NMDA-associated glycine binding site.Mol. Chem.

Neuropathol. 1998; 35 (1-3): 1-12.

9. Kashaw SK, Kashaw V, Mishra P, Jain NK, Stables JP. Synthesis, anticonvulsant and

CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-

phenyl/ethyl-4H-quinazolin-3-yl)-urea. Eur. J. Med. Chem. 2009; 44(11): 4335-43.

10. Kaymakciouglu BK, Rollas S, Korcegez E, Aricioglu F. Synthesis and biological

evaluation of new N-substituted-N'-(3,5-di/1,3,5-trimethylpyrazole-4-yl)thiourea/urea

derivatives. Eur J Pharm Sci. 2005; 26(1):97-103.

11. Ragavendran JV, Sriram D, Patel SK, Reddy IV, Bharathwajan N, Stables J, Yogeeswari

P. Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide

and hydrazone pharmacophore. Eur. J. Med. Chem. 2007; 42(2):146-51.

12. Da Silva CM, Da Silva DL, Modolo LV, Alves RB, Maria ADR, Martins CVB, Fatima

AD. Schiff bases: A short review of their antimicrobial activities. J. Advance Res. 2011;

2: 1–8.

13. Zhu X, Wang C, Zhiping L, Yuanlin D. Synthesis, characterization and biological

activity of the Schiff base derived from 3,4-dihydroxybenzaldehyde and

thiosemicarbazid, and its complexes with nickel(II) and iron(II) -antimicrobials.

Transition Metal Chemistry. 1997; 22(1): 9-13.

http://www.ncbi.nlm.nih.gov/pubmed/17994680http://www.ncbi.nlm.nih.gov/pubmed/19830722http://www.ncbi.nlm.nih.gov/pubmed/19830722http://www.ncbi.nlm.nih.gov/pubmed/19830722http://www.ncbi.nlm.nih.gov/pubmed?term=Nichols%20AC%5BAuthor%5D&cauthor=true&cauthor_uid=10343967http://www.ncbi.nlm.nih.gov/pubmed?term=Yielding%20KL%5BAuthor%5D&cauthor=true&cauthor_uid=10343967http://www.ncbi.nlm.nih.gov/pubmed/10343967http://www.ncbi.nlm.nih.gov/pubmed/10343967http://www.ncbi.nlm.nih.gov/pubmed/?term=Kashaw%20SK%5BAuthor%5D&cauthor=true&cauthor_uid=19674817http://www.ncbi.nlm.nih.gov/pubmed/?term=Kashaw%20V%5BAuthor%5D&cauthor=true&cauthor_uid=19674817http://www.ncbi.nlm.nih.gov/pubmed/?term=Mishra%20P%5BAuthor%5D&cauthor=true&cauthor_uid=19674817http://www.ncbi.nlm.nih.gov/pubmed/?term=Jain%20NK%5BAuthor%5D&cauthor=true&cauthor_uid=19674817http://www.ncbi.nlm.nih.gov/pubmed/?term=Stables%20JP%5BAuthor%5D&cauthor=true&cauthor_uid=19674817http://www.sciencedirect.com/science/article/pii/S0223523409003018http://www.sciencedirect.com/science/article/pii/S0223523409003018http://www.sciencedirect.com/science/article/pii/S0223523409003018http://www.ncbi.nlm.nih.gov/pubmed/?term=Kaymakciouglu%2C+B.K.%3B+Rollas%2C+S.%3B+Korcegez%2C+E.%3B+Aricioglu%2C+F.+Eur+J+Med+Chem+2005%2C+26%2C+97http://www.ncbi.nlm.nih.gov/pubmed/17011080http://www.ncbi.nlm.nih.gov/pubmed/17011080http://link.springer.com/search?facet-author=%22Xinde+Zhu%22http://link.springer.com/journal/11243




14. Bernardino AMR,Gomes AO, Machado GMC, Canto-cavalheiro MM, Leon L, Amaral V,

Charret KS, Freitas ACC. Synthesis and leishmanicidal activities of 1-(4-X-phenyl)-N'-

[(4-Y-phenyl)methylene]-1H-pyrazole-4-carbohydrazides. Eur.J.Med.Chem. 2006;41:80–

87.

15. Duarte CD, Tributino JLM, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F,

Bechara EJH, De-Paula, FS, Goulart MOF, Ferreira J, Calixto JB, Nunes, MP, Bertho

AL, Miranda ALP, Barreiro EJ, Fraga CAM. Synthesis, pharmacological evaluation and

electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-Nacylhydrazone

derivatives : Discovery of LASSBio-881, a new ligand of cannabinoid receptors. Bioorg.

Med. Chem.2007; 15: 2421-2433.

16. Al-Zoubi W. Biological Activities of Schiff Bases and Their Complexes: A Review of

Recent Works.Inter. J.Org. Chem. 2013; 3:73-95.

17. Przybylski P, Huczynski A, Pyta K, Brzezinski B,Bartl F. Biological Properties of Schiff

Bases and Azo Derivatives of Phenols. Curr. Org. Chem. 2009; 13, 124-148.

18. Cakir B, Dag O,Yildirim E, Erol K,Sahin MF. Synthesis and anticonvulsant activity of

some hydrazones of 2-[(3H)-oxobenzoxazolin-3-yl-aceto]hydrazide. J. Fac. Pharm. Gazi.

2001;18: 99-106.

19. Swinyard EA, Brown WC, Goodman LS. Comparative assays of antiepileptic drugs in

mice and rats.J. Pharmacol. Exp. Ther. 1952; 106, 106(3):319-330.

20. Swinyard EA, Woodhead JH, White HS, Franklin MR. General principles: experimental

selection, quantification, and evaluation of anticonvulsants. In: Levy RH, Mattson RH,

Melrum B, Penry JK. Antiepileptic Drugs. New York: Raven Press; 1989. pp. 85–102.

21. Snead OC. Pharmacological models of generalized absence seizures in rodents J. Neural.

Transm. Suppl. 1992; 35:7-19.

22. Dunham MS, Miya TA. A note on a simple apparatus for detecting neurological deficit in

rats and mice. J Am Pharm Assoc Am Pharm Assoc (Baltim). 1957;46(3):208-209.

23. Hejsek M, Wiedermannova I. Derivatives of phtalic acid anhydride I. Synthesis and

studies of reaction phthalic acid anhydride. Fac Rer Nat 2001, 40, 15-23.

24. Vamecq J, Bac P, Herrenknecht C, Maurois P, Delcourt P, Stables JP. Synthesis and

anticonvulsant and neurotoxic properties of substituted N-phenyl derivatives of the

phthalimide pharmacophore.J. Med. Chem. 2000;43(7):1311-1319.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Dunham%2C+M.S.%3B+Miya%2C+T.A.+J++Am++Pharmac++Assoc++Sci++Edit+++1957%2C++46%2C+208.http://www.ncbi.nlm.nih.gov/pubmed/10753468http://www.ncbi.nlm.nih.gov/pubmed/10753468http://www.ncbi.nlm.nih.gov/pubmed/10753468




25. Yogeeswari P, Sriram D, Saraswat V, Ragavendran JV, Kumar MM, Murugesan S

Thirumurugan R, Stables JP. Synthesis and anticonvulsant and neurotoxicity evaluation of

N4-phthalimido phenyl (thio) semicarbazides. Eur J Pharm Sci. 2003; 20: 341-6.

26. Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug

development: II. Anticonvulsant drug screening. Epilepsia. 1978;19(4):409-28.

27. Porter RJ, Hessie BJ, Cereghino JJ, Gladding GD, Kupferberg HJ, Scoville B, White BG.

Advances in the clinical development of antiepileptic drugs. Fed. Proc. 1985;

44(10):2645-9.

28. White HS, Johnson M, Wolf HH, Kupferberg HJ. The early identification of

anticonvulsant activity: role of the maximal electroshock and subcutaneous

pentylenetetrazol seizure models. Ital J Neurol Sci. 1995;16(1-2):73-7.

29. Gladding, GD.; Kupferberg HJ, Swinyard EA. Handbook of Experimental Pharmacology,

Antiepileptic Drugs, Springer, Berlin, Tokyo, 1985.

30. Dimmock JR1, Puthucode RN, Smith JM, Hetherington M, Quail JW, Pugazhenthi

U, Lechler T, Stables JP. (Aryloxy)aryl semicarbazones and related compounds: a novel

class of anticonvulsant agents possessing high activity in the maximal electroshock

screen.J. Med. Chem.1996; 39(20):3984-97.

31. Thirumurugan R, Sriram D, Saxena A, Stables J, Yogeeswari P. 2,4-Dimethoxyphenyl

semicarbazones with anticonvulsant activity against three animal models of seizures:

synthesis and pharmacological evaluation. Bioorg. Med. Chem. 2006;14(9):3106-3112.

32. Azam F, Alkskas IA, Khokra SL, Prakash O. Synthesis of some novel N4-(naphtha[1,2-

d]thiazol-2-yl)semicarbazides as potential anticonvulsants. Eur. J.Med.Chem. 2009;

44(1):203-11.
http://www.ncbi.nlm.nih.gov/pubmed/?term=Krall%20RL%5BAuthor%5D&cauthor=true&cauthor_uid=699894http://www.ncbi.nlm.nih.gov/pubmed/?term=Penry%20JK%5BAuthor%5D&cauthor=true&cauthor_uid=699894http://www.ncbi.nlm.nih.gov/pubmed/?term=White%20BG%5BAuthor%5D&cauthor=true&cauthor_uid=699894http://www.ncbi.nlm.nih.gov/pubmed/?term=Kupferberg%20HJ%5BAuthor%5D&cauthor=true&cauthor_uid=699894http://www.ncbi.nlm.nih.gov/pubmed/?term=Swinyard%20EA%5BAuthor%5D&cauthor=true&cauthor_uid=699894http://www.ncbi.nlm.nih.gov/pubmed/?term=Krall%2C+R.+L.%3B++Penry%2C+J.+K.%3B+White%2C+B.+G.%3B+Kupferberg%2C+H.+J.%3B+Swinyard%2C+E.+A.++Epilepsia++1978%2C+19%2C+409.http://www.ncbi.nlm.nih.gov/pubmed/?term=Porter%20RJ%5BAuthor%5D&cauthor=true&cauthor_uid=3891417http://www.ncbi.nlm.nih.gov/pubmed/?term=Hessie%20BJ%5BAuthor%5D&cauthor=true&cauthor_uid=3891417http://www.ncbi.nlm.nih.gov/pubmed/?term=Cereghino%20JJ%5BAuthor%5D&cauthor=true&cauthor_uid=3891417http://www.ncbi.nlm.nih.gov/pubmed/?term=Gladding%20GD%5BAuthor%5D&cauthor=true&cauthor_uid=3891417http://www.ncbi.nlm.nih.gov/pubmed/?term=Kupferberg%20HJ%5BAuthor%5D&cauthor=true&cauthor_uid=3891417http://www.ncbi.nlm.nih.gov/pubmed/?term=Scoville%20B%5BAuthor%5D&cauthor=true&cauthor_uid=3891417http://www.ncbi.nlm.nih.gov/pubmed/?term=White%20BG%5BAuthor%5D&cauthor=true&cauthor_uid=3891417http://www.ncbi.nlm.nih.gov/pubmed/?term=Porter%2C+R.+J.%3B++Hessie%2C+B.+J.%3B+Cereghino%2C+J.+J.%3B+Gladding%2C+G.+D.+%3B+Kupferberg%2C+H.+J.%3B+Scoville+%2C+B.%3B+White%2C+B.+G.++Fed+Proc++1985%2C+44%2C+2645http://www.ncbi.nlm.nih.gov/pubmed/?term=White%20HS%5BAuthor%5D&cauthor=true&cauthor_uid=7642355http://www.ncbi.nlm.nih.gov/pubmed/?term=Johnson%20M%5BAuthor%5D&cauthor=true&cauthor_uid=7642355http://www.ncbi.nlm.nih.gov/pubmed/?term=Wolf%20HH%5BAuthor%5D&cauthor=true&cauthor_uid=7642355http://www.ncbi.nlm.nih.gov/pubmed/?term=Kupferberg%20HJ%5BAuthor%5D&cauthor=true&cauthor_uid=7642355http://www.ncbi.nlm.nih.gov/pubmed/?term=White%2CH.S.%3B+Johnson%2C+M.%3B+Wolf%2C+H.+H.+%3B+Kupferberg%2C+H.J.++Ital++J+Sci++1995%2C+16%2C+73.http://www.ncbi.nlm.nih.gov/pubmed/?term=Dimmock%20JR%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Puthucode%20RN%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Smith%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Hetherington%20M%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Quail%20JW%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Pugazhenthi%20U%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Pugazhenthi%20U%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Lechler%20T%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Stables%20JP%5BAuthor%5D&cauthor=true&cauthor_uid=8831764http://www.ncbi.nlm.nih.gov/pubmed/?term=Thirumurugan%20R%5BAuthor%5D&cauthor=true&cauthor_uid=16413192http://www.ncbi.nlm.nih.gov/pubmed/?term=Sriram%20D%5BAuthor%5D&cauthor=true&cauthor_uid=16413192http://www.ncbi.nlm.nih.gov/pubmed/?term=Saxena%20A%5BAuthor%5D&cauthor=true&cauthor_uid=16413192http://www.ncbi.nlm.nih.gov/pubmed/?term=Stables%20J%5BAuthor%5D&cauthor=true&cauthor_uid=16413192http://www.ncbi.nlm.nih.gov/pubmed/?term=Yogeeswari%20P%5BAuthor%5D&cauthor=true&cauthor_uid=16413192http://www.ncbi.nlm.nih.gov/pubmed/?term=Thirumurugan%2C+R.+D.%3B+Saxena%2C+S.A.%3B+Stables%2C+J.P.%3B+Yogeeswari%2C+P.+Bioorg+Med+Chem+2006%2C+14%2C++3106.http://www.ncbi.nlm.nih.gov/pubmed/?term=Azam%20F%5BAuthor%5D&cauthor=true&cauthor_uid=18396352http://www.ncbi.nlm.nih.gov/pubmed/?term=Alkskas%20IA%5BAuthor%5D&cauthor=true&cauthor_uid=18396352http://www.ncbi.nlm.nih.gov/pubmed/?term=Khokra%20SL%5BAuthor%5D&cauthor=true&cauthor_uid=18396352http://www.ncbi.nlm.nih.gov/pubmed/?term=Prakash%20O%5BAuthor%5D&cauthor=true&cauthor_uid=18396352http://www.ncbi.nlm.nih.gov/pubmed/?term=Azam%2C+F.%3B+Alkskas%2C++I.A.%3B+Khora%2CS.L.%3B+Prakash%2C+O.+Eur+J+Med+Chem+2009%2C+44%2C+203.

international journal of innovative pharmaceutical...

Documents