Evaluation of Anticonvulsant Activity of Novel Substituted 2-Mercaptobenzimidazole Derivatives

 

Ravi N Tiwari1*, KG Bothara1, Gurmeet Singh Chhabra1 and Sarang Kulkarni2

1Department of Pharmaceutical Chemistry, NMIMS University Shirpur Campus Dist. Dhule (M.S) India

2Siddhant College of Pharmacy Sudumbare, Pune (M.S.) India

*Corresponding Author E-mail:  ravisun4@rediffmail.com

 

ABSTRACT:

Mannich bases of sulphonamide substituted 2-mercaptobenzimidazole compounds were synthesized from 2-mercaptobenzimidazole by reacting with aldehyde like formaldehyde and the various sulphonamides. Synthesized compounds were characterized by spectral studies and evaluated for antibacterial activities.  The statistical analysis was done by students“ t ”test and the values were expressed as Mean ± SEM.

 

KEYWORDS: Mannich Bases Sulphonamide Substituted 2-Mercaptobenzimidazole, Anti-Convulsant Activity.

 


INTRODUCTION:

A reaction between a compound having a reactive hydrogen atom, an aldehyde and a secondary amine1 became a general reaction by the name of Mannich. This reaction is useful in making N-methyl derivatives and many drug molecules. The drugs with 2-mercaptobenzimidazole moiety were found to possess anti-convulsant2, anti-estrogenic3, anti-microbial4, anti HIV5 and anti-tumour6 activities. All these observations and essential role of the substituted 2-mercaptobenzimidazole derivatives prompted us to synthesize various S-substituted 2-mercaptobenzimidazole and to evaluate their anti-convulsant activities.

 

MATERIAL AND METHODS:

Melting points were determined by open-ended capillary tube in the electrical melting point apparatus and are uncorrected and the purity of the compounds were checked by TLC using Silica Gel as stationary phase and  the spots were visually detected in an  Iodine chamber. The structure of the synthesized compounds was elucidated by FT-IR7 (Shizamadu-8400 series) in KBr disc and FT-1H NMR7 (Brucker 400 MHz) in DMSO-d6.

 

Synthesis of  2- Mercaptobenzimidazole:

o-phenylenediamine [2.18gm] was dissolved in the solution of [1.44gm] of KOH in 20ml of methanol of 4ml of water. To this solution (CS2) carbon disulphide [1.28gm] was added slowly with constant shaking. The mixture was refluxed for 8 hrs.

 

The resultant solution was neutralized with ice cold acetic acid. Whole 2-mercaptobenzimidazole separated as colorless solid. It was filtered washed with cold water and recrystallize from CHCl3 petroleum ether mixture.

 

Preparation of Mannich bases of 2-Mercaptobenzimidazole:

Equimolar quantities (0.01mole) of 2-mercaptobenzimidazole and secondary amine were dissolved in methanol (30 ml) in a beaker under perfect ice cold condition and stirred constantly and then 0.01 moles of series of aldehyde (such as formaldehyde and acetaldehyde) was added slowly and heated to reflux for 3hrs. The content was kept over night in the freezer. Crystallized product obtained was recrystallized from alcohol. The %yield, Rf value, melting point and spectral data were reported in Table 1.

 

Anti-convulsant activity [MES Method]:

The anti-epileptic activity was carried out by Maximal electrical shock induced convulsion method8. Adult albino mice of either sex weighing of 20 – 30 g were used for the study. Mice were treated with newly synthesized 2-mercaptobenzimidazole (20mg/kg,ip) and Std drug, Phenytoin (20mg/kg,ip). After 30 min, the animals were subjected to electro shock through ear electrodes of 150 mA for 0.2 sec by electro convulsiometer and the presence and absence of extensor response was noted and duration of time was analyzed statistically by students “ t ”  test  and expressed in Mean ± SEM and tabulated  in Table 2.


RESULTS

Table 1: Physical Data of Newly Synthesized Compounds

Compd code

Melting point  oC

Rf value

Log P

IR spectra (cm-1)

1H NMR spectra

RNT-1

140-143

0.3268

4.286

3480,1306,1463,1751, 3010,729

7.26 – 8.06(m, Ar-H), 5.78(s,CH2), 5.29(S, NH)

RNT-2

128-131

0.5412

6.657

3427,1605,1300,1461, 719,776

7.12 – 7.41(m, Ar-H), 5.15(s, NH), 2.58(s, CH2)

RNT-3

160-164

0.3227

5.343

3456,1663,1450,1470, 1300,1590,1350,748

7.16 – 7.32(m, Ar-H), 2.32(s,CH2), 5.54(s,NH)

RNT-4

110-113

0.5228

4.567

3356,1461,1310,1616, 1350,741

7.18 – 7.96(m, Ar-H), 2.52 (s,CH2), 5.28(s, NH)

RNT-5

180-184

0.6455

5.412

3452,3018,1302,1339, 1457,774,1610

7.33-7.88(m, Ar-H) 2.28(s,CH2), 5.11(s,NH)

RNT-6

126-130

0.4588

6.552

3360,3039,1465,1294, 1615,1345,774

7.62 – 8.04(m, Ar-H), 2.77(s,CH2), 5.21(s,NH)

RNT-7

170-173

0.3276

3.629

3453,1226,3030,1310, 1613,1652,772

7.32 – 7.92(m, Ar-H), 2.22 (s,CH2),5.42(s,NH),

RNT-8

186-189

0.6289

6.348

3440,3063,1457,1330, 1605,1357,778

7.4 – 8.6(m, Ar-H), 7.21(s,NH), 2.32(s, CH2)

 

Table 2: Anti-Convulsant Evaluation of Newly Synthesized Compounds

S. No.

Treatment

Duration (in sec)    (Mean ± SEM)

Recovery/ Death

Extensor

Clonus

Stupor

1

Control

31.50 ± 0.9220

22.66 ± 1.7638

69.33 ± 3.2830

Recovery

2

Phenytoin Standard

16.667 ± 1.0541**

9.50 ± 0.9574**

24.66 ± 2.1551**

Recovery

3

RNT-1

19.44 ± 1.5433**

12.24 ± 0.8349**

22.41 ± 1.7651**

Recovery

4

RNT-2

38.46 ± 1.2318

21.14 ± 1.1556

38.00 ± 1.5411

Recovery

5

RNT-3

21.23 ± 0.9841**

15.30 ± 0.8834**

24.32 ± 1.1266**

Recovery

6

RNT-4

22.17 ± 1.1211**

13.35 ± 0.6288**

28.65 ± 1.8013**

Recovery

7

RNT-5

20.44 ± 1.6782**

12.66 ± 1.9890**

26.34 ± 1.6931**

Recovery

8

RNT-6

26.46 ± 1.8256*

18.67 ± 1.7643*

32.78 ± 2.3461*

Recovery

9

RNT-7

36.00 ± 1.8739

23.49 ± 1.8729

36.77 ± 1.8972

Recovery

10

RNT-8

24.52 ± 1.9821*

20.48 ± 1.8211*

34.29 ± 1.5931*

Recovery

** P < 0.001 vs. control indicates highly significant, * P < 0.01 vs. control indicates moderately significant.

 


Scheme

 

DISCUSSION:

Totally a series of eight novel 2-mercaptobenzimidazole derivatives were synthesized and elucidated by spectral data and evaluated for their anti-convulsant activities. Compound RNT-1, RNT-3, and RNT-4 and RNT-5 has shown highly significant anti-convulsant activity due to the substitution with Phthalimide, Acetanilide, Indole and Piprazine respectively. Compound RNT-6 and RNT-8 shows moderate anti-convulsant activity. Compounds RNT-2 and RNT-7 were devoid from anti-convulsant activity. The maximum anti-convulsant activities were observed in the animals administered with 20 mg/kg body weight of the synthesized compounds as well as in those animals which received phenytoin (20 mg/kg).

 

REFERENCES:

1.       C. Mannich and W. Krosche, Arch.Pharm., 250, 647 (1912)

2.       K.J. Rajendra Prasad and C. Kavitha, Ind. J. Het. Chem., (12), (2003)

3.       C. Biberger, T. Golob, G. Walter and E. Von Angerer, Arch.Pharm., 333 (9), 305-311, (2000)

4.       V.V. Mulwad, M.B. Dalvi and B.S. Mahaddalkar, Ind. J. Chem., (7), 1477-1479, (2002)

5.       Hua Yan, Tomoko Chiba, Yashihiro Kitamura Hideka Miura and Masayuki Fujino, Antivir.Chem.Chemother., 16 (6), 363-373, (2005)

6.       Christina Aschea, Walter Frankb and Antje Albertb, Bio.Org.Med.Chem., 13 (3), 817-837, (2005)

7.       John R. Dyer Applications of Absorption Spectroscopy of Organic Compounds, Prentice-Hall of India (P), New Delhi, (1969), First Edition, 33-38.

8.       S. K. Kulkarni, “Handbook of Experimental Pharmacology“, 3rd Edn, Vallabh Prakashan 125, (1987)

 

 

 

Received on 22.10.2009                             Modified on 21.12.2009

Accepted on 23.01.2010                            © RJPT All right reserved

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 466-467