The Preparation and Biological Evaluation of Some New 6-Iodo-2-Ethyl- 4(3H)-3 (5-Substituted Benzothiazole-2’-Yl) Quinazolinone Derivatives as an Anticonvulsant

 

Dahikar G. D.*, Yeole P.G., Ganjiwale R.O. and Rahangdale V.T.

Institute of Pharmaceutical Education and Research, Borgaon (Meghe) Wardha.442001, India.

*Corresponding Author E-mail: girishdd1@rediffmail.com

ABSTRACT:

Epilepsy is a very common disorder, characterized by seizures, which take various forms and result from episodic neuronal discharges, the form of the seizure depending on the part of the brain affected. Epilepsy affects 0.5-1 % of the population. Often there is no recognizable cause, although it may develop after brain damage, such as trauma, infection or tumor growth, or other kinds of neurological disease, including various inherited neurological syndromes. Epilepsy is treated mainly with drugs, though brain surgery may be used for severe cases. Current antiepileptic drugs are effective in controlling seizures in about 70 % of patients, but their use is often. It is tendency to experience anticonvulsant agent which blocks experimentally produced seizures in laboratory animal.  6-iodo-2-ethyl-4(3H) - 3 (5-substituted benzothiazole-2’-yl) quinazolinones compound were prepared by condensing 5-substituted - 2- amino benzothiazoles and 6- iodo-2-ethyl-3, 1-benzoxazine-4-one, then prepared compounds were evaluated for anticonvulsant activity by maximal electroshock method against standard drug like phenobarbitone at 20 mg/ kg dose.

The chemical structures of all these compounds were confirmed by Mass, IR, ¹HNMR spectral and elemental analysis. Simultaneously effect of electron donating and withdrawing groups also checked on 6-iodo-2-ethyl-4(3H)-3(5-substituted benzothiazole-2’-yl) quinazolinones.

 

 

 

INTRODUCTION:

Literature survey reveals that 2-amino benzothiazole derivatives possessed potent anticonvulsant activity¹. Similarly substituted 4(3H) - quinazolinones exhibit potential anticonvulsant activity^2,3. Herein report the synthesis of new series of 6-iodo-2-ethyl- 4(3H) -3(5-substituted benzothiazole-2’-yl) quinazolinones. The compounds have been design by condensing 5-substituted- 2-amino benzothiazoles and 6-iodo-2-ethyl-3,1-benzoxazine-4-one to get title molecule with potent anticonvulsant activity.

 

As it is reported that both quinazolinones and benzothiazoles exhibit anticonvulsant activity, it was thought worthwhile to synthesize compound containing both moieties and to evaluate them for their anticonvulsant activity.

 

In order to understand the effect of various substituent groups it was thought to use halogen (Iodine) substituted 2-ethyl- 3,1- benzoxazine-4-one and  2-amino benzothiazole substituted with various groups like CH_3, OCH_3, Cl and NO₂ for the synthesis of 6-iodo-2-ethyl-4 (3H)-3(5-substituted benzothiazole-2’-yl) quinazolinones.

 

MATERIALS AND METHODS:

General:

For the synthesis of title compounds, intermediates were prepared with reported methods; this involves the synthesis of 5-substituted-2-amino benzothiazoles⁴ and 6-iodo-2-ethyl- 3, 1-benzoxazine-4-one⁵.

 

Synthesis of 6-iodo-2-ethyl-4(3H)-3(5-substituted benzothiazole-2’-yl) quinazolinones:

Ia] 6-iodo-2-ethyl-4(3H)-3(benzothiazoe-2’-yl) quinazolinone: In a 100ml round bottom flask; 2-amino benzothiazole (1.5g) (0.01 mole) (a) and 6-iodo-2-ethyl-3,1-benzoxazine-4-one  (3.04 g) (0.01mole) (I) was added in 20 ml glacial acetic acid and 1.5 g of sodium acetate. This mixture was refluxed for 25 hours on an oil bath at about 115-120 ^oC, it was cooled and poured on 100-150 g crush ice gave a precipitate (Ia).

Synthetic scheme:

 

Compd. No.                  Ia                Ib                Ic                Id                Ie

R                                     -H               -CH₃           -OCH₃        -Cl               -NO₂

 

 

The precipitate was filtered, washed with cold water, dried and recrystallized with glacial acetic acid. The yield was (2.17g) (71.00 %) and m.p. 158-160^o C. The remaining Ib, Ic, Id and Ie compounds were prepared by using 0.01 moles of each of   5-substituted -2-amino benzothiazoles and 6-iodo-2-ethyl-3,1-benzoxazine-4-one using above prescribed procedure. The reflux time required for all these derivatives were in the range of 25-30 hrs. The melting points were taken in open capillaries and are uncorrected; all products were purified by crystallization using ethanol and hot water.

 

Experimental section:

Spectral and elemental data:

Ia 6-iodo-2-ethyl-4 (3H)-3 (benzothiazole-2’-yl) quinazolinone:

Mol. wt. 437, IR: (KBR):cm^-1 3075, 3175 (-CH), 2918, 2851 (-CH₂-CH₃), 1707 (C=O), 1590 (C=H), 1230 (C-N), 675 (C-I), 660 (C-S),  ¹HNMR: (CDCl₃): δ ppm (q, 2.816-2.891, 4H, CH₂), (t, 1.435-1.485, 3H, CH₃), (7.087- 8.435, 8H, C₆H₆). C, H, N values (%) 46.73, 2.73, 9.64.

 

Ib   6-iodo-2-ethyl-4 (3H)-3 (5-methyl benzothiazole-2’-yl) quinazolinone:

Mol. wt. 451, IR: (KBR): cm^-1 3165, 3065 (-CH), 2918, 2850 (-CH₂-CH₃), 1705 (C=O), 1593 (C=H),1231 (C-N), 692 (C-I), 658 (C-S), ¹HNMR: (CDCl₃): δ ppm (q, 2.816-2.891,4H, CH₂), (t, 1.435-1.485,3H,CH₃), (7.087- 8.435, 8H, C₆H₆). C, H, N values (%) 47.85, 3.33, 9.38.

 

Ic     6-iodo-2-ethyl-4 (3H)-3 (5-methoxy benzothiazole-2’-yl) quinazolinone:

Mol. wt. 467, IR: (KBR): cm^-1 3236, 3050 (-CH), 2918, 2850 (-CH₂-CH₃), 1686 (C=O), 1588 (C=H), 1232 (C-N), 665 (C-I), 663 (C-S), ¹HNMR: (CDCl₃): δ ppm (q, 2.816-2.891, 4H, CH₂), (t, 1.435-1.485, 3H, CH₃), (7.087- 8.435, 8H, C₆H₆). C, H, N values (%) 46.24, 2.98, 8.88.

 

Id   6-iodo-2-ethyl-4 (3H)-3 (5-chloro benzothiazole-2’-yl) quinazolinone:

Mol. wt. 471, IR: (KBR): cm^-1 3233,3100 (-CH), 2985, 2950, 2875 (-CH₂-CH₃), 1686 (C=O), 1589 (C=H), 1234 (C-N), 997 (C-Cl),  692 (C-I), 662 (C-S), ¹HNMR: (CDCl₃): δ ppm (q, 2.816-2.891, 4H, CH₂), (t,1.435-1.485, 3H, CH₃), (7.087- 8.435, 8H, C₆H₆). C, H, N values (%) 43.33, 2.33, 8.97.

 

Ie   6-iodo-2-ethyl-4 (3H)-3 (5-nitro benzothiazole-2’-yl) quinazolinone:

Mol. wt. 482, IR: (KBR): cm^-1 3108 (-CH), 2918, 2850 (-CH₂-CH₃), 1707 (C=O), 1593 (C=H), 1500,1495 (-NO₂), 1233 (C-N), 694 (C-I), 664 (C-S), ¹HNMR: (CDCl₃): δ ppm (q, 2.816-2.891, 4H, CH₂), (t, 1.435-1.485, 3H, CH₃), (7.087- 8.435, 8H, C₆H₆). C, H, N values (%) 42.29, 2.25, 11.60.

 

RESULT AND DISCUSSION:

All the compounds were characterized by their physical, analytical and spectral data. They were given separately in experimental section. The IR spectra of the substituted benzothiazoles  showed the presence of the characteristic absorption peaks at 1650-1600 cm^-1 (N-H deformation) and 3500-3460 cm^-1 (NH₂ stretching) while the title compounds (Ia-Ie) showed disappearance of peak at 1650-1600 cm^-1(N-H deformation) and 3500-3460 cm^-1(NH₂ stretching) due to conversion of free amino group into cyclic nitrogen. Halogen containing compounds (Ia-Ie) showed the peak at 760-590 cm^-1 (C-X stretching). The nitro compound showed the peak at 1500, 1495 cm^-1.The FAB mass and PNMR spectral data of compounds (Ia-Ie) were found in conformity with the structure assign. In FAB mass spectra molecular (M⁺) peak confirm the molecular weight of the compounds (Ia-Ie), the PNMR spectra shows quartet and triplet of CH₂-CH₃ respectively at 1-3 δ ppm while the multiplates of aromatic rings shows in the range of 7- 9 δ ppm.

 

Pharmacology:

The anticonvulsant activity of title compounds Ia, Ib, Ic, Id and Ie were carried out using maximal electroshock method⁶. The sample solutions were prepared in PEG-200 solvent. The animals (mice of 20-25g body weight) were treated with control (PEG-200, dose 1ml/100g, ip).These compounds exhibited anticonvulsant activity at 20 mg/kg dose level. The anticonvulsant activity ranges from 70 % to 89% of the standard drug like Phenobarbitone at 20 mg/kg dose level.

 

Table: Anticonvulsant screening:

Treatments	Dose	Duration of tonic hind leg extension in sec.(mean ±SEM)	Percentage of animal protected
Control	1 mg/100 g	34.4 ± 3.135	025.58 %
Standard	20 mg/kg	08.8 ± 0.968	100.00 %
Ia	20 mg/kg	10.4 ± 0.930	084.61%
Ib	20 mg/kg	11.4 ± 1.286	077.19 %
Ic	20 mg/kg	12.4 ± 0.677	070.96 %
Id	20 mg/kg	09.8 ± 0.278	089.29 %
Ie	20 mg/kg	10.0 ± 1.047	088.00 %

< 0.05 (One way ANOVA, Dunnett test)

 

ACKNOWLEDGEMENTS:

I wish to thank the Institute of Pharmaceutical Education and Research, Borgaon (Meghe), Wardha for providing required facilities. I am very thankful to Himedia and Sigma-Aldrich for the supply of chemicals.

CONCLUSION:

The activities of compounds were compared with standard drug activity like phenobarbitone. There is no statistically significant difference between standard and sample values were obtained.

 

REFERENCES:

1        Domino E F, Perterson R J and Unna K R. J Pharmacol Expt. Therap. 1951; 103,342.

2        James F Wolfe, et.al. J Med Chem. 1990; 33: 161-166.

3        Archana V K, et. al. Indian Journal of Chemistry. 2001; 41B: 2371-2375.

4        Bhargava P H and Jose K A. J Indian Chem. Soc. 1960; pp. 35 and 314.

5        David T, Zentmyer E C, Wagner. J Org Chem. 1949; 19: pp. 967-980.

6        Swinyard E D, Brown W C, Goodman L S, Comparative assay of antiepileptic drug in mice and rats. J Pharmacol Expt. Therap. 1952; 106: 319-330.

 

 

 

Received on 02.01.2010        Modified on 09.02.2010

Accepted on 07.03.2010        © AJRC All right reserved