Analgesic Activity of 2-Hetero Substituted -4-Quinazolinones

 

V. Niraimathi* and C. Vamsadhara

Department of Pharmaceutical Chemistry, College of Pharmacy, Madras Medical College, Chennai-600 003, Tamil Nadu, India.

*Corresponding Author E-mail: vnm_anr@yahoo.co.in

 

ABSTRACT:

Analgesic activity of newly synthesized series of 2-heterosubstituted-4-quinazolones (NN, NP, NC, NNB, NPB, NCB) were studied in mice. The analgesic activity was carried out at healthy male Swiss albino mice by writhing method and tail immersion method. Aspirin (150mg/kg p.o) and pentazocin (10mg/kg i.p) were used as positive controls for writhing and tail immersion method respectively. The synthetic compounds were administered orally in the dose of 30mg/kg, 90mg/kg as 1% CMC suspension. Results indicate that statistically significant reduction was obtained at 30mg dose level for compounds NP, NPB and NC by writhing Method. Their p value less than 0.05.

 

KEYWORDS: Quinazolinone; analgesic activity.

 


INTRODUCTION:

It is evident from the literature that quinazolines exhibit potent central nervous system (CNS) activities, e.g. analgesic, anti-inflammatory, anticonvulsant, antiparkinsonism1 . The title compounds were synthesized by thermal condensation and cyclisation of drug amide with anthranilic acid and dibromo anthranilc acid. The synthesis, antimicrobial activity, experimental data and spectral data of the said derivatives had already been accepted for publication2-5. This present work has demonstrated that 2-heterosubstitutted-4-quinazolinones exhibited good analgesic activity.

 

 

The structures of synthesized compounds:

          NN                          NP                          NC                      

  

           NNB                       NPB                        NCB

 

2-Pyridyl-4-quinazolone NN

6,8-Dibromo-2-pyridyl-4-quinazolone NNB

2-Pyrazinyl-4-quinazolone NP

6,8-Dibromo-2-pyrazinyl-4-quinazolone NPB

2-Carbamazepinyl-4-quinazolone NC

6, 8-Dibromo-2-carbamazepinyl- 4-quinazolone NCB

 

MATERIALS AND METHODS:

Clearance from the Institutional Animal Ethics Committee, Madras medical College, Chennai, was obtained for carrying out the experiments. Inbred, Male healthy Swiss albino mice (20-25gm) maintained at a room temperature of  25  ± 5º C with relative humidity of (75 ± 5%) under a 12 h light / dark cycle were used. All the animals were acclimatized for a week before use. The animals were housed in poly-propylene cages with standard animal feed. The synthesized compounds were evaluated for analgesic activity. The test compounds and the standard drugs were administered in the form of homogenous suspension (1% carboxy methyl cellulose as vehicle) by the same route of administration. Statistical analyses of the biological activity of the synthesized compounds on animals were evaluated using Kruskal-Wallis test followed by Dunnett’s test. P values <0.05 were considered to be significant.

 

ANALGESIC ACTIVITY:

Test for analgesic activity was performed by acetic acid induced writhing method and tail immersion method.

 


 

Table I: Effect  of 2-hetero substituted-4-quinazolones  ( writhing  method)

Compound / dose  (mg/kg p.o)

Number  of  writhes

p – value comparison  with  vehicle control

Median

Range

Vehicle control

39.5

0,92

---

Standard (Aspirin)

13

0,78

0.16

NN  -  30

15.5

0,48

0.06

NN  -  90

39

4,94

1.00

NNB- 30

21

0,60

0.27

NNB- 90

18

0,52

0.33

NP   - 30

4

0,62

0.01*

NP   - 90

23.5

0,70

0.83

NPB – 30

6

0,66

0.02*

NPB – 90

30

0,90

1.00

NC  -  30

7.5

0,42

0.02*

NC  -  90

6.5

0,70

0.04*

NCB – 30

27

0,78

0.93

NCB –90

17.5

0,50

0.20

n=6;   * - p < 0.05

Note: Evaluated by Kruskal - Wallis Test followed by Dunnett’s t test.

 

Table II Effect of 2 - hetero  substituted - 4 – quinazolones (tail immersion method)

Compound/Dose

(mg/kg p.o)

Latency  Period  (in seconds )

30 Minutes

60  Minutes

120 Minutes

180  Minutes

Median

Range

Median

Range

Median

Range

Median

Range

Vehicle control

3

3, 4

5

3, 9

4.5

3, 8

3.5

3, 10

Standard Pentazocine

4.5

2, 9

7

3, 9

5.5

3, 8

6.5

3, 9

NN 30

3

2, 4

3

2, 4

3

3, 3

3.5

3, 6

NN 90

3.5

2, 20

3

2, 4

3

2, 3

3

3, 6

NNB 30

3.5

3, 5

3.5

3, 5

3

2, 5

4*

4, 7

NNB 90

3.5

3, 5

3.5

3, 5

3

2, 5

4*

4, 7

NP 30

3

2, 8

3

2, 4

3

2,4

3.5

3, 4

NP 90

3

3, 4

3

3, 3

3

3, 4

3

3, 4

NPB 30

3

3, 4

3

3, 5

3

3, 5

4

3, 5

NPB 90

3

3, 4

3.5

3, 6

3.5

3, 7

3.5

3, 7

NC 30

3

3, 5

3

3, 5

3.5

3, 5

4

3, 5

NC 90

3

2, 3

3

3, 4

3.5

3, 4

5.5

4, 8

NCB 30

3

2, 3

3

2, 4

3.5

2, 4

3.5

3, 4

NCB 90

3

2, 10

3

2, 4

3

2, 8

4

3, 6

n=6;    * - p < 0.001 in comparison with vehicle control Note: Evaluated by Kruskal - Wallis Test followed by Dunnett’s t test.

 


 

Writhing method:

Swiss albino mice (20-25gm) of male sex were used for the study. The animals were divided into 14 groups of 12 mice each and were treated as per the regimen in table I. standard drug (aspirin 150mg/kg p.o) and synthesized compounds were administered orally as 1% CMC suspension in the dose level of 30mg/kg, 90mg/kg. The analgesic activity of test compounds was evaluated by their activity to protect writhing syndrome. 30 minutes after the administration of the test compounds the animals were injected 0.6% w/v acetic acid intraperitonially6.The writhing produced in the animals were countered for 30 minutes and recorded. The number of writhes produced in the treated group was compared with that of the vehicle control group. The percent analgesic activity (PAA) was calculated by the formula

 

PAA= 

No of writhes in vehicle control ­– No of writhes in test  X  100

                       No of writhes in vehicle control

 

Tail Immersion method7:

Mice were selected by immersing the tail in hot water at temperature 55 ± 5°C and the basal reaction time was noted.  The mice showing a positive response within 3-5 seconds time duration for withdrawal of the tail completely out of water were included for the study. The selected animals were divided into groups of six each. The synthesized compounds were administered orally as 1% CMC suspension in the dose level of 30mg/kg, 90mg/kg and the standard drug pentazocin 10mg/kg intraperitonially. After oral administration of test compounds, at time intervals 30, 60, 120 and 180 minutes, the latency period in seconds (the time to withdraw the immersed tail from warm water) was recorded. Maximum cut off time of 15sec was followed to avoid undue tissue damage of the tail due to heat.

 

RESULTS AND DISCUSSION:

Evaluation of antinociception activity is one of the basic methods used in the search of new analgesics. It was observed from the results that all the compounds NN, NNB, NP, NPB, NC and NCB showed reduction in the number of writhes when compared to vehicle control (table I). It was noted that the degree of protection offered by NP and NPB was higher than that of standard at 30mg dose level, while NC exhibited protection at 30 and 90 mg/kg dose levels. This model of analgesic activity pertains to peripheral mechanism. Hence the compounds NP, NPB and NC show antinociceptive activity of peripheral nature. The results were recorded in table I.

 

When antinociception was investigated by tail immersion method, the tail flick latency time recorded at 30, 60,120 and 180 minutes revealed that the synthesized compounds NN, NP, NPB, NC and NCB at 30mg/Kg and 90mg/Kg failed to increase the latency withdrawal of tail from warm water when compared to control; compound NNB at 30mg and 90mg showed statistically significant activity when compared to control. The analgesic activity by this method could be attributed to central mechanism. The study related data are pertained in table II.

 

The results of the analgesic activity of the present series showed the statistically significant analgesic activity by writhing method, hence this series could be developed as a novel class of analgesic agents.

 

ACKNOWLEDGEMENT:

The authors are thankful to Madras Medical College, Chennai for extending laboratory facilities to carry out this work.

 

REFERENCES:

1.      Shrimali, M., Kalsi, R., Dixit, K.S., and Barthwal, J.P., Substituted quinazolones as potent anticonvulsants and enzyme inhibitors, Arzneimittel forschung, 1991, 41(5): 514-9.

2.      Niraimathi V, Kesavan K and Vamsadhara C. Acta Ciencia Indica. 2006; XXXII: 3201.

3.      Niraimathi V, Vamsadhara C and Kesavan K. International Journal of Chemical Sciences coded as IJCS/09/1559 in press.

4.      Niraimathi V, Kesavan K and Vamsadhara C. Acta Ciencia Indica coded as 42/C 08/08-09 in press.

5.      Niraimathi V, Vamsadhara C and Lata Sriram. Journal of Pharmaceutical Sciences.2009, 8(3): 159-161.

6.      Koster, R.M., Anderson, M., Debeer, E.T., Acetic acid for analgesic screening, Fed., Proc., 1957, 18, 412-417.

7.      Ghosh, M.N., Fundamental of Experimental Pharmacology, 1984, Second Edition, Scientific Book Agency, Calcutta 1-230.

 

 

 

 

Received on 25.03.2010       Modified on 23.04.2010

Accepted on 29.05.2010      © RJPT All right reserved

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1093-1095