P. Paneersalvam1, T. Raj, M. P. S. Lshar, B. Singh, V. Sharma and B. A. Rather*

Bio-Organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev University Amritsar-143 005, India 1Department of Pharmaceutical Chemistry, C. L. Baid Mehta College of Pharmacy, Jyothi Nagar, Rajiv Gandhi Salai, Thorapakkam, Chennai - 600 097, India

*Corresponding Author:
B. A. Rather Bio-Organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev University Amritsar-143 005, India E-mail: rather_bilu@rediffmail.com
Date of Submission 13 July 2009
Date of Revision 11 January 2010
Date of Acceptance 15 May 2010
Indian J. Pharm. Sci., 2010, 72 (3): 375-378  

DOI: 10.4103/0250-474X.70488

Abstract

Schiff bases (9a-l) of 3-amino-6,8-dibromo-2-phenyl-quinazolin-4-(3H)-ones (8) with various substituted aldehydes were obtained by refluxing 1:1 molar equivalents of the reactants in dry ethanol for 6 h. The aminoquinazoline (8) was inturn obtained from 3,5-dibromoantharlinic acid via intermediate (7). All the synthesized compounds (9a-l) were evaluated for their anticonvulsant activity on albino mice by maximal electroshock method using phenytoin as a standard. The compound (9l) bearing a cinnamyl function displays a very high activity (82.74 %) at dose level of 100 mg/kg b.w.

Keywords

Anticonvulsant, maximal electroshock method, Schiff base, Quinazolin-4-(3H)-one, 3-aminoquinazolines

Quinazolinones and their Schiff bases are an important class of heterocyclic systems, enjoying considerable interest on account of their diverse range of biological activities [1-9] such as antimicrobial, analgesic and antiinflammatory, anticonvulsant, anticancer, antitubercular, antimalarial, antiviral, antihelmintic and, in particular, very high anticonvulsant activity. Anticonvulsant quinazolinones include methaqualone (1) [10], which acts on voltage dependant sodium channels in a manner similar to rilozole (2) [11,12], 2-(chloromethyl)-1- (4-methoxyphenyl)-quinazolin-4(1H)-one (3) and 2-methyl-3-(5-phenyl-4,5-dihydroisoxazoli-3-ylamino) quinazolin-4(3H)-one (4, fig 1). Structural modification of the quinozolines nucleus i.e., introduction of Ph- and -CH3 group at C2 position [13], bromination of benzene ring at C6 and C8, introduction of various substituted phenyl moieties [14], bridged phenyl rings [15], heterocyclic rings [16] and aliphatic moieties [17] at position-3 are reported to enhance the anticonvulsant activity. The high anticonvulsant activity of quinazolines is also a consequence of their high membrane permeability [18].

Figure

Fig 1: Some of potent anticonvulsant compounds.
1 is methaqualone, 2 is rilozole, 3 is 2-(chloromethyl)-1-(4- methoxyphenyl)-quinazolin-4(1H)-one (3) and 4 is 2-methyl-3-(5- phenyl-4,5-dihydroisoxazoli-3-ylamino)quinazolin-4(3H)-one

Earlier, we had reported [19,20] synthesis and antimicrobial activity of Schiff bases of 3-amino- 6,8-dibromo-2-phenyl-quinazolin-4-(3H)-ones (9a-l). Taking cognizance of the reported high anticonvulsant activity of the quinazolines, it was decided to synthesize the Schiff bases of 3-amino-quinazolines according to the earlier reported procedure [19,20] and evaluate their anticonvulsant activity.

Synthesis of Schiff bases (9a-l) of 3-amino-6,8- dibromo-2-phenyl-quinazolin-4(3H)-ones [19,20] (8) with various substituted aldehydes was achieved by refluxing their equimolar dry ethanol solution for 6 h. The Schiff bases (9a-l) were filtered, dried and recrystallised from absolute ethanol (fig. 2). All compounds (9a-l) were analyzed using detailed spectroscopic (IR, 1H NMR, 13C NMR, Mass) and elemental analysis.

Figure

Fig 2: Synthesis of Schiff bases of 3-amino-6,8-dibromo-2-phenyl quinazolin-4(3H)-ones 9(a-l)
Synthesis of Schiff bases of 3-amino-6,8-dibromo-2-phenyl quinazolin-4(3H)-ones 9a-l from reaction of 8 with different aldehydes a-l, (a) R= Ph-, (b) R= p-MeO-Ph-, (c) R= o-OH-Ph-, (d) R= p-N(CH3)2-Ph-, (e) R= m-NO2-Ph-, (f) R= p-Me-Ph-, (g) R= p-OH-Ph-, (h) R= p-Cl-Ph-, (i) R= p-NO2-Ph-, (j) R= m,m,p-(OCH3)3-Ph-, (k) R= p-OH,m-OMe-Ph-, (l) R=-CH=CH-Ph

The animal study protocols were approved by Institutional Animal Ethics Committee’s (IAEC) approval. Anticonvulsant activity of all compounds (9a-l, Table 1) was evaluated by maximal electroshock (MES) method [21]. Swiss mice (n=6) of either sex selected by random sampling technique were used for the study. Phenytoin at the dose of 10 mg/kg (i.p.) was administered as standard drug for comparison. The test compounds were suspended in polyethylene glycol in the ratio of 1:9/ml in water and were given i.p. at doses of 100-200 mg/ kg body weight. Dosing volume was 0.25 ml per 25 g. The animals were held at suitable position and corneal electrodes were placed on the cornea of the mice and applied 50 mA current for 0.2 sec after half an hour administration of the test compounds. Then the time spent by animals in each phase of convulsion was recorded. Animals in which extensor response was abolished were taken as protected mice. Compound 9l (82.74 %) was found to possess high anticonvulsant activity which is followed by 9g (81.61 %), 9i (81.48 %), 9k (81.48 %), 9j (80.29 %) at the dose of 100 mg/ kg. Moderate anticonvulsant activity was observed for the compounds 9e (79.03%) followed by 9d (79.01 %), 9f (77.77 %), 9h (77.77 %), 9c (74.07 %) and 9b (72.88 %). Compound 9a showed very low anticonvulsant activity of (68.14%) at the dose level of 100 mg/kg.

Compounds Dose (mg / kg) Flexion phase Extensor phase
Mean± SEMa % protection Mean± SEMa % protection
9a 100 5.66±0.4375 27.99 4.3±0.21875 68.14
  200 4.62±0.3125 35.52 3.6±0.21875 73.33
9b 100 5.66±0.4375 21.01 3.66±0.21875 72.88
  200 4.82±0.3125 32.73 3.50±0.21875 74.07
9c 100 5.66±0.4375 27.99 4.3±0.21875 74.07
  200 4.62±0.3125 35.52 3.6±0.21875 76.29
9d 100 5.66±0.4375 21.01 3.66±0.21875 79.01
  200 4.82±0.3125 32.73 3.50±0.21875 80.59
9e 100 4.5±0.21875 37.2 3.5±0.21875 79.03
  200 3.74±0.2187 48.36 3.2±0.15625 82.07
9f 100 4.5±0.21875 37.2 2.83±0.15625 77.77
  200 3.9±0.21875 45.57 2.62±0.15625 79.25
9g 100 5.33±0.3125 25.62 2.83±0.15625 81.61
  200 4.9±0.3125 31.62 2.42±0.09375 83.70
9h 100 5.0±0.3125 30.22 3.0±0.15625 77.77
  200 4.8±0.3125 33.01 2.8±0.15625 79.25
9i 100 5.3±0.3125 26.03 2.5±0.09375 81.48
  200 4.98±0.3125 30.50 2.2±0.09375 83.70
9j 100 5.83±0.4375 18.57 3.0±0.15625 80.29
  200 5.1±0.3125 28.83 2.8±0.15625 82.96
9k 100 5.66±0.4375 20.94 2.5±0.09375 81.48
  200 5.22±0.3125 27.15 2.2±0.09375 84.44
9l 100 6.5±0.4027 9.21 2.66±0.15625 82.74
  200 5.31±0.3125 25.90 2.30±0.09375 84.07
Phenytoin 10 4.8±0.3125 32.48 0.00±0.00 100
Control - 7.16±0.5625 - 13.5±0.6875 -

Table 1: Anticonvulsant activity of compounds

Structure activity relationship (fig. 3, Table 2) for all the compounds was developed on the % protection data of extensor phase at dose of 100 mg/kg. Compounds 9l, g, i, bearing CH=CH-Ph, -p-OH-Ph, -p- NO2-Ph moieties, showed maximum % protection of 82.74, 81.61 and 81.48. Moderate % protection of 79.01, 77.77, 74.07 and 72.88 was observed for compounds 9d, f, c, b, respectively, possessing electron donating groups such –p-N(CH3)2-Ph, -p-Me-Ph, -o-OH-Ph, -p-OMe-Ph. However, very low anticonvulsant activity was observed for 9a bearing unsubstituted aromatic ring.

Figure

Fig 3: Quinazolone schiff base

R Activity
-CH=CH-Ph, -p-OH-Ph, -NO2-Ph High
-N(CH3)2, -Me-Ph, -o-OH-Ph, -OMe-Ph Moderate
Ph Low

Table 2: Structure activity relationship

In conclusion, the present study indicates that compounds 9l, g, i Possessing styryl, p-OH-Ph or -p-NO2-Ph were found to posses high anticonvulsant activity, which may be attributed extended conjugation in case of 9l or hydrogen bonding ability of parasubstituent as in the case of 9g, i. While the compounds 9b, c, d, f bearing electron donating groups (-N(CH3)2, -Me, -o-OH, -OMe), display moderate activity; among the latter para-substituted compound (9d) is most active thereby confirming our earlier inference. On the other hand compound bearing unsubstituted phenyl group showed low activity. These compounds shall serve as ‘Lead’ molecules for further development.

References