Application of Topliss Modified Approach in the Design and Synthesis of GABA- Nergic Anticonvulsants


RL Sawant1* and MS Bhatia2

1P.D.V.V.P.Fs College of Pharmacy, Vilad Ghat, Post MIDC, Ahmednagar 414 111 (M.S.).

2Bharti Vidyapeeths College of Pharmacy, Near Chitranagari, Kolhapur 416 013 (M. S.)1

*Corresponding Author E-mail:



(14Z)-8-(4-Substituted phenyl) dibenzo[1,2,4]triazolo[b,f][1,4]diazocin-2(3H) ones (3a-e) have been synthesized. The substituents at fourth position of the phenyl ring for initial and final set of compounds have been selected according to Topliss modified approach. The synthesized compounds were structurally characterized by TLC, elemental analysis, IR and NMR spectra studies. The anticonvulsant potential of synthesized compounds was evaluated by using Rotarod, Actophotometer and Electroconvulsometer. The anticonvulsant activity evaluation of initial set of compounds (3a-d) revealed that electron releasing substituents with high lipophilicity if placed at fourth position in phenyl ring should increase the anticonvulsant activity. Based on this observation, 4-dimethylamino substituted compound (3e) was synthesized and found to have increased activity. Topliss modified approach can be successfully used for the design and development of GABA-nergic anticonvulsants containing dibenzodiazepine skeleton.


KEY WORDS: Dibenzo[1,2,4]triazolo[b,f][1,4]diazocin-2(3H)-one, Topliss approach, Anticonvulsant activity, Gamma amino butyric acid (GABA).



A very common problem in drug design is to find the optimum substitution on a benzene ring in an active lead compound for maximization of potency of drug. Since most of all reported medicinally active compounds incorporate an unfused benzene ring, it is essential to search out the optimum substitution on it to maximize the potency. The presence of even a single phenyl ring in a drug structure offers many positions for substitution of variety of substituents. All theses possible substitutions might not really be worth synthesizing. The Topliss modified approach1-3 helps to select a limited number of substituents having good discrimination between lipophilic, electronic and steric factors. In order to overcome the problem of synthetic difficulty Topliss has suggested a useful strategy for the stepwise selection of the substituents for synthesis of new analogues of an active lead to maximize the chances of synthesizing the most potent compound in the given series as early as possible4.


Epilepsy afflicts 1-2% of the worlds population and often goes untreated; nearly 70% of those with a form of epilepsy fail to receive proper treatment5. The most of the currently used antiepileptic agents induce non-specific CNS depression. Hence, current research trends are oriented to design antiepileptics directly acting on Gamma amino butyric acid (GABA) skeleton to increase the potency and selectivity of action6. Biochemical and pharmacological evidence strongly implicates the GABA synapse as major site of action for the benodiazepines7-8.


In the present work, a series of (14Z)-8-(4-Substituted phenyl)dibenzo [1,2,4]triazolo[b,f][1,4]diazocin-2(3H)-ones was synthesized to develop potent GABA-nergic anticonvulsant. The benzodiazepine part is expected to bind with GABA modulin to remove the steric hindrance and triazolo moiety may either move towards GABA receptor cleft or help the endogenous GABA molecules to take easy entry into the receptor cleft. The substituents on the phenyl ring for the initial and final sets of compounds were selected according to Topliss modified approach.



Melting points of the synthesized compounds were determined in open capillary tubes are therefore uncorrected. Purity of final compounds was checked by silica gel G plate using benzene-ethanol as developer. IR spectra were recorded on JASCO FTIR 5300 spectrophotometer using KBr-discs. 1H NMR spectra were recorded on Varian NMR 400 MHz spectrophotometer using TMS as an internal standard and DMSO-d6 as solvent. The structures of the final compounds were established on the basis of elemental analysis and spectral data.


Synthesis of 2-(4-substituted benzoyl) benzoic acids (1a-e) Fridel craft acylation9 method was followed for the synthesis of 2-(4-substituted benzoyl) benzoic acids. To the mixture of phthalic anhydride (0.085 mole) and substituted benzene (0.085 mole), powdered unhydrous aluminium chloride (0.180 mole) was added under stirring. The reaction mixture was refluxed for 3 h until the evolution of hydrogen chloride practically ceased. After cooling, crushed ice was added to the reaction mixture followed by conc. hydrochloric acid until the solution becomes clear. Steam distilled to remove unreacted substituted benzene. Residue on cooling gives crude product. It was treated with sodium carbonate and recrystallized from ethanol.


Synthesis of (11Z)-11-(4-substituted phenyl)dibenzo [b,f][1,4]diazocin-6(5H)ones (2a-e)10

A mixture of 2-(4-substituted benzoyl) benzoic acid (0.025 mole), o-phenylenediamine (0.025 mole) and conc. sulphuric acid (2 ml) in 20 ml dimethyl sulphoxide was refluxed for 4 h. The solid product obtained after addition of ice cold water to the reaction mixture was recrystallized from ethanol.


Synthesis of (14Z)-8-(4-substituted phenyl) dibenzo [1,2,4] triazolo [b,f][1,4] diazocin-2(3H)-ones (3a-e)

A mixture of (11Z)-11-(4-substituted phenyl) dibenzo[b,f][1,4]diazocin-6(5H)one (0.005 mole) and ethyl hydrazine carboxylate (0.0075) in 20 ml dry ethanol containing 0.5 g of sodium was refluxed for 2 h. The reaction mixture was poured in ice water and acidified with concentrated hydrochloric acid to get solid product which was recrystallized from ethanol.


(14Z)-8-(4- Phenyl)dibenzo[1,2,4]triazolo [b,f][1,4] diazocin-2(3H)-ones (3a)

Yield 59.17 %; m.p. 224C; Anal. Calcd. for C21H14N4O; Requires: C, 74.54; H, 4.17; N, 16.56 %; Found: C, 74.41; H, 4.22; N, 16.40 %. IR (KBr, cm-1):

3220 (N-H), 3080 and 3030 (C-H), 1710 (C=O), 1410 (C=C). 1H NMR δ: 2.55 (s, 1H, CONH-N=), 6.57-8.19 (m, 13H, aromatic).


(14Z)-8-(4-Methoxy phenyl)dibenzo[1,2,4]triazolo [b,f][1,4] diazocin-2(3H)-ones (3b)

Yield 50.00 %; m.p. 255C; Anal. Calcd. for C22H16N4O2; Requires: C, 71.73; H, 4.38; N, 15.21 %; Found: C, 71.65; H, 4.52; N, 15.30 %. IR (KBr, cm-1):

3210 (N-H), 3080 and 3030 (C-H), 1690 (C=O), 1430 (C=C), 1220 (C-O-C). 1H NMR δ: 2.54 (s, 1H, CONH- N=), 6.99-8.20 (m, 12H, aromatic), 3.83 (s, 3H, OCH3).


(14Z)-8-(4-Chloro phenyl)dibenzo[1,2,4]triazolo [b,f][1,4] diazocin-2(3H)-ones (3c)

Yield 43.34 %; m.p. 238C; Anal. Calcd. for C21H13ClN4O; Requires: C, 67.66; H, 3.51; N, 15.03 %; Found: C, 67.52; H, 3.58; N, 14.93 %. IR (KBr, cm-1): 3190 (N-H), 3080 and 3030 (C-H), 1700 (C=O), 1450 (C=C), 1150 (Ar-Cl). 1H NMR δ: 2.54 (s, 1H, CONH-N=), 6.60-8.20 (m, 12H, aromatic).


(14Z)-8-(4-Methyl phenyl)dibenzo[1,2,4]triazolo [b,f][1,4] diazocin-2(3H)-ones (3d)

Yield 48.74 %; m.p. 245C; Anal. Calcd. for C22H16N4O; Requires: C, 74.98; H, 4.58; N, 15.90 %; Found: C, 75.04; H, 4.71; N, 15.78 %. IR (KBr, cm-1): 3185 (N-H), 3080 and 3030 (C-H), 1720 (C=O), 1440 (C=C). 1H NMR δ: 2.56 (s, 1H, CONH-N=), 6.60-8.20 (m, 12H, aromatic), 2.34 (s, 3H, CH3).


(14Z)-8-(4-Dimethylamino phenyl)dibenzo[1,2,4]triazolo [b,f][1,4] diazocin-2(3H)-ones (3e)

Yield 66.68 %; m.p. 265C; Anal. Calcd. for C23H19N5O; Requires: C, 72.42; H, 5.02; N, 18.36 %; Found: C, 72.33; H, 4.90; N, 18.22 %. IR (KBr, cm-1): 3195 (N-H), 3080 and 3030 (C-H), 2855 (N-Me), 1690 (C=O), 1495 (C=C). 1HNMR δ: 2.53 (s, 1H, CONH-N=), 6.61-8.20 (m, 12H, aromatic), 2.90 (s, 6H, N (CH3)2).



Motor activity (Rota rod test)11

The mice were trained to remain on an accelerating Rota rod (2 cm diameter) rotating at 10 rpm. A group of two mice was used for one compound and average readings were taken. Trained animals were administered intraperitoneally the test compounds in a dose of 200 mg/kg in fine suspension form with the help of Tween 80. The standard drug diazepam (Calmpose, Ranbaxy Lab. Ltd.) at 20 mg/kg dose was used for comparison. The treated mice were placed on the rod and the time of fall from the rod was noted.


TABLE 1: Characterization data of the title compounds (3ae)







Mol. Formula


Yield (%)



Initial Set














C21H14N4O C22H16N4O2




















Final Set











Motor activity (using Actophotometer)11

The effect of test compounds on the spontaneous locomotor activity of mice was measured by employing Actophotometer. A group of four mice was used for each compound. A dose of 200 mg/kg in the fine suspension form in water with the help of Tween 80 was injected intraperitoneally. Mice were housed in Actophotometer and control readings were recorded for every 5 minutes. The same group after receiving test compounds was housed in Actophotometer and locomotor activity was recorded for every 5 minutes. The standard drug diazepam (Calmpose, Ranbaxy Lab. Ltd.) was administered intraperitoneally to one group at a dose of 20 mg/kg.


Synthetic Scheme:

Anticonvulsant activity12

Albino rats of either sex, weighing between 100-200 g were used as experimental animals. Each group contained two animals. Minimum shock to induce seizures was found to be 0.99 mA. A control group of animals was received a 0.5 % v/v Tween 80 suspension and 0.5 % v/v propylene glycol and a second group received Mazetol (S.G. Chemicals, Baroda) containing carbamazepine as standard at a dose of 20 mg/kg in propylene glycol by intraperitoneal injection. Tween 80 suspensions (0.5 % v/v) of the test compounds were similarly administered at a dose of 200 mg/kg. The shock was delivered after each 30 minutes for two hours and degree of protection against convulsion was noted.



The purity and homogeneity of all the title compounds were confirmed by their sharp melting points and TLC. In all cases these compounds were obtained in solid state and the yields varied from maximum 66% to minimum 43%. The synthesized compounds were subjected to physico-chemical characterization (Table-1) and elemental analysis. The structures of these compounds were confirmed by C, H and N analytical data, IR and 1H NMR spectral data. Pharmacological evaluation of initial set of compounds (3a-d) indicates that compound bearing methyl substituent at fourth position of the phenyl ring (3d) is having maximum anticonvulsant activity. The methyl group has positive π value and negative σ value which reveals that the electron releasing substituents (-ve σ values) with high lipophilicity (+ve π values) if placed at fourth position of phenyl ring should increase the anticonvulsant activity. Based on this observation, 4-dimethylamino substituted compound (3e) was synthesized and found to have increased anticonvulsant activity.



The entire study reveals that Topliss modified approach can be successfully used for the design and development of GABA-nergic anticonvulsants containing dibenzodiazepine skeleton. The substituents on the phenyl ring can be efficiently selected using this approach with committed improvement in biological activity.



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Received on 21.07.2008 Modified on 06.08.2008

Accepted on 10.08.2008 RJPT All right reserved

Research J. Pharm. and Tech. 1(3): July-Sept.. 2008;Page 273-275