Current Research on Antiepileptic Compounds

Epilepsy affects about 1% of the world’s population. Due to the fact all antiepileptic drugs (AEDs) have some undesirable side effects and about 30% of epileptic patients are not seizure-free with the existing AEDs, there is still an urgent need for the development of more effective and safer AEDs. Based on our research work on antiepileptic compounds and other references in recent years, this review covers the reported work on antiepileptic compounds which are classified according to their structures. This review summarized 244 significant anticonvulsant compounds which are classified by functional groups according to the animal model data, although there are some limitations in the data. This review highlights the properties of new compounds endowed with promising antiepileptic properties, which may be proven to be more effective and selective, and possibly free of unwanted side effects. The reviewed compounds represent an interesting possibility to overcome refractory seizures and to reduce the percentage of patients with a poor response to drug therapy.


Introduction
Epilepsy is one of the more common and frequent neurological disorders in man, characterized by excessive temporary neuronal discharges resulting in uncontrolled convulsions that affect more than 2 million Americans and 60 million people worldwide [1]. If not treated, it is associated with progressively impaired cognition and function, brain damage, and other neurologic deficits. Although in many cases, epilepsy can be adequately controlled through administration of antiepileptic drugs (AEDs), it is estimated that roughly 20%-30% of patients have seizures that are resistant to available medical therapies [2][3][4].
Conventional AEDs like phenobarbital, primidone, phenytoin, carbamazepine, ethosuximide and the benzodiazepines are widely used. All currently approved antiepileptic drugs have dose-related toxicity and idiosyncratic side effects [5][6][7][8][9][10][11]. Therefore, the search for a newer, more effective, more selective agent with lesser side effects continues to be an area of investigation of medicinal chemists worldwide.
Anticonvulsant activities of new synthesized compounds were evaluated according to the Antiepileptic Drug Development Program of the National Institutes of Health (NIH) with the maximal electroshock (MES) test, the subcutaneous pentylenetetrazol (sc-PTZ) test, and the neurotoxicity was evaluated by the rotarod neurotoxicity test.
Xie et al., reported a new series of 7-alkoxyl-4,5-dihydro- [1,2,4]triazolo[4,3-a]quinoline derivatives. Their anticonvulsant activities were evaluated by the MES test and the sc-PTZ test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test with a median toxic dose (TD 50 ) value of 54.5 mg/kg, MES and sc-PTZ tests showed that compound 1 (Table 1) was the most potent of this series with an effective dose (ED 50 ) value of 11.8 and 6.7 mg/kg and protective index (PI = TD 50 /ED 50 ) value of 4.6 and 8.1, respectively [12].
Jin et al., prepared a novel type of 7-hydroxyl-3,4-dihydro-2(1H)-quinolines. In the anti-MES test, compound 3 showed ED 50 of 12.3 mg/kg (Table 1), TD 50 of 547.5 mg/kg, and the PI of 44.5 which was much greater than the PI of the reference drugs phenytoin, phenobarbital, carbamazepin and valproate [14]. Sun et al., reported the synthesis of 8-alkoxy-4,5-dihydro- [1,2,4]triazole [4,3-a]quinoline-l-one derivatives and evaluated their anticonvulsant activities by MES test, sc-PTZ test, and rotarod test. The results demonstrated that compound 4 and compound 5 were the most potent anticonvulsants (Table 1), with ED 50 values of 17.17 mg/kg and 24.55 mg/kg and PI values of 41.9 and 29.3 of compound 4 in the MES and sc-PTZ tests, respectively, and compound 5 having ED 50 values of 19.7 mg/kg and 21.2 mg/kg and PI values of 36.5 and 33.9 in the MES and sc-PTZ tests, respectively. The PI values of compounds 4 and 5 were many folds better than that of the reference drugs which mentioned above, which have PI values in the range of 1. 6-8.1 in the MES test and <0. 22-5.2 in the sc-PTZ test [15].
Wei et al., synthesized a series of 2-substituted-7-heptyloxy-4,5-dihydro- [1,2,4]triazolo[4,3-a]quinolin-1(2H)-ones and evaluated their anticonvulsant activities. Pharmacological tests showed that compound 6 was the most active and also had the lowest toxicity (Table 1). In the anti-MES test, it showed ED 50 of 8.2 mg/kg, TD 50 of 318.3 mg/kg, and PI of 39.0 which was much greater than the PI of the reference drugs phenytoin and carbamazepine [16]. Guan (Table 1) [17]. Guan et al., reported the synthesis of a series of novel 5-phenyl- [1,2,4]triazolo [4,3-a]quinoline derivatives and evaluated their anticonvulsant activities. The MES test showed that compound 8 was found to be the most potent compound with an ED 50 value of 6.5 mg/kg and a PI value of 35.1 which was much higher than the PI of the reference drug phenytoin (Table 1) [18].
Guo et al., synthesized a series of 5-alkoxy- [1,2,4]triazolo [4,3-a]quinoline derivatives. Their anticonvulsant activities were evaluated by MES test and their neurotoxicity was measured by the rotarod test. The results demonstrated that compound 9 was the most potent anticonvulsant (Table 1), with ED 50 of 19.0 mg/kg and PI value of 5.8 in the MES test [19].
Wei et al., established a series of 1-formamidotriazolo [4,3-a]quinoline derivatives and evaluated their anticonvulsant activities. Compound 11 showed an ED 50 of 30.1 mg/kg (Table 1), TD 50 of 286 mg/kg, and PI of 9.5 which is greater than the reference drug carbamazepine with the PI value of 6.0 [21].
Kumar et al., demonstrated synthesis of a series of quinoline-incorporated substituted thiadiazole and evaluated their anticonvulsant activity. Compound 16 showed protection against the MES model at 30 mg/kg and showed activity at both 0.5 and 4 h period at dose level of 30 mg/kg indicating the compound to be highly potent and long acting (Table 1) [26].

The Quinazoline or Quinazolinone Functional Groups
As new horizons in anticonvulsant therapy, the quinazolines and quinazolinone structural class has been proved to be useful for the design and development of potent anticonvulsant agents [27,28].
Wang et al., synthesized several series of novel 5-alkoxytetrazolo[1,5-a]quinazoline derivatives. Anticonvulsant activities were evaluated using the MES test. Compound 17 protected completely against MES-induced seizure at a dose of 100 mg/kg (Table 2), and was the best active compound in this series [29].
Zheng et al., prepared a series of novel 5-phenyl- [1,2,4]triazolo [4,3-c]quinazolin-3-amine derivatives and screened their anticonvulsant activities by the MES test and their neurotoxicity was evaluated by the rotarod neurotoxicity test. The most promising compound was 18 (Table 2), which showed an ED 50 value of 27.4 mg/kg and a PI value of 5.8. These values were superior to those provided by valproate (ED 50 and PI values of 272 and 1.6, respectively) in the MES test in mice [30].
El  (Table 2). Compounds 19, 20 and 21 showed better anticonvulsant activity and much lower toxicity comparable with the reference drugs valproate and methaqualone [31].
El-Azab et al., reported a novel series of 7-substituted-4(3H)-quinazolinone and evaluated their antitumor and anticonvulsant activities. Compounds 22, 23, 24, 25, 26 and 27 showed advanced anticonvulsant activity as well as lower neurotoxicity than reference drugs valproate and methaqualone (  20, models in mice. The most active one was compound 33 with ED 50 value of 82.5 mmol/kg (MES) and 510.5 mmol/kg (sc-PTZ) ( Table 2). This molecule was more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs [36].
Saravanan et al., demonstrated some novel quinazolinone derivatives and screened their antiepileptic activity using MES and sc-PTZ seizure tests. The most active one was compound 34 that revealed protection in MES at a dose of 30 mg/kg (ip) after 0.5 and 4 h ( Table 2). This molecule also provided protection in the sc-PTZ at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h) [37]. Table 2. Anticonvulsant activity of quinazoline or quinazolinone compounds.
Molecules 2015, 20, page-page revealed protection in MES at a dose of 30 mg/kg (ip) after 0.5 and 4 h ( Table 2). This molecule also provided protection in the sc-PTZ at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h) [37].  19 2 Molecules 2015, 20, page-page revealed protection in MES at a dose of 30 mg/kg (ip) after 0.5 and 4 h ( Table 2). This molecule also provided protection in the sc-PTZ at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h) [37].

The Thiazole or Benzothiazole Functional Groups
In the past few decades, the literature has been enriched with progressive findings about the anticonvulsant activities of various substituted thiazole derivatives [38,39].
Siddiqui et al., prepared a series of 1,3-benzothiazol-2-yl-semicarbazones and evaluated their anticonvulsant activity. Compounds 35, 36 and 37 had shown 100% protection at both the time intervals, that is, 0.5 and 4 h ( Table 3). None of the compounds had shown the sign of neurotoxicity [40].  Table 2). This molecule also provided protection in the sc-PTZ at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h) [37].

The Thiazole or Benzothiazole Functional Groups
In the past few decades, the literature has been enriched with progressive findings about the anticonvulsant activities of various substituted thiazole derivatives [38,39].
Siddiqui et al., prepared a series of 1,3-benzothiazol-2-yl-semicarbazones and evaluated their anticonvulsant activity. Compounds 35, 36 and 37 had shown 100% protection at both the time intervals, that is, 0.5 and 4 h ( Table 3). None of the compounds had shown the sign of neurotoxicity [40].  Table 2). This molecule also provided protection in the sc-PTZ at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h) [37].

The Thiazole or Benzothiazole Functional Groups
In the past few decades, the literature has been enriched with progressive findings about the anticonvulsant activities of various substituted thiazole derivatives [38,39].

The Thiazole or Benzothiazole Functional Groups
In the past few decades, the literature has been enriched with progressive findings about the anticonvulsant activities of various substituted thiazole derivatives [38,39].

The Thiazole or Benzothiazole Functional Groups
In the past few decades, the literature has been enriched with progressive findings about the anticonvulsant activities of various substituted thiazole derivatives [38,39].

The Thiazole or Benzothiazole Functional Groups
In the past few decades, the literature has been enriched with progressive findings about the anticonvulsant activities of various substituted thiazole derivatives [38,39].
Siddiqui et al., prepared a series of 1,3-benzothiazol-2-yl-semicarbazones and evaluated their anticonvulsant activity. Compounds 35, 36 and 37 had shown 100% protection at both the time intervals, that is, 0.5 and 4 h ( Table 3). None of the compounds had shown the sign of neurotoxicity [40].
All the newly synthesized compounds were screened for their anticonvulsant activity and were compared with the standard drug phenytoin sodium. Compounds 42 and 43 showed complete protection against MES-induced seizures (Table 3) [43].
All the newly synthesized compounds were screened for their anticonvulsant activity and were compared with the standard drug phenytoin sodium.

45
Molecules 2015, 20, page-page All the newly synthesized compounds were screened for their anticonvulsant activity and were compared with the standard drug phenytoin sodium.  (Table 3) [42].
Siddiqui et al., also synthesized a series of sulphonamide derivatives and evaluated their possible anticonvulsant activity and neurotoxicity. Compounds 44 and 45 were active at lower doses of 100 and 30 mg/kg, respectively, after 4.0 h ( Table 3). Compounds 44 and 45 showed activity at 300 mg/kg after 4 h in sc-PTZ screening. Two compounds 44 and 45 showed delayed toxicity that was toxic only after 4.0 h, which were comparable with that of Carbamazepine (300 mg/kg) [44].
Farag et al., reported many derivatives of heterocyclic compounds containing a sulfonamide thiazole moiety and evaluated the anticonvulsant effect. Compound 46 obviously showed anticonvulsant activity with no tonic stretching stage and protected all the animals tested ( Figure 1) [45].

The Benzothiazines or Benzoxazinone Functional Groups
Zhang et al., synthesized a novel series of 7-alkoxy-2H-1,4-benzothiazin-3(4H)-ones and a new series of 7-alkoxy-4H- [1,2,4] [1,4]thiazine derivatives. The anticonvulsant activity of these compounds was evaluated by MES test and tarod test following intraperitoneal injection in KunMing mice. Compound 56 was the most active compound, with an ED 50 of 17.0 mg/kg, TD 50 of 243.9 mg/kg and PI of 14.3 ( Figure 2). The neurotoxicity was the lowest among the synthesized compounds. Meanwhile, it was also significantly lower than carbamazepine that was used as reference. [50].

The Oxadiazole or Benzoxazinone Functional Groups
The oxadiazole scaffold is very versatile and has been subjected to extensive study in recent years. Compounds containing oxadiazole rings have been studied for many biological activities [53].
Tabatabai et al., synthesized a series of some derivatives of 2-(2-phenoxy)phenyl-1,3,4-oxadiazole. Although the most effective compound 63 was a weaker anticonvulsant than diazepam (Table 4), it should be mentioned that it had a good margin of safety and LD50, which were 15-fold its ED50 [55].

The Oxadiazole or Benzoxazinone Functional Groups
The oxadiazole scaffold is very versatile and has been subjected to extensive study in recent years. Compounds containing oxadiazole rings have been studied for many biological activities [53].
Tabatabai et al., synthesized a series of some derivatives of 2-(2-phenoxy)phenyl-1,3, 4-oxadiazole. Although the most effective compound 63 was a weaker anticonvulsant than diazepam (Table 4), it should be mentioned that it had a good margin of safety and LD 50 , which were 15-fold its ED 50 [55].
Harish     (Figure 3). These compounds were more active and had lower neurotoxicity than the control drugs ethosuximide and phenytoin [61].                       (Table 4). These compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg) [57].
Siddiqui et al., reported a synthesis of new 5-(1H-indol-3-yl)methyl-4-(substituted-aryl)-2, 4-dihydro-3H-1,2,4-triazole-3-thiones. All the newly synthesized compounds were screened for their anticonvulsant activity in the MES model and were compared with the standard drugs phenytoin sodium and carbamazepine. Among these compounds, 71 was found to be the most active in the series that showed protection against seizures both after 0.5 h and 4 h at 30 mg/kg body mass (Table 4) [58].
Wei et al., demonstrated a synthesis of novel 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo [d] oxazoles and evaluated the anticonvulsant activity with the MES test and sc-PTZ test. Compound 76 was the most active and also had the lowest toxicity ( Figure 3). In the anti-MES potency test, it showed ED 50 of 29.5 mg/kg, a TD 50 of 285 mg/kg, and a PI of 9.7 which was greater than the reference drug, carbamazepine that has a PI of 6.4 [60].     (Figure 3). These compounds were more active and had lower neurotoxicity than the control drugs ethosuximide and phenytoin [61].

The Pyridine Functional Group
Pyridines and substituted pyridines are an important family of heterocyclic compounds that has attracted significant interest in medicinal chemistry in recent years [63]. Prasanthi et al., reported synthesis of dialkyl 4-(benzo[d] [1,3]dioxol-6-yl)-1,4-dihydro-2,6-dimethyl-1-substituted pyridine-3,5-dicarboxylates. The present study revealed that compound 80 showed promising anticonvulsant activity compared to phenytoin (Figure 4). Further, the prediction data of the molecular properties supports that compound 80 might involve hydrogen bonding interaction with target site, and displayed good binding in silico absorption and lower binding rate of plasma to protein, which made it to be a good candidate for treatment of epilepsy [64].

The Pyrazole Functional Group
Pyrazole and its derivatives consist of five-membered heterocycles with two ortho-nitrogen-atoms.

The Imidazole Functional Group
Imidazole and its derivatives are a class of 5-membered heterocyclic structures having two non-adjacent nitrogen atoms. Recent studies revealed that the substituted imidazole derivatives have attracted much attention due to their broad spectrum of pharmacological activities such as anti-inflammatory, analgesic [75,76]. Literature survey shows that imidazole-heterocyclic compounds could be new classes of anticonvulsant agents by the virtue of their potential anticonvulsant properties [77].
Karakurt et al., described a series of 2-acetylnaphthalene derivatives. Quantification of anticonvulsant protection was calculated via the i.p. route (ED50 and TD50) for the most active candidate (92) (Figure 6). Observed protection in the MES model was 38.46 mg/kg and 123.83 mg/kg in mice and 20.44 mg/kg, 56.36 mg/kg in rats, respectively [78].

The Imidazole Functional Group
Imidazole and its derivatives are a class of 5-membered heterocyclic structures having two non-adjacent nitrogen atoms. Recent studies revealed that the substituted imidazole derivatives have attracted much attention due to their broad spectrum of pharmacological activities such as anti-inflammatory, analgesic [75,76]. Literature survey shows that imidazole-heterocyclic compounds could be new classes of anticonvulsant agents by the virtue of their potential anticonvulsant properties [77].
Karakurt et al., described a series of 2-acetylnaphthalene derivatives. Quantification of anti-convulsant protection was calculated via the i.p. route (ED 50 and TD 50 ) for the most active candidate (92) (Figure 6). Observed protection in the MES model was 38 Figure 5. Structures of compounds 84-91.

The Imidazole Functional Group
Imidazole and its derivatives are a class of 5-membered heterocyclic structures having two non-adjacent nitrogen atoms. Recent studies revealed that the substituted imidazole derivatives have attracted much attention due to their broad spectrum of pharmacological activities such as anti-inflammatory, analgesic [75,76]. Literature survey shows that imidazole-heterocyclic compounds could be new classes of anticonvulsant agents by the virtue of their potential anticonvulsant properties [77].
Karakurt et al., described a series of 2-acetylnaphthalene derivatives. Quantification of anticonvulsant protection was calculated via the i.p. route (ED50 and TD50) for the most active candidate (92) (Figure 6). Observed protection in the MES model was 38.46 mg/kg and 123.83 mg/kg in mice and 20.44 mg/kg, 56.36 mg/kg in rats, respectively [78].   (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82]. Ulloora et al., designed and synthesized new 2-arylimidazo[1,2-a]pyridines carrying suitably substituted 1,2,3-triazoles. The anticonvulsant study was carried out by MES and sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity in both the durations of 0.5 and 4 h indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82]. ]pyridines carrying suitably substituted 1,2,3-triazoles. The anticonvulsant study was carried out by MES and sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity in both the durations of 0.5 and 4 h indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82]. ]pyridines carrying suitably substituted 1,2,3-triazoles. The anticonvulsant study was carried out by MES and sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity in both the durations of 0.5 and 4 h indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82]. ]pyridines carrying suitably substituted 1,2,3-triazoles. The anticonvulsant study was carried out by MES and sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity in both the durations of 0.5 and 4 h indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82]. ]pyridines carrying suitably substituted 1,2,3-triazoles. The anticonvulsant study was carried out by MES and sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity in both the durations of 0.5 and 4 h indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82]. ]pyridines carrying suitably substituted 1,2,3-triazoles. The anticonvulsant study was carried out by MES and sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity in both the durations of 0.5 and 4 h indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82].  12 active pyrazoline, cyanopyridone, cyanopyridine, 2-aminopyrimidine and pyrimidine-2-thione systems. The target compounds were screened for their in vivo anticonvulsant activity following MES and sc-PTZ methods at a small test dose of 10 mg/kg. Compounds 95, 96, 97, 98, 99 and 100 displayed potent anticonvulsant activity without displaying any toxicity (Table 5) [81]. Ulloora et al., designed and synthesized new 2-arylimidazo[1,2-a]pyridines carrying suitably substituted 1,2,3-triazoles. The anticonvulsant study was carried out by MES and sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity in both the durations of 0.5 and 4 h indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82].  12 active pyrazoline, cyanopyridone, cyanopyridine, 2-aminopyrimidine and pyrimidine-2-thione systems. The target compounds were screened for their in vivo anticonvulsant activity following MES and sc-PTZ methods at a small test dose of 10 mg/kg. Compounds 95, 96, 97, 98, 99 and 100 displayed potent anticonvulsant activity without displaying any toxicity (Table 5) [81]. Ulloora et al., designed and synthesized new 2-arylimidazo[1,2-a]pyridines carrying suitably substituted 1,2,3-triazoles. The anticonvulsant study was carried out by MES and sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity in both the durations of 0.5 and 4 h indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug diazepam [82].

The Pyrimidine Functional Group
Pyrimidine is an aromatic heterocyclic organic compound similar to pyridine. One of the three diazines, six-membered heterocyclics with two nitrogen atoms in the ring, has the nitrogens at positions 1 and 3 in the ring. Pyrimidines that have a broad spectrum of bioactivities (antibacteria, anticancer and anti-inflammation and so on) are an important one of the heterocyclic compounds [83][84][85].
Alam et al., synthesized a number of N-(4,6-substituted diphenylpyrimidin-2-yl) semicarbazones and tested their anticonvulsant activity against the two seizure models, MES and sc-PTZ. Three compounds (102, 103 and 104) were found to be significantly active as they showed protection at the lowest dose of 30 mg/kg after 0.5 h and did not show any sign of neurotoxicity except in case of compound 102 which was found to be neurotoxic at 300 mg/kg after 4.0 h (Figure 7) [86].
Deng et al., described the synthesis and anticonvulsant activities of 7-(substituted-phenyl)-6, 7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones and their derivatives. The majority of the compounds synthesized showed inhibition effects on MES-induced convulsion. The most promising compound 105 showed significant anticonvulsant activity in MES test with ED 50 value of 19.7 mg/kg (Figure 7). It was safer than reference drugs with much higher PI value. In addition, the protective effect of compound 105 against seizures induced by PTZ, ISO, TSC, 3-MP, and bicuculline in the chemical-induced seizure tests suggested that compound 103 displayed broad spectrum activity in several models [87].
Jiang et al., reported a novel series of 7-substituted-5-phenyl-[1,2,4]triazolo[1,5-a] pyrimidines. Their anticonvulsant activities were measured through the MES test, and carbamazepine (ED 50 = 11.8 mg/kg) and valproate (ED 50 = 272 mg/kg) were used as the reference drugs. Amongst the compounds tested, compound 106 was the most active in inhibiting convulsion with ED 50 value of 84.9 mg/kg that was higher than valproate but lower than carbamazepine (Figure 7 (Figure 7). In the rotarod motor impairment screen, compound 110 did not show any motor impairment, even at the maximum dose of 300 mg/Kg. The pharmacophore hypothesis also fits best for compounds 110 and 111 [90].

13
Pyrimidine is an aromatic heterocyclic organic compound similar to pyridine. One of the three diazines, six-membered heterocyclics with two nitrogen atoms in the ring, has the nitrogens at positions 1 and 3 in the ring. Pyrimidines that have a broad spectrum of bioactivities (antibacteria, anticancer and anti-inflammation and so on) are an important one of the heterocyclic compounds [83][84][85].
Alam et al., synthesized a number of N-(4,6-substituted diphenylpyrimidin-2-yl) semicarbazones and tested their anticonvulsant activity against the two seizure models, MES and sc-PTZ. Three compounds (102, 103 and 104) were found to be significantly active as they showed protection at the lowest dose of 30 mg/kg after 0.5 h and did not show any sign of neurotoxicity except in case of compound 102 which was found to be neurotoxic at 300 mg/kg after 4.0 h (Figure 7) [86].
Deng et al., described the synthesis and anticonvulsant activities of 7-(substituted-phenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones and their derivatives. The majority of the compounds synthesized showed inhibition effects on MES-induced convulsion. The most promising compound 105 showed significant anticonvulsant activity in MES test with ED50 value of 19.7 mg/kg (Figure 7). It was safer than reference drugs with much higher PI value. In addition, the protective effect of compound 105 against seizures induced by PTZ, ISO, TSC, 3-MP, and bicuculline in the chemical-induced seizure tests suggested that compound 103 displayed broad spectrum activity in several models [87].
Jiang et al., reported a novel series of 7-substituted-5-phenyl-[1,2,4]triazolo[1,5-a] pyrimidines. Their anticonvulsant activities were measured through the MES test, and carbamazepine (ED50 = 11.8 mg/kg) and valproate (ED50 = 272 mg/kg) were used as the reference drugs. Amongst the compounds tested, compound 106 was the most active in inhibiting convulsion with ED50 value of 84.9 mg/kg that was higher than valproate but lower than carbamazepine (  (Figure 7). In the rotarod motor impairment screen, compound 110 did not show any motor impairment, even at the maximum dose of 300 mg/Kg. The pharmacophore hypothesis also fits best for compounds 110 and 111 [90].

The Phthalazine Functional Group
As a heterocyclic compound, the molecular formula of phthalazine is C 8 H 6 N 2 . Because of the broad spectrum of bioactivities such as anticonvulsion, vasorelaxation, anti-inflammation and cardiotonic effect, its derivatives are generally used for treating disease [91][92][93].

The Phthalazine Functional Group
As a heterocyclic compound, the molecular formula of phthalazine is C8H6N2. Because of the broad spectrum of bioactivities such as anticonvulsion, vasorelaxation, anti-inflammation and cardiotonic effect, its derivatives are generally used for treating disease [91][92][93].
Zhang et al., designed and synthesized a new series of 6-alkoxy- [1,2,4]triazolo [3,4-a] phthalazines and evaluated their anticonvulsant activity and neurotoxicity by the MES test and the rotarod test respectively. The most promising compounds 112 and 113 showed a median effective dose of 7.1 and 11.0 mg/kg (Figure 8), and had protective index values of 5.2 and 8.0, respectively. The two compounds were further found to have potent activity against seizures induced by PTZ, ISO, TSC, 3-MP but not seizures induced by strychnine [94].
Sun et al., investigated a new phthalazine tetrazole derivative. Compound 114 exhibited higher activity (ED50 = 6.8 mg/kg) and lower neurotoxicity (TD50 = 456.4 mg/kg) (Figure 8), resulting in a higher PI = 67.1 compared with carbamazepine (PI = 6.4). In addition, compound 114 exhibited significant oral anticonvulsant activity (ED50 = 24 mg/kg) against MES-induced seizure with low neurotoxicity (TD50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5.  (Figure 8). It displayed a wide margin of safety with protective index much higher than the standard drug carbamazepine [96].

The Triazine Functional Group
Triazine is a six membered heterocyclic ring compound containing three nitrogen atoms. The triazine moiety has also attracted the attention of chemists because many triazines are biologically active and are used in medicine, especially as anti-AIDS, anticancer, and antitubercular agents, for their anti-anxiety and anti-inflammatory activities, as well as used in agriculture [97][98][99]. Kaushik

The Triazine Functional Group
Triazine is a six membered heterocyclic ring compound containing three nitrogen atoms. The triazine moiety has also attracted the attention of chemists because many triazines are biologically active and are used in medicine, especially as anti-AIDS, anticancer, and antitubercular agents, for their anti-anxiety and anti-inflammatory activities, as well as used in agriculture [97][98][99]. Kaushik  quantitative median dose of 7 mg/kg. In sc-PTZ screening, compound 120 increased the seizure latency to clonic convulsion and with effective at a median dose of 35 mg/kg (Figure 9) [102].

The Triazolethione Functional Group
Many compounds bearing a triazole moiety were found to possess anticonvulsant properties in various animal models of epilepsy. Therefore, some people want to loop through a combination of triazole-thione compounds to improve the antiepileptic activity.
Luszczki  (Table 6), showed significant anticonvulsant activity in both the screenings with ED50 values of 23.9 mg/kg and 13.4 mg/kg, respectively, in the MES screen and 178.6 mg/kg and 81.6 mg/kg, respectively, in the sc-PTZ test. They displayed a wide margin of safety with PI, median hypnotic dose (HD50) and median lethal dose (LD50) which were much higher than that of the standard drugs [105].
Plech et al., designed and synthesized 4-alkyl-1,2,4-triazole-3-thione derivatives. A group of derivatives showed strong anticonvulsant activity. The characteristic features of the most active compounds were rapid onset and long lasting effects. Among the tested compounds, compound 125 was assayed for the different PI values at different preprocessing times (Table 6), and the results of that were ranging from 2.8 to 9.7 [106].

The Triazolethione Functional Group
Many compounds bearing a triazole moiety were found to possess anticonvulsant properties in various animal models of epilepsy. Therefore, some people want to loop through a combination of triazole-thione compounds to improve the antiepileptic activity.
Plech et al., designed and synthesized 4-alkyl-1,2,4-triazole-3-thione derivatives. A group of derivatives showed strong anticonvulsant activity. The characteristic features of the most active compounds were rapid onset and long lasting effects. Among the tested compounds, compound 125 was assayed for the different PI values at different preprocessing times (Table 6), and the results of that were ranging from 2.8 to 9.7 [106].
Siddiqui et al., designed various 1-(amino-N-arylmethanethio)-3-(1-substituted-benzyl-2,3dioxoindolin-5-yl) ureas. Their in vivo anticonvulsant screenings were performed by the two most adopted seizure models, MES and sc-PTZ. At 300 mg/kg, compounds 127 and 128 showed significant protective effect on MES-and sc-PTZ-induced seizures ( Figure 10). Even at the lower dose of 100 mg/kg, compound 128 exhibited good protection on MES-induced seizure. These two compounds exhibited marked protective effect against seizures in a 6 Hz psychomotor seizure test, and could be used as lead compounds for future investigations [110].
Siddiqui et al., designed various 1-(amino-N-arylmethanethio)-3-(1-substituted-benzyl-2,3dioxoindolin-5-yl) ureas. Their in vivo anticonvulsant screenings were performed by the two most adopted seizure models, MES and sc-PTZ. At 300 mg/kg, compounds 127 and 128 showed significant protective effect on MES-and sc-PTZ-induced seizures ( Figure 10). Even at the lower dose of 100 mg/kg, compound 128 exhibited good protection on MES-induced seizure. These two compounds exhibited marked protective effect against seizures in a 6 Hz psychomotor seizure test, and could be used as lead compounds for future investigations [110].

The Cyclopropanecarboxylate Functional Group
He et al., synthesized twenty three 1-(2-arylhydrazinecarboxamido)-2,2-dimethylcyclopropanecarboxylate derivatives and tested their anticonvulsant activity using the MES, sc-PTZ screens. Their neurotoxicity was determined by applying the rotorod test. The most active compound 130 showed protection against the MES-induced seizures with ED50 value of 9.8 mg/kg and TD50 value of 332.2 mg/kg after i.p. to mice (Figure 11), which provided compound 128 with a PI of 33.9 in the MES test [112].
Zhong et al., reported fourteen ethyl 2,2-dimethyl-1-(2-substituted-hydrazinecarboxamido) cyclopropanecarboxylate derivatives and tested the anticonvulsant activity using the MES, sc-PTZ screens. The most active compound 131 showed protection against MES-induced seizures with an ED50 value of 9.2 mg/kg and TD50 value of 387.5 mg/kg after i.p. to mice (Figure 11), which provided compound 129 with a PI of 42.1 in the MES test [113].

The Cyclopropanecarboxylate Functional Group
He et al., synthesized twenty three 1-(2-arylhydrazinecarboxamido)-2,2-dimethylcyclopropanecarboxylate derivatives and tested their anticonvulsant activity using the MES, sc-PTZ screens. Their neurotoxicity was determined by applying the rotorod test. The most active compound 130 showed protection against the MES-induced seizures with ED 50 value of 9.8 mg/kg and TD 50 value of 332.2 mg/kg after i.p. to mice (Figure 11), which provided compound 128 with a PI of 33.9 in the MES test [112].
Zhong et al., reported fourteen ethyl 2,2-dimethyl-1-(2-substituted-hydrazinecarboxamido) cyclopropanecarboxylate derivatives and tested the anticonvulsant activity using the MES, sc-PTZ screens. The most active compound 131 showed protection against MES-induced seizures with an ED 50 value of 9.2 mg/kg and TD 50 value of 387.5 mg/kg after i.p. to mice (Figure 11), which provided compound 129 with a PI of 42.1 in the MES test [113].

The Pyrrolidine-2,5-dione Functional Group
Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic and medical chemistry [114].

The Pyrrolidine-2,5-dione Functional Group
Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic and medical chemistry [114].

The Pyrrolidine-2,5-dione Functional Group
Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic and medical chemistry [114].

The Pyrrolidine-2,5-dione Functional Group
Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic and medical chemistry [114].

The Pyrrolidine-2,5-dione Functional Group
Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic and medical chemistry [114].

The Pyrrolidine-2,5-dione Functional Group
Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic and medical chemistry [114].

The Pyrrolidine-2,5-dione Functional Group
Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic and medical chemistry [114].

The Pyrrolidine-2,5-dione Functional Group
Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic and medical chemistry [114].
He et al., synthesized new 6-methyl-1-substituted-4,6-diazaspiro [2.4]heptane-5,7-diones and tested the anticonvulsant activity using the MES and sc-PTZ screens. Their neurotoxicity was determined by the rotarod test. The most active of the series was compound 166 (Table 8), which showed a MES ED 50 value of 12.5 mg/kg in mice. The TD 50 was 310 mg/kg, providing compound 166 with a PI of 24.8 in the MES test which is better than that of Phenytoin [138].
He et al., investigated some new N-3-arylamide substituted 5,5-cyclopropanespirohydantoin derivatives synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (sc-PTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. The most active compound 167 showed the MES-induced seizures with ED 50 value of 9.2 mg/kg and TD 50 value of 421.6 mg/kg after i.p. to mice (Table 8) (Table 8) [142].
Botros et al., described new bivalent ligands derived from phenytoin. Initial anticonvulsant screening was performed using MES and PTZ screens in mice. Most of the test compounds were found to be effective in at least one seizure model at a dose of 100 mg/kg. Compound 176 exhibited marked anticonvulsant activity in both MES and PTZ screens (Table 8) [143].
Byrtus et al., established a synthesis of N-Mannich from 5-cyclopropyl-5-phenyl-and 5-cyclopropyl-5-(4-chlorophenyl)-hydantoins and tested their anticonvulsant activity. The quantitative studies after oral administration to rats showed that several molecules were more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. From the whole series, the most active was compound 177 with the ED 50 value of 5.29 mg/kg in the MES test (Table 8) (Table 8). These compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug [145].  (Table 8), with lesser neurotoxicity. Some title compounds showed lesser depression on central nervous system compared to phenytoin [146].  19 phenytoin, it was more active in the anti-convulsion assays. Additionally compound 171 with ED50 of 26.06 mg/kg in a psychomotor seizure test  in mice showed comparable activity to a new generation anticonvulsant-levetiracetam [141].   (Table 8) [142].
Botros et al., described new bivalent ligands derived from phenytoin. Initial anticonvulsant screening was performed using MES and PTZ screens in mice. Most of the test compounds were found to be effective in at least one seizure model at a dose of 100 mg/kg. Compound 176 exhibited marked anticonvulsant activity in both MES and PTZ screens (Table 8) [143].
Byrtus et al., established a synthesis of N-Mannich from 5-cyclopropyl-5-phenyl-and 5-cyclopropyl-5-(4-chlorophenyl)-hydantoins and tested their anticonvulsant activity. The quantitative studies after oral administration to rats showed that several molecules were more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. From the whole series, the most active was compound 177 with the ED50 value of 5.29 mg/kg in the MES test (Table 8) (Table 8). These compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug [145].

The Oxime Ether Functional Group
Due to the lipophilic aryl portion facilitating penetration of the blood-brain barrier, the introduction of oxime ether groups to the compounds as a small oxygen functional group had been studied. Meanwhile, oxime ether linkages also are used as a mechanism for pro-drug generation [147].

20
of oxime ether groups to the compounds as a small oxygen functional group had been studied. Meanwhile, oxime ether linkages also are used as a mechanism for pro-drug generation [147].
Karakurt et al., prepared oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the compounds exhibited anticonvulsant activities. Compounds 187, 188 and 189 (salt) were found to be active at 30 mg/kg at the half-hour time point without neurotoxicity at the same dose level (Table 9). Meanwhile, these derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148]. Karakurt   Meanwhile, oxime ether linkages also are used as a mechanism for pro-drug generation [147]. Karakurt et al., prepared oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the compounds exhibited anticonvulsant activities. Compounds 187, 188 and 189 (salt) were found to be active at 30 mg/kg at the half-hour time point without neurotoxicity at the same dose level (Table 9). Meanwhile, these derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148].
Karakurt et al., reported synthesis of twenty-three new oxime ester derivatives of nafimidone. MES and sc-Met tests were employed for their anticonvulsant activities and rotarod test for neurological deficits. Compound 190 was the most active one in sc-Met test at all dose levels at 4 h (Table 9) [149]. 20 of oxime ether groups to the compounds as a small oxygen functional group had been studied. Meanwhile, oxime ether linkages also are used as a mechanism for pro-drug generation [147]. Karakurt et al., prepared oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the compounds exhibited anticonvulsant activities. Compounds 187, 188 and 189 (salt) were found to be active at 30 mg/kg at the half-hour time point without neurotoxicity at the same dose level (Table 9). Meanwhile, these derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148]. Karakurt (Table 8) [151]. [149] 191 20 of oxime ether groups to the compounds as a small oxygen functional group had been studied. Meanwhile, oxime ether linkages also are used as a mechanism for pro-drug generation [147].
Karakurt et al., prepared oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the compounds exhibited anticonvulsant activities. Compounds 187, 188 and 189 (salt) were found to be active at 30 mg/kg at the half-hour time point without neurotoxicity at the same dose level (Table 9). Meanwhile, these derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148]. Karakurt (Table 8) [151]. [150] 192 20 of oxime ether groups to the compounds as a small oxygen functional group had been studied. Meanwhile, oxime ether linkages also are used as a mechanism for pro-drug generation [147].

20
Due to the lipophilic aryl portion facilitating penetration of the blood-brain barrier, the introduction of oxime ether groups to the compounds as a small oxygen functional group had been studied. Meanwhile, oxime ether linkages also are used as a mechanism for pro-drug generation [147].
Guan et al., synthesized a series of 6-alkoxy- [1,2,4]triazolo [4,3-b]pyridazine derivatives. In initial screening and quantitative evaluation, compound 194 was the most active agent, exhibiting the lowest toxicity at the same time (Table 10). In the anti-MES test, it showed ED 50 of 17.3 mg/kg and TD 50 of 380.3 mg/kg, and the PI of 22.0 which is much better than PI of the reference drugs [156].
Guan et al., synthesized a series of 6-alkoxy- [1,2,4]triazolo [4,3-b]pyridazine derivatives. In initial screening and quantitative evaluation, compound 194 was the most active agent, exhibiting the lowest toxicity at the same time (Table 10). In the anti-MES test, it showed ED50 of 17.3 mg/kg and TD50 of 380.3 mg/kg, and the PI of 22.0 which is much better than PI of the reference drugs [156].
Uysal et al., designed and synthesized sixteen 2/3-benzoylaminopropionanilide derivatives. The anticonvulsant activity profile of the synthesized compounds was determined by MES and sc-Met seizure tests. In the rotarod test, all of them exhibited no toxicity to the nervous system. Compounds 208, 209 and 210 were found to be more potent in the MES or sc-Met tests ( Figure 12). Those compounds have emerged as lead compounds for future investigations [165].  Wang et al., synthesized a series of new purines containing triazole and other heterocycle substituents and evaluated their preliminary anticonvulsant activity and neurotoxicity by using the MES, sc-PTZ and rotarod tests. Among the compounds studied, compound 217 was the most potent compound, with a ED 50 of 23.4 mg/kg and a high protective index of more than 25.6 after intraperitoneal administration in mice ( Figure 12). Compound 217 showed significant oral activity against MES-induced seizures in mice, with an ED 50 of 39.4 mg/kg and a PI above 31.6 [169].
Kahveci et al., designed and synthesized a series of new 1,2,4-triazole-3-one derivatives bearing the salicyl moiety. The anticonvulsant activities of all compounds were evaluated by the Anticonvulsant Screening Program of the U.S. National Institutes of Health. The most active compound 219 showed significant anticonvulsant activity with an ED 50 of 81.1 mg/kg at an approximate TPE (time of peak effect) of 1 h (Figure 12) [171].
Deng et al., reported a synthesis of 10-alkoxy-5,6-dihydrotriazolo [4,3-d]benzo[f ] [1,4] oxazepine derivatives and screened their anticonvulsant activities by the MES test and their neurotoxicity was evaluated by the rotarod test. In the MES test, compound 220 was found to possess better anticonvulsant activity and higher safety than market drugs carbamazepine and phenytoin with an ED 50 value of 6.9 mg/kg a PI value of 9.5 ( Figure 12) [172].
Piao et al., reported a novel series of 9-alkoxy-6,7-dihydro-5H-benzo[c] [1,2,4]triazolo[4,3-a] azepine derivatives and screened their anticonvulsant activity by the MES test and the sc-PTZ test. The results revealed that all of the compounds exhibited anticonvulsant activity, compound 221 was found to possess the most potent anticonvulsant activity in the anti-MES potency test (Figure 12), it had a ED 50 value of 12.3 mg/kg, a TD 50 value of 73.5 mg/kg, and a PI of 6.0, which was slightly lower than the PI of the prototype drug carbamazepine (ED 50 = 8.8, PI = 8.1). In the sc-PTZ test, compound 222 was the most active, with an ED 50 value of 19.8 mg/kg, a TD 50 value of 80.8 mg/kg and a PI value of 4.1, which are greatly higher than that of carbamazepine (ED 50    Guan et al., demonstrated a synthesis of novel series of N-(2-hydroxyethyl)amide derivatives and screened their anticonvulsant activities by the MES test, and their neurotoxicity was evaluated by the rotarod test. The MES test showed that compounds 241, 242 and 243 were found to show a better anticonvulsant activity and also had lower toxicity than the market anti-epileptic drug valproate ( Figure 13).
Senthilraja et al., synthesized a new series of 2-(4-dimethylaminophenyl)-3-substituted thiazolidin-4-one-5-yl-acetyl acetamides/benzamides. The title compounds were investigated for their anticonvulsant Guan et al., demonstrated a synthesis of novel series of N-(2-hydroxyethyl)amide derivatives and screened their anticonvulsant activities by the MES test, and their neurotoxicity was evaluated by the rotarod test. The MES test showed that compounds 241, 242 and 243 were found to show a better anticonvulsant activity and also had lower toxicity than the market anti-epileptic drug valproate ( Figure 13).
Senthilraja et al., synthesized a new series of 2-(4-dimethylaminophenyl)-3-substituted thiazolidin-4-one-5-yl-acetyl acetamides/benzamides. The title compounds were investigated for their anticonvulsant activities, among the test compounds, compound 244 emerged as the most active compound of the series and as moderately more potent than the reference standard diazepam ( Figure 13) [182].

Conclusions
All in all, based on our laboratory work and the recent literature, this review summarized some significant anticonvulsant compounds which are classified by functional groups and according to data obtained by studies designed in animal models. This review illustrates the various attempts made to discover and develop antiepileptic compounds with more effective and selective effects, and reduced secondary actions. The extensive work reviewed here may represent a starting point to allow a better understanding of antiepileptic therapeutic developments as well as to suggest ideas on design and synthesis of novel antiepileptic compounds.