Current Research on Antiepileptic Compounds - Semantic Scholar

Review

Current Research on Antiepileptic Compounds Cheng-Xi Wei 1,† , Ming Bian 1,† and Guo-Hua Gong 1,2, * Received: 29 July 2015 ; Accepted: 6 November 2015 ; Published: 20 November 2015 Academic Editor: Derek J. McPhee 1 2

* †

Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao 028000, China; [email protected] (C.-X.W.); [email protected] (M.B.) Affiliated Hospital of Inner Mongolia University for Nationalities, Tongliao 028000, Inner Mongolia, China Correspondence: [email protected]; Tel./Fax: +86-475-831-4245 These authors contributed equally to this work.

Abstract: 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. Keywords: epilepsy; antiepileptic compounds; structure activity relationship

1. 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 [2–4]. 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 [5–11]. 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.

Molecules 2015, 20, 20741–20776; doi:10.3390/molecules201119714

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Molecules 2015, 20, 20741–20776 Molecules Molecules 2015, 2015, 20, 20, page–page page–page

Molecules 2015, 20, page–page 2. Quinoline Functional 2. The Quinoline Functional Group 2.The The Quinoline FunctionalGroup Group

Quinoline is Quinoline isis nitrogen-containing nitrogen-containing heterocyclic aromatic compound. Pharmacologically active 2. The Quinoline Functional Group heterocyclic Quinoline nitrogen-containing heterocyclic aromatic aromatic compound. compound. Pharmacologically Pharmacologicallyactive active substances display a broad range of biological activity. Quinoline has been found to possess anti-malarial, substances a broad rangerange of biological activity. activity. QuinolineQuinoline has been found to possess anti-malarial, substancesdisplay display a broad of biological has been found to possess Quinoline is nitrogen-containing heterocyclicanticonvulsant, aromatic compound. Pharmacologically active antibacterial, anthelmintic, anti-inflammatory, and antibacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, and analgesic analgesic anti-malarial,antifungal, antibacterial, antifungal,cardiotonic, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, substances display a broad range of biological activity. Quinoline has been found to possess anti-malarial, activity. Our studied aa lot quinoline for activity activity. Our laboratory laboratory has studied lot of of quinoline derivatives for antiepileptic antiepileptic activity [12–23]. and analgesic activity. has Our laboratory has studiedderivatives a lot of quinoline derivatives for [12–23]. antiepileptic antibacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, and analgesic Xie et al., reported a new series of 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline Xie et al., reported a new series of 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline derivatives. derivatives. activity [12–23]. activity. Our laboratory has studied a lot of quinoline derivatives for antiepileptic activity [12–23]. Their anticonvulsant activities were evaluated by Their Xie anticonvulsant activities were series evaluated by the the MES MES test test and and the the sc-PTZ sc-PTZ test, test, and and their their et al., reported a new of 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline Xie et al., reported a new series of 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline derivatives. neurotoxicity was evaluated by the rotarod neurotoxicity test with a median toxic dose (TD 50 ) value 50 neurotoxicity by the rotarod test with a median toxic dose 50) value derivatives. was Theirevaluated anticonvulsant activitiesneurotoxicity were evaluated by the MES test and the(TD sc-PTZ test, Their anticonvulsant activitiestests were evaluated by the MES test and was the the sc-PTZ test, andof their of 54.5 mg/kg, MES that compound 11 (Table potent this of 54.5 mg/kg, MES and and sc-PTZ sc-PTZ tests showed showed that compound (Table 1) 1) was theamost most potent of dose this and their neurotoxicity was evaluated by the rotarod neurotoxicity test with median toxic neurotoxicity was evaluated by 50 the rotarod neurotoxicity test with a median toxic dose=(TD 50) value value of and 6.7 and protective 50 50 series an effective dose 50 50 50 50)) and value of 11.8 11.8tests andshowed 6.7 mg/kg mg/kg and protective index (PI (PI = TD TDthe 50/ED /ED 50)) series with an of effective dose (ED (ED (TD50with ) value 54.5 mg/kg, MES sc-PTZ that compound 1 index (Table 1) was most of 54.5 mg/kg, MES and sc-PTZ tests showed that compound 1 (Table 1) was the most potent of this value of 4.6 and 8.1, respectively [12]. value 4.6this andseries 8.1, respectively [12]. dose (ED ) value of 11.8 and 6.7 mg/kg and protective index potentofof with an effective series with an effective dose (ED50) value of 11.850and 6.7 mg/kg and protective index (PI = TD50/ED50) (PI = TD50 /ED50 ) value of 4.6 and 8.1, respectively [12]. value of 4.6 and 8.1, respectively Table 1. Table[12]. 1. Quinoline Quinoline anticonvulsant anticonvulsant compounds. compounds. 77 R R111 878 R1

66

55Table 1. Quinoline 55 anticonvulsant 44 compounds. O O Table anticonvulsant C H 44 1. Quinoline C compounds. H 6 4

6

5 N N

N N4 33 N N R R 11 22 N 8 N3 N 1-10 1-10 R 1 2

6

776 7

5

4

N N H H 11 88 N H 11-15 11-15 1 8

33

C777H15 15 15

223

C7H15

O O O

2 16 16

N N

N N N N

N

N N

O

Compound R R Compound No. No. R R111 1-10 -H 11-157-OCH2Ph(4-F) 16 11 -H 7-OCH22Ph(4-F) Compound No. R R1 Compound No. R R 22 -Ph 7-OCH Ph 1 -Ph 7-OCH222Ph 1 2 Ph(4-F) -H 7-OCH -H 7-OCH 331 =O 7-OCH 222Ph =O 7-OCH Ph 2 Ph(4-F) 27-OCH Ph -Ph -Ph 7-OCH66H 2 Ph 442 =O 8-n-OC 13 =O 8-n-OC6H13 13 3 =O 7-OCH 2 Ph =O 7-OCH2Ph 553 =O 8-n-OC 15 =O 8-n-OC777H H15 15 4 =O 8-n-OC 6 H13 =O 8-n-OC 6H13 6645 =O 7-n-OC 55 15 =O 7-n-OC777H H15 15,, 2-COC 2-COC H =O 8-n-OC222H 7 H5 15 =O 8-n-OC 7H15 7756 -H 5-Ph(3-F) =O 7-n-OC H , 2-COC 7 15 2 H5 -H 5-Ph(3-F) 6 =O 7-n-OC 7H15, 2-COC 2H5 7 -H 5-Ph(3-F) 88 -H 7-n-C 13 -H 7-n-C666H H13 13,, 5-Ph, 5-Ph, 4=5 4=5 -H 7-n-C6 H13 , 5-Ph, 4=5 -H 5-Ph(3-F) 9978 -H 5-n-OC 6 H 13 6 13 -H 5-n-OC65-n-OC H13 6 H13 89 -H 22 -H 7-n-C 6H13, 5-Ph, 4=5 10 -CONH 7-n-OC 666H 13 10 -CONH-CONH 2 7-n-OC H13 13 10 7-n-OC 2 6 H13 9 -H 5-n-OC 6H13 11 5-(1,3,4-triazole), 888H , 1=2 and 3=4 17 11 5-(1,3,4-triazole),8-n-OC 8-n-OC , and 3=4 11 5-(1,3,4-triazole), 8-n-OC H17 17 , 1=2 and 3=4 17 10 -CONH 2 7-n-OC 6H13, 12 6-(1,3,4-triazole), 1-n-OC 12 6-(1,3,4-triazole), 1-n-OC H 13 , 2=O 6 13 6 13 12 6-(1,3,4-triazole), 1-n-OC6H13, 2=O O OH O and 3=4 OH 11 5-(1,3,4-triazole), 8-n-OC228H17, 1=2 12 6-(1,3,4-triazole), 1-n-OC 6 H 13 , 2=O N N N N O O H H OH H 13 2 OH 13 13 O O 13

1=2 and 1=2 and3=4, 3=4,8-OCH 8-OCH2222Ph, Ph, Ph, 1=2 and 3=4, 8-OCH

O

1=2 and 3=4, 8-OCH2Ph, 14 14 14

14 15 15 15

2 2O 2 HN HN O O HN

1=2 and 3=4, 1=2 and 3=4,8-OCH 8-OCH2222Ph, Ph, Ph, 1=2 and 3=4, 8-OCH

O

S S S S N N

N H

O O N N N

N N N N 1=2 and 3=4, 8-OCH2Ph,

1=2 and 1=2 and 3=4, 2-Cl, 1=2 and3=4, 3=4,2-Cl, 2-Cl, 33

N H

Reference Reference [12] [12] Reference Reference [13] [13] [12] [12] [14] [14] [13] [13] [15] [14] [15] [14] [15] [16] [16] [15] [17] [16] [17] [16] [17] [18] [18] [18] [17] [19] [19] [19] [18] [20] [20] [20] [19] [21] [21] [21] [20] [22] [22] [22] [21] [22] [23] [23] [23]

[23] OH OH

[24] [24] [24]

OH

[24]

O

O O NH NH O

Cl Cl

[25] [25] [25]

Cl [25] NH S 1=2 and 3=4, 2-Cl, 3 S Cui Cui et et al., al., reported reported aa synthesis synthesis of of 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]Cui et al., reported a synthesis of 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines. Anticonvulsant activity was evaluated quinolines. Anticonvulsant activity was evaluated in in the the MES MES test, test, sc-Met sc-Met test, test, and and rotarod rotarod neurotoxicity neurotoxicity quinolines. Anticonvulsant activity ofwas evaluated in the MES test, sc-Met test, and rotarod Cui et al., reported a synthesis 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]test. 50 test. The The safest safest compound compound was was 22 (Table (Table 1), 1), with with TD TD50 50 values values of of greater greater than than 300 300 mg/kg mg/kg which which was was neurotoxicity test. The safest compound was 2 (Table with TDsc-Met greater than 300 mg/kg 50 values quinolines. Anticonvulsant activity was evaluated in the1), MES test, test,ofand rotarod neurotoxicity better than most of the market drugs [13]. better than most of the market drugs [13]. which was better than mostwas of the market1),drugs test. The safest compound 2 (Table with[13]. TD50 values of greater than 300 mg/kg which was Jin Jin et et al., al., prepared prepared aa novel novel type type of of 7-hydroxyl-3,4-dihydro-2(1H)-quinolines. 7-hydroxyl-3,4-dihydro-2(1H)-quinolines. In In the the anti-MES anti-MES test, test, better than most of the market drugs [13]. compound 50 50 compound 33 showed showed ED ED50 50 of of 12.3 12.3 mg/kg mg/kg (Table (Table 1), 1), TD TD50 50 of of 547.5 547.5 mg/kg, mg/kg, and and the the PI PI of of 44.5 44.5 which which Jin et al., prepared a novel type of 7-hydroxyl-3,4-dihydro-2(1H)-quinolines. In the anti-MES test, 221), TD50 of 547.5 mg/kg, and the PI of 44.5 which 20742 compound 3 showed ED50 of 12.3 mg/kg (Table

15

2

Molecules 2015, 20, 20741–20776

Jin et al., prepared a novel type of 7-hydroxyl-3,4-dihydro-2(1H)-quinolines. In the anti-MES test, compound 3 showed ED50 of 12.3 mg/kg (Table 1), TD50 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 ED50 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 ED50 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 51 [47]. test with ED50 value of 13.6 mg/kg (Figure 1). Meanwhile, its neurotoxicity was extremely low, with Deng et al., reported synthesis of 7-alkoxy-triazolo-[3,4-b]benzo[d]thiazoles. In the MES test, most PI > 51 [47]. of the compounds synthesized showed good effects on convulsion. Among the compounds studied, Deng et al., reported synthesis of 7-alkoxy-triazolo-[3,4-b]benzo[d]thiazoles. In the MES test, compound 51 was found to be the most potent compound with ED50 value of 8.0 mg/kg and PI value most of the compounds synthesized showed good effects on convulsion. Among the compounds of 15.0 (Figure 1), possessing better anticonvulsant activity and higher safety than market drugs studied, compound 51 was found to be the most potent compound with ED50 value of 8.0 mg/kg and carbamazepine and phenytoin. Compound 51 exhibited activities of broad spectrum in several animal PI value of 15.0 (Figure 1), possessing better anticonvulsant activity and higher safety than market models [48]. drugs carbamazepine and phenytoin. Compound 51 exhibited activities of broad spectrum in several Siddiqui et al., synthesized a number of new 8-substituted-4-(2/4-substituted phenyl)-2Hanimal models [48]. [1,3,5]triazino[2,1-b][1,3]benzothiazole-2-thiones and evaluated their anticonvulsant in a mouse seizure model and were comparable with the standard drug phenytoin. Compounds 52, 53, 54 and 55 showed complete protection after time periods of 0.5 h and 4 h (Figure 1) [49]. 20747 5. 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

Molecules 2015, 20, 20741–20776

Siddiqui et al., synthesized a number of new 8-substituted-4-(2/4-substituted phenyl)-2H-[1,3,5] triazino[2,1-b][1,3]benzothiazole-2-thiones and evaluated their anticonvulsant in a mouse seizure model and were comparable with the standard drug phenytoin. Compounds 52, 53, 54 and 55 showed complete protection after time periods of 0.5 h and 4 h (Figure 1) [49]. 5. 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]triazolo[4,3-d]benzo[b][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 ED50 of 17.0 mg/kg, TD50 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]. Siddiqui et al., reported a series of (Z)-2-(substituted aryl)-N-(3-oxo-4-(substituted carbamothioyl)-3, 4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)hydrazine carboxamides. The anti-convulsant activity was assessed by the MES test, sc-PTZ test and intraperitoneal thiosemicarbazide test (i.p. TSC). Compounds 57, 58, 59 and 60 were the most active ones, protecting 83%–100% of the animals against MES-induced seizures (Figure 2), and also exhibited potent anticonvulsant activity in Molecules 2015, 20, page–page chemical-induced seizures [51]. Piao et etal., al.,prepared preparedaaseries seriesofof 7-benzylamino-2H-1,4-benzoxazin-3(4H)-ones.Their Theiranticonvulsant anticonvulsant Piao 7-benzylamino-2H-1,4-benzoxazin-3(4H)-ones. activities were evaluated by the MES test and their neurotoxicity was evaluated by the rotarod rotarod activities were evaluated by the MES test and their neurotoxicity was evaluated by the neurotoxicity test. The MES test showed that compound 61 was the most potent with ED 50 value neurotoxicity test. The MES test showed that compound 61 was the most potent with ED50 value of of 31.7 mg/kg PI value of 7.2 (Figure 2) [52]. 31.7 mg/kg andand PI value of 7.2 (Figure 2) [52].

S

O F

N 56

N N

O

HN F

N H

O

R1 57 58 59 60

N

H N

H N

O

O R1=H R1=4-Cl R1=4-Cl R1=3-NO2

R2=CH3 R2=CH3 R2=OCH3 R2=4-Cl

N HN

O S

R2

61

Figure Figure 2. 2. Structures Structures of of compounds compounds 56–61. 56–61.

6. The Oxadiazole or Benzoxazinone Functional Groups 6. The Oxadiazole or Benzoxazinone Functional Groups The oxadiazole scaffold is very versatile and has been subjected to extensive study in recent years. The oxadiazole scaffold is very versatile and has been subjected to extensive study in recent Compounds containing oxadiazole rings have been studied for many biological activities [53]. years. Compounds containing oxadiazole rings have been studied for many biological activities [53]. Bhat et al., prepared a series of 3-(4-acetyl-5H/methyl-5-substituted phenyl-4,5-dihydro-1,3,4Bhat et al., prepared a series of 3-(4-acetyl-5H/methyl-5-substituted phenyl-4,5-dihydro-1, oxadiazol-2-yl)-2H-chromene-2-ones and evaluated their anticonvulsant activity and neurotoxicity. 3,4-oxadiazol-2-yl)-2H-chromene-2-ones and evaluated their anticonvulsant activity and neurotoxicity. Compound 62 was found to be potent and had activity at a lower dose of 30 mg/kg in MES-test (Table 4). Compound 62 was found to be potent and had activity at a lower dose of 30 mg/kg in MES-test All the compounds were less toxic as compared with the standard drug phenytoin [54]. (Table 4). All the compounds were less toxic as compared with the standard drug phenytoin [54]. Tabatabai et al., synthesized a series of some derivatives of 2-(2-phenoxy)phenyl-1,3,4-oxadiazole. Tabatabai et al., synthesized a series of some derivatives of 2-(2-phenoxy)phenyl-1,3, Although the most effective compound 63 was a weaker anticonvulsant than diazepam (Table 4), it 4-oxadiazole. Although the most effective compound 63 was a weaker anticonvulsant than diazepam should be mentioned that it had a good margin of safety and LD50, which were 15-fold its ED50 [55]. (Table 4), it should be mentioned that it had a good margin of safety and LD50 , which were 15-fold its Harish et al., reported a series of novel 1-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-piperazine ED50 [55]. derivatives. The anticonvulsant effects of these derivatives on MES-induced seizures were Harish et al., reported a series of novel 1-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-piperazine experimented in male Wistar rats and phenytoin was used as reference drug. Compounds 64, 65, 66 derivatives. The anticonvulsant effects of these derivatives on MES-induced seizures were and 67 showed excellent anticonvulsant activity in MES model (Table 4) [56]. Harish et al., investigated a series of new 2-methyl-2-[3-(5-piperazin-1-yl-[1,3,4]oxadiazol-2-yl)20748 were screened for their anticonvulsant activity phenyl]-propionitrile derivatives. All the compounds against MES seizure and their neurotoxic effects were determined by rotorod test. Compounds 68, 69 and 70 were found to be the most potent of this series (Table 4). These compounds showed no

Molecules 2015, 20, 20741–20776

experimented in male Wistar rats and phenytoin was used as reference drug. Compounds 64, 65, 66 and 67 showed excellent anticonvulsant activity in MES model (Table 4) [56]. Molecules 2015, 20, page–page Molecules 2015, 2015, 20, 20, page–page page–page Molecules Molecules 2015, 20, 20, page–page page–page Molecules 2015, Table 4. Anticonvulsant oxadiazole or benzoxazinone compounds. Molecules 2015, 20, page–page

Table 4. Anticonvulsant oxadiazole or benzoxazinone compounds. Table 4. Anticonvulsant Anticonvulsant oxadiazole or benzoxazinone benzoxazinone compounds. Table 4. oxadiazole or compounds. Table 4. Anticonvulsant oxadiazole or benzoxazinone compounds. O Table 4. Anticonvulsant oxadiazole or benzoxazinone compounds. Table 4. Anticonvulsant oxadiazole or benzoxazinone compounds. O O O

O O O NO OO O N N N O O Molecules 2015, 20, page–page N N O NO N N N N O N N N N O N N N NO N N N O N N O N O N O N O N O N R1 N N O N N N O Ncompounds. O O O R O Table 4. Anticonvulsant oxadiazole or1Nbenzoxazinone N N NO O O N R O O S O O NH 1 O N N R1 O N O O O S R R O N S NH2 O2R O O 1 N NH R1 O 2 R O SNO NH ON O 2 R Molecules 2015, 20, page–page S NH O 2 O R N S R NH2 O O N 2 O O2N NN N O62 64-70 63 O O 2 64-70 62 63 O N 2N 64-70 62 63 O N 2N 4. Anticonvulsant N Table oxadiazole or benzoxazinone compounds. 64-70 62 63 O N N 2 R R 63 Compound No.62 O R 1 R1 Reference Compound Reference 64-70 62No. 64-70 Compound No. R R Reference O11 Compound No. R R Reference O 63 R O N R1 Compound No. R 1 Reference O R O Compound No. R 1 Reference N S CF Compound No. R3 Reference O NH2 R1 CF R 3 CF3 4-OCH 3 N N CF O 64 64O 4-OCH 3 6464 3 CF 4-OCH 3 4-OCH3 3 N CF 64 4-OCH 3 3 NO 64 4-OCH 3N N N NOO22N2 64 62 O NO 4-OCH3 2 64-70 [56] 63 O NO 2 O O Molecules 2015, 2015, 20, 20, page–page page–page NO2 N R O Molecules 1 NO 2 O O Molecules 2015, 20, page–page N S Compound No. R R 1 Reference O NH 23 4-OCH R O O 65 65 4-OCH 3 O 4-OCH 65 4-OCH 3 4-OCH3 65Table O 65 3 4. Anticonvulsant oxadiazole or benzoxazinone compounds. CF Table 4. 4. Anticonvulsant Anticonvulsant oxadiazole or benzoxazinone compounds. 65 4-OCH 3 3 65 4-OCH 3 Table compounds. O2N oxadiazole or benzoxazinone 64 4-OCH 3 Cl [56] 64-70 63 O 62 Cl O [56] Cl O [56] O NO Cl 2 O [56] S Cl No. OCompound 66N N 4-OCH 3 R1 [56] Reference S Cl R O 66 [56] 4-OCH 3 S O 66 NN NN 4-OCH 3 N 4-OCH O O 66 3 4-OCH3 6666 SS N Cl N 4-OCH 3 N SN CF N N 66 4-OCH 3 N 3 Cl O 65 H C Cl N 4-OCHN3 N O H3C C 3 Cl 64 O N O O O N H R1 4-OCH3 O O O O Cl 3C N R H O O Cl 1 N SO 3 N R1 O H3C NO2NH C N NH O R N N SS R 3 NH22 4-OCH3 N NH Cl 2 R O [56] 67 67 4-OCH 3 NNO O O 67 4-OCH 3 N 4-OCH O O 67 3 O 6767 4-OCH S 4-OCH3 4-OCH O2N N 66 67OO H OO C 2 65 4-OCH333 64-70 64-70 O 62 63 H3C C 3 2N 62 63 H 3 64-70 62 63 Cl HH33CCR NC CF Compound No. R 1 Reference Compound No. R CF R11 Reference NC CF3H33C3 NC Compound R R Reference 68 No. 3Cl NC [56] CF 68 3 CFCF 68 3 3 NC NCF3 NC 68 NO2 CF 3 68 S NO CF 66 67 64 4-OCH33 4-OCH3 6864 68 3 NO22 4-OCH O 4-OCH NO 64 2 O NO NC 3 22 [57] NO NO O NC Cl 2 NO2 O NC 69 [57] NO O H C 2 3 NC 3 69 [57] O NC 69 [57] O NC O 69 [57] O 69 [57] NC NCF3 69 [57] Cl O 65 4-OCH 3 65 4-OCH 6965 67 68 Cl NC 33 4-OCH3 Cl O 4-OCH Cl NC S Cl NC S NO2Cl NC 70 70 NC H3 C 70 Cl SS NC [56] Cl 70 [56] Cl SO Cl S 70 NC [56] 70 Cl S Cl NC CF 66 4-OCH33 69 [57] 34-OCH Cl 66 SS Cl 7066 Cl 4-OCH3 N N68 N Cl N N N Cl 2Cl H3C NO N Cl N N O N NHN HH33CC O NHN NC O O O O O O SO NH NC N O O 70 Cl Cl NH N O O O NH N O 67 4-OCH 3 O 69 OCl [57] O O 3 Cl NH N4-OCH 67 ON N NCl 4-OCH 67 3 NN N OO Cl a series N Ninvestigated N Harish et al., new 2-methyl-2-[3-(5-piperazin-1-yl-[1,3,4]oxadiazol-2-yl)R N Clof N N N R N O N H N N N R N N NN H3C CN O N N screenedO N H N Cl R N H N O phenyl]-propionitrile derivatives. All the compounds were for their anticonvulsant activity N H N 3 N R N3C N H O N O H N N N NC O R N O H NR=4-Flouorophenyl 76 NC N 71H O O S 77 N CF N 76 wereNC against MES seizure their neurotoxic CF effects determined rotorod 71 and 70 3 76 O test. Compounds 68, 77 by R=4-Flouorophenyl 71 NC O 77 R=4-Flouorophenyl CF33 76 78 R=Cyclohexyl O O 6871 71 NH 77 R=4-Flouorophenyl 68 76 this series 784).R=4-Flouorophenyl R=Cyclohexyl 77 68 69 and 70 were found to be71Othe most potent of (Table These compounds showed no 76 78 R=Cyclohexyl Cl 77 R=4-Flouorophenyl 78 R=Cyclohexyl R=Cyclohexyl NO2 Cl O NO 78 O dose 2 H H 78 R=Cyclohexyl NO N O neurotoxicity at the maximum administered (100 mg/kg) [57]. 2 N H NH H N N N O H NN O R NC NO R N N O N H H N OH NC N reported R1 1 et al.,N N N O N H OH N H Siddiqui a synthesis of new 5-(1H-indol-3-yl)methyl-4-(substituted-aryl)-2, R N NC N N R 1 H H 69 [57] 2 N N N N R N N N 69 1 [57] R O H N S N R1 N N N N N [57] 69 R22 O H NH S All N R1 N O N N O N O R H 4-dihydro-3H-1,2,4-triazole-3-thiones. synthesized were screened for their N the newly 2 N Ncompounds N F O 71 H R R=4-Flouorophenyl 2 N N O SSClCl H N F R76 2 N O N77 N N O S F N S Cl O 72 R =H R =2-OCH F 78 R=Cyclohexyl anticonvulsant activity were compared standard drugs N N with the 1 O RMES 2 model O N O Cl 3 3 and N NC N F N phenytoin 72 R Rin=H =Hthe =2-OCH N O NC F O 72 R22=2-OCH =2-OCH NH N O N O 2 N 3 3S N 73 R1=HR R2=2-CH N111=H R NC 72 R N NH2 O 7072 O S 22=2-OCH 3these 73 R =H R =2-CH sodium and carbamazepine. Among compounds, 71 was found to be the most active in the O N R =H R N NH 70 O 1 3 H N S H NH 11=H 2R 3R2=2-OCH 2 73 74 R R =2-CH O 72 =H NH 2 3 70 73 R =2-Cl R =2-OCH 1 3 2 RR1=H =H RR2=2-CH =2-CH O 1 R 2 3 3N O 2 74 =2-Cl =2-OCH N both after 0.5 h NH R NH 1 2 3 1 2 3 N Cl R1 73 2 series that showed protection against seizures and 4 h at 30 mg/kg body mass 74 R =2-Cl R =2-OCH 73 R =H R =2-CH 3 2 Cl 3 75 R171 =4-Cl 1R2=2-OCH 79 74 RR11=2-Cl =2-Cl RR22=2-OCH =2-OCH 33 N 3Cl 75 R =4-Cl =2-OCH 79 N77 R=4-Flouorophenyl 74 R 2=2-OCH R76 H=2-OCH3 111=4-Cl 2R 3R 75 R R 79 2 N 74 =2-Cl N 2 3 1 2 75 R =4-Cl R R2=2-OCH =2-OCH3 (Table 4) [58]. 79 78 R=Cyclohexyl S 75 O 2Figure N NR11=4-Cl75 3R2Structures R1=4-Cl 3. =2-OCH3 of compounds 71–79. 79 79 N F N Figure 3. Structures of compounds 71–79. N Siddiqui et al.,Ndesigned and synthesized a series of 5-carbomethoxybenzoxazole derivatives. O Figure 3. Structures of compounds 71–79. N N O Figure 3. Structures of compounds 71–79. 72 R =H R =2-OCH H H O 1 2 3 NH O Figure 3. Structures of compounds 71–79. O74 and Othus having potent O more NH 73 Figure of compounds O N3. Structures N O O Compounds 72, R73, 75 were found to be lipophilic 71–79. (Figure NH23),O NH =2-CH 1 O 2N 3 ClR1=Hof R Malik et al., prepared aNseries 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione Cl Malik et al., prepared a series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione R Cl H N 74 R1of =2-Cl R2N=2-OCH3 N 2 N N pyrrolidine-2,5-dione anticonvulsant activity [59]. N Malik et et al., al., prepared prepared a series series 3-(benzo[d]isoxazol-3-yl)-N-substituted N S Preliminary Malik of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione N Nactivities. N N and evaluated their anticonvulsant activity was performed O Rof N Malik et Malik al.,their prepared aa series 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione Rwas N 75 RN 79 R N N and evaluated anticonvulsant activities. Preliminary anticonvulsant activity performed 1a=4-Cl 2=2-OCH 3 etanticonvulsant al.,anticonvulsant prepared series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione F N O H and evaluated their activities. Preliminary anticonvulsant activity was performed N N Rwas N O H N and evaluated their anticonvulsant activities. Preliminary anticonvulsant activity performed N N was N activity O compound using MES and tests after injection into mice. ED 50 value of 14.90 mg/kg O 77 O 77 Hsc-PTZ and evaluated their anticonvulsant activities. Preliminary was performed N R2=2-OCH 72 ip R1ip =H O using MES and sc-PTZ tests after injection into mice. ED 50anticonvulsant value of compound was 14.90 mg/kg 3 and evaluated their anticonvulsant activities. Preliminary anticonvulsant activity was performed O using MES MES and and sc-PTZ sc-PTZ71 tests after after ip injection into mice. EDof 50 compounds value of of77compound compound 77 was was 14.90 14.90 mg/kg mg/kg O 77 Figure 3. Structures 71–79. 20749 NH 76 using tests ip injection into mice. ED 50 value 2 73 R =H R =2-CH R=4-Flouorophenyl (Figure 3). Similarly the most potent one in sc-PTZ was compound 78 with an ED 50 value 76 71 1 2 3 using MES and sc-PTZ tests aftertests ip injection into mice. ED 50 value of compound 77 was 14.90 mg/kg 77 R=4-Flouorophenyl 76 71 (Figure 3). Similarly the most potent one in sc-PTZ was compound 78 with an ED 50 value of ofmg/kg using MES and sc-PTZ after ip injection into mice. ED 50 value of compound 77 was 14.90 77 (Figure 3). 3). Similarly Similarly the the most most74potent potent one in sc-PTZ sc-PTZ was compound compound 78 with with an an ED ED5050 value value of of 78 R=4-Flouorophenyl R=Cyclohexyl R1=2-Clone R2=2-OCH 78 R=Cyclohexyl 3 (Figure in was 78 42.30 mg/kg (Figure These compounds more active and lower neurotoxicity than 78had R=Cyclohexyl (Figure 3). Similarly the3). most potent one inwere sc-PTZ was compound 78 with an ED50 an value ofthe 42.30 mg/kg (Figure 3). These compounds were more active and had lower neurotoxicity than the (Figure 3). etSimilarly the potent one in active sc-PTZ was compound 78 ED 50 value of 75 R2=2-OCH 79 with O Rmost Malik al.,These prepared series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione 1a=4-Cl 3 42.30 mg/kg (Figure 3). These compounds were more and had lower neurotoxicity than the O 42.30 mg/kg (Figure 3). compounds were more active and and had lower neurotoxicity than the H H were control drugs ethosuximide and phenytoin [61]. O 42.30 mg/kg (Figure 3). These compounds more active had lower neurotoxicity than the H H control drugs drugs ethosuximide and phenytoin [61]. 42.30 mg/kg (Figure 3). These werePreliminary more activeanticonvulsant and had loweractivity neurotoxicity than the N compounds N [61]. H H and R anticonvulsant activities. was performed Ntheirand Revaluated control ethosuximide and phenytoin N N 1ethosuximide N NN control drugs phenytoin [61]. Figure 3. Structures of compounds 71–79. N

H3 C N O

67

4-OCH3

H3 C NC

CF3

Molecules 2015, 20, 20741–20776

68

NO2 NC Wei et al., demonstrated a synthesis Oof novel 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d] 69 [57] oxazoles and evaluated the anticonvulsant activity with the MES test and sc-PTZ test. Compound 76 was the most active and also had the Cl lowest toxicity (Figure 3). In the anti-MES potency test, NC it showed ED50 of 29.5 mg/kg, a TD 50 of S285 mg/kg, and a PI of 9.7 which was greater than the 70 reference drug, carbamazepine that has a PI ofCl 6.4 [60].

N N O

O

NH Cl

O N

N H

O 72 73 74 75

N O N

R1=H R1=H R1=2-Cl R1=4-Cl

H N

R

O 77 R=4-Flouorophenyl 78 R=Cyclohexyl

76

71

R1

N

N N N

N H

O

H N S

R2

R2=2-OCH3 R2=2-CH3 R2=2-OCH3 R2=2-OCH3

N N

N

N

O NH2

N

F O

79

Figure Figure 3. 3. Structures Structures of of compounds compounds 71–79. 71–79.

Malik et al., prepared a series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione Malik et al., prepared a series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione and evaluated their anticonvulsant activities. Preliminary anticonvulsant activity was performed and evaluated their anticonvulsant activities. Preliminary anticonvulsant activity was performed using MES and sc-PTZ tests after ip injection into mice. ED50 value of compound 77 was 14.90 mg/kg using MES and sc-PTZ tests after ip injection into mice. ED50 value of compound 77 was 14.90 mg/kg (Figure 3). Similarly the most potent one in sc-PTZ was compound 78 with an ED50 value of (Figure 3). Similarly the most potent one in sc-PTZ was compound 78 with an ED50 value of 42.30 mg/kg (Figure 3). These compounds were more active and had lower neurotoxicity than the 42.30 mg/kg (Figure 3). These compounds were more active and had lower neurotoxicity than the control drugs ethosuximide and phenytoin [61]. control drugs ethosuximide and phenytoin [61]. Malik et al., synthesized a novel series of (5-amino-3-substituted-1,2,4-triazin-6-yl)(2-(6-halo9 substituted-benzo[d]isoxazol-3-yl) pyrrolidin-1-yl)methanone. The MES test showed that compound 79 was the most potent compound (Figure 3), with an ED50 value of 6.20 mg/kg (oral/rat) and a PI value of >48.38 which was much higher than the PI of the reference drug phenytoin [62]. 7. 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]. Prasanthi et al., prepared a series of new N-diethylmalonyl derivatives of nifedipine and other isosteric analogues. Anticonvulsant screening was performed using sc-PTZ and MES induced seizures. The majority of the compounds were effective in sc-PTZ and MES screening. Compound 81 showed good activity displaying the maximum protection (Figure 4) [65]. Guan LP et al., described a series of new 5-alkoxy-[1,2,4]triazolo[4,3-a]pyridine derivatives and evaluated their anticonvulsant activity and neurotoxicity with the MES and rotarod tests, respectively. The most promising compounds, 82 and 83 showed ED50 values of 13.2 and 15.8 mg/kg and had a PI value of 4.8 and 6.9, respectively (Figure 4) [66].

20750

The majority of the compounds were effective in sc-PTZ and MES screening. Compound 81 showed good activity displaying the maximum protection (Figure 4) [65]. Guan LP et al., described a series of new 5-alkoxy-[1,2,4]triazolo[4,3-a]pyridine derivatives and evaluated their anticonvulsant activity and neurotoxicity with the MES and rotarod tests, respectively. The most promising compounds, 82 and 83 showed ED50 values of 13.2 and 15.8 mg/kg and had a PI Molecules 2015, 20, 20741–20776 value of 4.8 and 6.9, respectively (Figure 4) [66]. R O O O O

O

O

O

O

O O

O

N

N O

N H

N N

O O

80

O

82 R=Cl 83 R=Br

81 Figure 4. 4. Structures of compounds compounds 80–83. 80–83. Figure Structures of

Molecules 2015, 20, page–page

8. The 8. ThePyrazole PyrazoleFunctional FunctionalGroup Group Ahsan MJ et al., designed and synthesized a series of fourteen 3a,4-dihydro-3H-indeno[1,2-c] Pyrazole and its derivatives consist of consist five-membered heterocycles withheterocycles two ortho-nitrogen-atoms. Pyrazole and its derivatives of five-membered with two pyrazole-2-carboxamide/carbothioamide analogues. Among the compounds synthesized, some exhibited These compounds have received attention in the field of current medicinal and pharmacological ortho-nitrogen-atoms. These compounds have received attention in the field of current medicinal and marked effect on seizure model under minimal clonicity (6 Hz psychomotor seizure test). Compound research, and are reported to have a broad spectrum of biological activities, such as antitumor, pharmacological andactive are reported to have a broad biological activities, such as 89 was found to research, be the most compound of the seriesspectrum showing of 75% (3/4, 0.25–2.0 h) and 50% antimicrobial, antioxidantantioxidant and antimalarial activities [67–70]. antitumor, antimicrobial, and antimalarial activities [67–70]. (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity (Figure 5). Kaushik et et al., al., established synthesis of N N′-[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) 1 -[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) Kaushik established synthesis of Compound 90 showed protection in MES seizure and subcutaneous metrazol (sc-MET) seizure at methylene]2/4-substituted hydrazides and evaluated their anticonvulsant activity against MES- and methylene]2/4-substituted 300 mg/kg (Figure 5) [73]. hydrazides and evaluated their anticonvulsant activity against MES- and sc-PTZ-induced seizure seizure models models in in mice. mice. All compounds showed in MES model at at sc-PTZ-induced compounds showed protection protection in the the1,2,4-oxadiazolyl, MES model Farghaly A et al., synthesized a series ofAll new pyrazolo[3,4-b]pyrazines containing, 100 mg/kg, including compound 84 which showed activity at 0.5 h and 4.0 h periods indicating that 100 mg/kg, including compound 84thiazolidinonyl, which showed activity at 0.5 hand andother 4.0 h periods that thiadiazolyl, imidazothiadiazolyl, substituents differentindicating substituents. 84 was was potent potent having having aa rapid rapid onset onset and and long long duration duration of of action action (Figure (Figure 5). 5). Compound 84 showed showed 84 Compound 84 Compound 91 showed best results at reducing PTZ-induced tonic convulsions and mortality activity at at a dose dose of of 100 100 mg/kg mg/kg comparable activity comparable to to sodium sodium valproate valproate in in the the sc-PTZ sc-PTZ test test [71]. [71]. (Figure 5) a[74]. Siddiqui et al., had reported various 3,5-(substituted-diphenyl)-4,5-dihydro-pyrazole-1-acid phenylamides and evaluated their anticonvulsant activities. R2Compounds 85, 86, 87 and 88 were found O the animals NHof 25 mg/kg (Figure 5). They were also to protect 100% of in the MES screening at a dose R 1 S F O R1 O found to have appreciable anticonvulsant activity in sc-PTZ screening [72]. NH

10

N N N N

N

S

Cl

84

R1=H R1=H R1=Cl R1=Cl

O

O

NH

N NH

R2=4-Cl R2=4-Br R2=4-Cl R2=4-Br

O

Ph

N R2

85 86 87 88

N N

N O O 89 R1=4-Fluorophenyl R2=4-Fluorophenyl 90 R1=4-Pyridinyl R2=4-Chlorophenyl

N N

Ph

91

84–91. Figure 5. Structures of compounds 84–91.

9. The Imidazole Functional Group Siddiqui et al., had reported various 3,5-(substituted-diphenyl)-4,5-dihydro-pyrazole-1-acid phenylamides their anticonvulsant Compounds 85, 86,structures 87 and 88 having were found Imidazoleand andevaluated its derivatives are a class ofactivities. 5-membered heterocyclic two to protect 100% of the animals in the MES screening atthat a dose 25 mg/kgimidazole (Figure 5).derivatives They werehave also non-adjacent nitrogen atoms. Recent studies revealed theof substituted found to have appreciable in sc-PTZ screening [72]. attracted much attention anticonvulsant due to their activity broad spectrum of pharmacological activities such as Ahsan MJ et al., designed and Literature synthesized a series of fourteen 3a,4-dihydro-3H-indeno[1,2-c] anti-inflammatory, analgesic [75,76]. survey shows that imidazole-heterocyclic compounds pyrazole-2-carboxamide/carbothioamide analogues. Among the compounds synthesized, some could be new classes of anticonvulsant agents by the virtue of their potential anticonvulsant exhibited propertiesmarked [77]. effect on seizure model under minimal clonicity (6 Hz psychomotor seizure test). Compound 89 was to be the most active compound of the series showing 75% (3/4, 0.25–2.0 h) Karakurt et al.,found described a series of 2-acetylnaphthalene derivatives. Quantification of antiand 50% (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity convulsant 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]. 20751

H3C CH3 O HC

HN O

Cl

O

O N

CH3

O

F

R2 NH

R1 O

NH N N N

Molecules 2015, 20, 20741–20776

N

N

S

Cl

N N

S

O

R1

O

N NH

O

NH

O

Ph

N N

R

(Figure 5). Compound 90 showed protection in 2MES seizureOand O subcutaneous metrazol (sc-MET) N N 85 R15) =H[73].R2=4-Cl 89 R1=4-Fluorophenyl seizure at 300 mg/kg (Figure Ph R2=4-Fluorophenyl R1=H R2=4-Bra series of new Farghaly A et al.,86 synthesized pyrazolo[3,4-b]pyrazines containing, 87 R1=Cl R2=4-Cl 90 R1=4-Pyridinyl 1,2,4-oxadiazolyl, thiadiazolyl, imidazothiadiazolyl, thiazolidinonyl, substituents and other different 84 R2=4-Chlorophenyl 88 R1=Cl R2=4-Br 91 substituents. Compound 91 showed best results at reducing PTZ-induced tonic convulsions and mortality (Figure 5) [74]. Figure 5. Structures of compounds 84–91. 9. TheImidazole ImidazoleFunctional FunctionalGroup Group 9. The Imidazole class of of 5-membered 5-membered heterocyclic heterocyclic structures Imidazole and and its its derivatives derivatives are are aa class structures having having two two non-adjacent nitrogen atoms. atoms.Recent Recent studies revealed the substituted imidazole derivatives non-adjacent nitrogen studies revealed thatthat the substituted imidazole derivatives have have attracted attention to their broad spectrumofofpharmacological pharmacological activities activities such such as attracted muchmuch attention due due to their broad spectrum as anti-inflammatory, anti-inflammatory, analgesic analgesic [75,76]. [75,76]. Literature Literature survey survey shows shows that that imidazole-heterocyclic imidazole-heterocyclic compounds compounds could their potential potential anticonvulsant anticonvulsant could be be new new classes classes of of anticonvulsant anticonvulsant agents agents by by the the virtue virtue of of their properties [77]. properties [77]. Karakurt et al., al.,described describeda series a series of 2-acetylnaphthalene derivatives. Quantification of Karakurt et of 2-acetylnaphthalene derivatives. Quantification of antianti-convulsant protection was calculated via the i.p. route (ED and TD ) for the most active 50 50) for the50most active candidate convulsant protection was calculated via the i.p. route (ED50 and TD candidate (92) 6). Observed in the MESwas model was 38.46 and mg/kg andmg/kg 123.83 in mg/kg (92) (Figure 6).(Figure Observed protectionprotection in the MES model 38.46 mg/kg 123.83 mice in mice and 20.44 56.36 mg/kg, 56.36inmg/kg in rats, respectively [78]. and 20.44 mg/kg, mg/kg rats, respectively [78]. H3C CH3 O H3C

HN O N

Cl

O N

N

CH3

O O N

OH

N

N

N

H N

NH O

92

93

94

Figure 6. 6. Structures of compounds compounds 92–94. 92–94. Figure Structures of

Husain et al., established a synthesis of a series of 1,2,4-trisubstituted-1H-imidazole derivatives. Husain et al., established a synthesis of a series of 1,2,4-trisubstituted-1H-imidazole derivatives. Anticonvulsant activity was shown by the majority of the synthesized compounds in the MES and Anticonvulsant activity was shown by the majority of the synthesized compounds in the MES sc-PTZ screening when given i.p. to mice. In anticonvulsant screening, only one compound, 93, showed and sc-PTZ screening when given i.p. to mice. In anticonvulsant screening, only one compound, potent activity comparable to that of standard drugs phenytoin and carbamazepine (Figure 6) [79]. 93, showed potent activity comparable to that of standard drugs phenytoin and carbamazepine 11 (Figure 6) [79]. Amir et al., demonstrated synthesis of a series of novel imidazole incorporated semicarbazones. Compound 94 showed the highest activity among the compounds synthesized with no neurotoxic and depressant effects on CNS (Figure 6). Liver enzyme estimations (serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase) of the compound also showed no significant change in the enzyme levels [80]. Ulloora et al., prepared a variety of five new series of imidazo[1,2-a]pyridines carrying biologically 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

20752

systems. Thetarget targetcyanopyridone, compoundswere were screenedfor fortheir their invivo vivo anticonvulsant activity followingMES MES active pyrazoline, cyanopyridone, cyanopyridine, 2-aminopyrimidine andactivity pyrimidine-2-thione active pyrazoline, cyanopyridine, 2-aminopyrimidine and pyrimidine-2-thione systems. The screened in following and sc-PTZ methods atsmall a small test dose of mg/kg. 10 for mg/kg. Compounds 95, 96, 97, 98, 99 and 100 displayed systems. The targetcompounds compounds were screened their in vivoanticonvulsant anticonvulsant activity following MES active pyrazoline, cyanopyridone, cyanopyridine, 2-aminopyrimidine and pyrimidine-2-thione and sc-PTZ methods at a test dose of 10 Compounds 95, 96, 97, 98, 99 and 100 displayed andsc-PTZ sc-PTZ methods smalltest testdose dose 10mg/kg. mg/kg. Compounds 95,96, 96,97, 97,98, 98, 99and and 100displayed displayed systems. Themethods target compounds compounds were screened for their their in vivo vivo anticonvulsant anticonvulsant activity following MES systems. The target were screened for in activity following MES and atat aaaactivity small ofof 10 Compounds 95, 99 100 potent anticonvulsant without displaying any toxicity (Table 5) [81]. and sc-PTZ methods at small test dose of 10 mg/kg. Compounds 95, 96, 97, 98, 99 and 100 displayed systems. The target compounds were screened for their in vivo anticonvulsant activity following MES potent anticonvulsant any toxicity 5) [81]. potent anticonvulsant without displaying any toxicity(Table (Table [81]. and sc-PTZ methods at atactivity smallwithout test dosedisplaying of 10 mg/kg. mg/kg. Compounds 95, 96, 96, 97, 98, 99 and and 100 100 displayed and sc-PTZ methods aaaactivity small test dose of 10 Compounds 95, 97, 98, potent anticonvulsant activity without displaying any toxicity (Table 5)5) [81]. Ulloora et al., designed and synthesized new 2-arylimidazo[1,2-a]pyridines carrying suitably and sc-PTZ methods at small test dose of 10 mg/kg. Compounds 95, 96, 97, 98, 99 99 and 100 displayed displayed potent anticonvulsant activity without displaying any toxicity (Table 5) [81]. Ulloora etetal., designed and synthesized new 2-arylimidazo[1,2-a]pyridines carrying suitably Ulloora al., designed and synthesized new 2-arylimidazo[1,2-a]pyridines carrying suitably potent anticonvulsant activity without displaying any toxicity (Table 5) [81]. 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 by MES and sc-PTZ screening Ulloora et al., designed and synthesized new 2-arylimidazo[1,2-a]pyridines carrying suitably potent anticonvulsant activity without displaying anywas toxicity (Tableout 5) [81]. substituted The anticonvulsant sc-PTZ substituted 1,2,3-triazoles. The anticonvulsant study wascarried carriedout outby byMES MESand andcarrying sc-PTZscreening screening Ulloora1,2,3-triazoles. et al., al., designed designed and synthesized study new 2-arylimidazo[1,2-a]pyridines carrying suitably Ulloora et and synthesized new 2-arylimidazo[1,2-a]pyridines 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 Molecules 2015, 20, 20741–20776 substituted 1,2,3-triazoles. anticonvulsant study was carried outmethod. by MES The andcarrying sc-PTZ screening Ulloora et al., designedThe and synthesized new 2-arylimidazo[1,2-a]pyridines suitably methods, their study was rotarod most methods,while while theirtoxicity toxicity study wasperformed performed following rotarod method. The mostactive activewas was substituted 1,2,3-triazoles. The anticonvulsant studyfollowing was carried carried out by by MES and and sc-PTZ screening substituted 1,2,3-triazoles. The anticonvulsant study was out MES sc-PTZ screening methods, while their toxicity study was performed following rotarod method. The most active was compound 101 which displayed reasonably good activity inout both the of 0.5 and methods, while their toxicity was performed following rotarod The most active substituted 1,2,3-triazoles. The study anticonvulsant study was carried bymethod. MESdurations and sc-PTZ screening compound 101 which displayed good activity of 0.5 and 4was h4 h compound 101their which displayed reasonably goodfollowing activityin inboth boththe thedurations durations 0.5 andwas methods, while their toxicity studyreasonably was performed performed following rotarod method. The most most active was methods, while toxicity study was rotarod method. The active compound 101 which displayed reasonably good activity in both the durations ofof 0.5 and 444hh indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete compound 101 which displayed reasonably good activity in both the durations of 0.5 and h methods, while their toxicity study was performed following rotarod method. The most active was indicating that they rapid onset and duration action 5). complete indicating that theypossess possess rapid onset andlong long duration of action (Table 5).ItItItexhibited exhibited complete compound 101 which displayed reasonably good activityof in both(Table the durations ofof0.5 0.5 and 4 drug h protection against seizure and their activity at 20 mg/kg was comparable with that standard compound 101 which displayed reasonably good activity in both the durations of and 4 h indicating that they possess rapid onset and long duration of action (Table 5). exhibited complete protection against seizure and their activity at 20 mg/kg was comparable with that of standard drug compound 101 displayed reasonably good activity of in action both the durations of 0.5 and 4 h indicatingagainst that which they possess rapid onset and long duration (Table 5). It exhibited complete protection seizure and their activity with ofof standard drug protection against seizure and their activity at20 20mg/kg mg/kgwas was comparable with that standard drug indicating that they possess rapid onset andat long duration ofcomparable action (Table 5). that It exhibited complete diazepam [82]. 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 ofofstandard drug diazepam [82]. protection against seizure and their activity at 20 mg/kg was comparable with that standard drug indicating that they possess rapid onset and long duration of action (Table 5). It exhibited complete diazepam [82]. diazepamagainst [82]. seizure protection against seizure and their their activity activity at at 20 20 mg/kg mg/kg was was comparable comparable with with that that of of standard standard drug drug protection diazepam [82]. diazepamagainst [82]. seizure and protection and their activity at 20 mg/kg was comparable with that of standard drug Table 5. Anticonvulsant imidazole compounds. diazepam [82]. diazepam Table 5. Anticonvulsant imidazole compounds. diazepam [82]. [82]. Table 5.5.Anticonvulsant Table Anticonvulsantimidazole imidazolecompounds. compounds. Table 5. Anticonvulsant imidazole Table 5. Anticonvulsant imidazolecompounds. compounds. CH3 CH 3 Table 5. Anticonvulsant imidazole compounds. CH3 Table imidazole compounds. CH 3 N Table 5. 5. Anticonvulsant Anticonvulsant imidazole compounds. CH3N

Compound No. Compound No. Compound CompoundNo. No. Compound No. Compound No. Compound 95 No. Compound 9595 95 No. Compound No. 95 95 95 95 95 969696 96 96 96 96 96

979797 97 97 97 97 97 97

989898 98 98 98 98 98 999999 99 99 9999 99 99 100 100 100 100 100 100 100 100 100 101 101 101 101 101 101 101 101 101

CH3 NN CH 3 NN CHN 3 N N NN NNR R R N R95-101 N N 95-101 R 95-101 95-101 R R R 95-101 R RR 95-101 R RR 95-101 95-101

R R1R 1 1 RR 1 1 R1 R R11

R 1 R1 RR 1 RR1 11 R1 R R11

R R

HN R HN HNN N HN HN NN N HN N HN N N N HN N N NN N O O N N N N OO HNN H O N HH O N H O N H O N H H N NN NN N O O N N N N OO HNN H O N HH O N H O N H O N H H

N NN NN N O O N N N N N OO O CH3NN CH 3 CH O N CH3 3 N O O CH 3 N CH 3 CH CH33 N NN NN N HN N H2HN N2N 2 N NN HH 2NN N 2 N H2 N N H N H22N N HN HN HN HN HN S N HN S HN N H S HN SS HNN N HH S N H S N H S N H O N H

N N OO O N NO N O O N N

10. The Pyrimidine Functional Group

Reference Reference Reference Reference Reference Reference Reference Reference Reference

-F [81]

NO2 NO 2 NO 2 NO 2 NO 2 NO 2 NO NO2 2

-F-F-F -F-F -F -F -F

Cl ClCl ClCl Cl Cl Cl

CH3 CH 3 CH 3 CH 3 CH 3 CH3 CH CH33

SS SS S S S

O

S

FF FF F F F

F

121212 12 12 12 12 12

[81] [81] [81] [81] [81] [81] [81] [81]

-H -H -H -H -H -H -H -H -H -H -H -H -H -H -H -H -H -H -CH 3 -CH 3 -CH 3 -CH 3 -CH3 -CH3 -CH -CH33 -CH3

[82] [82] [82] [82] [82] [82] [82] [82] [82]

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 [83–85]. 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

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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 [83–85]. Molecules 2015, 20, 20741–20776 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 the lowest dose 30 and mg/kg h andtodid not show anyactive sign of except in case of compounds (102,of103 104)after were0.5 found be significantly as neurotoxicity they showed protection at the compound 102 which was found to be neurotoxic at 300 mg/kg after 4.0 h (Figure 7) [86]. lowest dose of 30 mg/kg after 0.5 h and did not show any sign of neurotoxicity except in case of Deng et described the synthesis and anticonvulsant 7-(substituted-phenyl)-6, compound 102al.,which was found to be neurotoxic at 300 mg/kgactivities after 4.0 hof(Figure 7) [86]. 7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones and their activities derivatives. The majority of the Deng et al., described the synthesis and anticonvulsant of 7-(substituted-phenyl)compounds synthesized showed inhibition effects on MES-induced convulsion.The The majority most promising 6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones and their derivatives. of the compound 105 showed significant anticonvulsant in MES test with ED50 The value of 19.7 mg/kg compounds synthesized showed inhibition effectsactivity on MES-induced convulsion. most promising (Figure 7). It was safer than reference drugs with activity much higher PItest value. addition, protective compound 105 showed significant anticonvulsant in MES withInED 50 value the of 19.7 mg/kg effect of7). compound 105than against seizures induced by PTZ, ISO,PITSC, 3-MP, and bicuculline in the (Figure It was safer reference drugs with much higher value. In addition, the protective chemical-induced seizure tests suggested that compound displayed broad spectrum activity in effect of compound 105 against seizures induced by PTZ,103 ISO, TSC, 3-MP, and bicuculline in the several models [87]. chemical-induced seizure tests suggested that compound 103 displayed broad spectrum activity in Jiang et al.,[87]. reported a novel series of 7-substituted-5-phenyl-[1,2,4]triazolo[1,5-a] pyrimidines. several models TheirJiang anticonvulsant were measured through the MES test, and carbamazepine et al., reportedactivities a novel series of 7-substituted-5-phenyl-[1,2,4]triazolo[1,5-a] pyrimidines. Their (ED = 11.8 mg/kg) and valproate (ED = 272 mg/kg) were used as the reference drugs. Amongst anticonvulsant activities were measured 50 through the MES test, and carbamazepine (ED50 = 11.8 mg/kg) 50 the compounds tested, compound 106 was most active indrugs. inhibiting convulsion with ED50tested, value and valproate (ED 50 = 272 mg/kg) were usedthe as the reference Amongst the compounds of 84.9 mg/kg than valproate butconvulsion lower than with carbamazepine 7) [88]. that was compound 106that waswas the higher most active in inhibiting ED50 value (Figure of 84.9 mg/kg Shaquiquzzaman et al., established syntheses of some new7)pyrimidine-5-carbonitrile derivatives. higher than valproate but lower than carbamazepine (Figure [88]. In the MES test, compounds 107, 108 syntheses and 109 were found be highly active at a dose level of Shaquiquzzaman et al., established of some newto pyrimidine-5-carbonitrile derivatives. 30 mg/kg at 0.5 h time interval (Figure 7), indicating their ability to prevent In the MES test, compounds 107, 108 and 109 were found to be highly active at a dose level of 30seizure mg/kg spread at ainterval relatively low7),dose [89]. their Shaquiquzzaman et seizure al., also reported a serieslow of at 0.5 h time (Figure indicating ability to prevent spread at a relatively dihydropyrimidine-5-carbonitrile derivatives evaluated their anticonvulsant activity against dose [89]. Shaquiquzzaman et al., also reported aand series of dihydropyrimidine-5-carbonitrile derivatives MESevaluated and sc-PTZ models. Compounds 110 and 111 MES were and found to bemodels. most active showing 110 activity and their anticonvulsant activity against sc-PTZ Compounds and bothwere in MES andtosc-PTZ screen at showing lower doses of 30both mg/kg at 0.5and h and 100 screen mg/kgatatlower 4 h (Figure 111 found be most active activity in MES sc-PTZ doses 7). of In the rotarod compound 110rotarod did notmotor show any motor impairment, even at 30 mg/kg at 0.5motor h andimpairment 100 mg/kg atscreen, 4 h (Figure 7). In the impairment screen, compound the maximum dose ofany 300 motor mg/Kg.impairment, The pharmacophore also fits bestoffor300 compounds 110 110 did not show even at hypothesis the maximum dose mg/Kg. The and 111 [90]. pharmacophore hypothesis also fits best for compounds 110 and 111 [90]. R1 O N

R4

NH NH

N

R3

102 R1=4-F R2=4-CH3 R3=CH3 R4=4-Cl

Br

103 R1=4-Cl R2=3,4-OCH3 R3=H R4=4-NO2

N

104 R1=4-Cl R2=4-CH3 R3=CH3 R4=4-Cl

R2

R

N N N H

O

N

N N

106 R=Hept

O NC

NH N

N

O

105

O NC

O

N H

N

NH

R N

N H

N

R

O

107 R=4-Br 108 R=4-OH 109 R=3-F

110 R=4-Br 111 R=3-NO2

Figure Figure 7. 7. Structures Structures of of compounds compounds 102–111. 102–111.

11. The Phthalazine Functional Group

13formula of phthalazine is C8 H6 N2 . Because of As a heterocyclic compound, the molecular the broad spectrum of bioactivities such as anticonvulsion, vasorelaxation, anti-inflammation and cardiotonic effect, its derivatives are generally used for treating disease [91–93]. 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

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11. 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 [91–93]. Molecules 2015, 20, 20741–20776 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 most promising promising compounds compounds 112 112 and and 113 113 showed showed aa median median effective effective dose respectively. The dose of of 7.1 7.1 and 11.0 mg/kg (Figure 8), and had protective index values of 5.2 and 8.0, respectively. The and 11.0 mg/kg (Figure 8), and had protective index values of 5.2 and 8.0, respectively. The two two compounds compounds were were further further found found to to have have potent potent activity activity against against seizures seizures induced induced by by PTZ, PTZ, ISO, ISO, TSC, TSC, 3-MP but not seizures induced by strychnine [94]. 3-MP but not seizures induced by strychnine [94]. Sun Sun et et al., al., investigated investigated aa new new phthalazine phthalazine tetrazole tetrazole derivative. derivative. Compound Compound 114 114 exhibited exhibited higher higher activity = 6.8 6.8 mg/kg) mg/kg)and andlower lowerneurotoxicity neurotoxicity(TD (TD5050= =456.4 456.4mg/kg) mg/kg) (Figure resultinginina activity (ED (ED50 50 = (Figure 8),8), resulting ahigher higherPIPI= =67.1 67.1compared comparedwith withcarbamazepine carbamazepine (PI (PI == 6.4). 6.4). In In addition, addition, compound compound 114 114 exhibited exhibited significant against MES-induced MES-induced seizure seizure with with low significant oral oral anticonvulsant anticonvulsant activity activity (ED (ED50 50 = = 24 24 mg/kg) mg/kg) against low > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. Compound neurotoxicity (TD 50 neurotoxicity (TD50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. Compound 114 114 tested in chemically induced animal models of seizure (PTZ,TSC ISO, TSC and to 3-MP) to was was also also tested in chemically induced animal models of seizure (PTZ, ISO, and 3-MP) further further investigate the anticonvulsant Compound 114 produced significant anticonvulsant investigate the anticonvulsant activity.activity. Compound 114 produced significant anticonvulsant activity activity against seizures induced by ISO, TSC and 3-MP [95]. against seizures induced by ISO, TSC and 3-MP [95]. Bian reported aa synthesis synthesis of of new new 6-substituted-[1,2,4]triazolo[3,4-a](tetrazolo[5,1-a]) 6-substituted-[1,2,4]triazolo[3,4-a](tetrazolo[5,1-a]) Bian et et al., al., reported phthalazine derivatives.All Allthe thecompounds compoundswere were evaluated their anticonvulsant activities using phthalazine derivatives. evaluated forfor their anticonvulsant activities using the the MES test. The most promising compound 115 showed significant anticonvulsant activity in MES MES test. The most promising compound 115 showed significant anticonvulsant activity in MES test test of 9.3 mg/kg 8). It displayed a wide margin of safety withindex protective 50 value withwith ED50 ED value of 9.3 mg/kg (Figure (Figure 8). It displayed a wide margin of safety with protective much index much higher than the standard drug carbamazepine [96]. higher than the standard drug carbamazepine [96]. O

Cl

R

N N 112 R=n-C6H4(p-Cl) 113 R=n-C7H15

CF3

O

O

N N

N N

N N

N N N 114

N N 115

Figure 8. Structures of compounds 112–115. Figure 8. Structures of compounds 112–115.

12. The Triazine Functional Group 12. The Triazine Functional Group Triazine is a six membered heterocyclic ring compound containing three nitrogen atoms. The 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 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 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 [97–99]. their anti-anxiety and anti-inflammatory activities, as well as used in agriculture [97–99]. Kaushik et al., designed and synthesized a new series of 2-(substituted aryloxy)-5-(substituted Kaushik et al., designed and synthesized a new series of 2-(substituted aryloxy)-5-(substituted benzylidene)-3-phenyl-2,5-dihydro-1H-[1,2,4]triazin-6-one. Their anticonvulsant activity was evaluated benzylidene)-3-phenyl-2,5-dihydro-1H-[1,2,4]triazin-6-one. Their anticonvulsant activity was by MES test, sc-PTZ test. Among the compound tested, compound 116 showed protection from evaluated by MES test, sc-PTZ test. Among the compound tested, compound 116 showed protection seizures in both the animal models at dose level of 30 mg/kg (Figure 9). The compound 116 showed from seizures in both the animal models at dose level of 30 mg/kg (Figure 9). The compound 116 activity both at 0.5 h and 4 h periods at dose level of 30 mg/kg, indicating the compound to be highly showed activity both at 0.5 h and 4 h periods at dose level of 30 mg/kg, indicating the compound to potent and long acting [100]. be highly potent and long acting [100]. Amir et al., demonstrated synthesis of new hydrazone incorporated triazines and evaluated for Amir et al., demonstrated synthesis of new hydrazone incorporated triazines and evaluated for their anticonvulsant activity through MES and sc-PTZ screenings. Among the tested compounds, their anticonvulsant activity through MES and sc-PTZ screenings. Among the tested compounds, compound 117 (MES ED50 54.31, sc-PTZ ED50 92.01) and compound 118 (MES ED50 46.05, sc-PTZ ED50 compound 117 (MES ED50 54.31, sc-PTZ ED50 92.01) and compound 118 (MES ED50 46.05, 83.90) emerged as the most active anticonvulsant agent having GABA-ergic effects (Figure 9). sc-PTZ ED50 83.90) emerged as the most active anticonvulsant agent having GABA-ergic effects Compounds 117 and 118 also showed less CNS depressant effect than the standard drug (Figure 9). Compounds 117 and 118 also showed less CNS depressant effect than the standard drug carbamazepine [101]. carbamazepine [101]. 14 thirty indole C-3 substituted 5-amino-6Ahuja et al., synthesized a series of (5-substituted-2-phenyl-1H-indol-1-yl)-4,5-dihydro-1,2,4-triazine-3(2H)-thiones. Compound 119 had significant activity in the MES test with minimal duration of limb extension (5.40 ˘ 0.61 s) and

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Molecules 2015, 20, page–page

Ahuja et al., synthesized a series of thirty indole C-3 substituted 5-amino-6-(5-substituted-2Molecules 2015, 20, 20741–20776 phenyl-1H-indol-1-yl)-4,5-dihydro-1,2,4-triazine-3(2H)-thiones. Compound 119 had significant activity in the MES test with minimal duration of limb extension (5.40 ± 0.61 s) and quantitative median dose quantitative median of 7 mg/kg. In sc-PTZ screening, 120 increased seizure of 7 mg/kg. In sc-PTZdose screening, compound 120 increased thecompound seizure latency to clonic the convulsion latency to clonic convulsion and with effective at a median dose of 35 mg/kg (Figure 9) [102]. and with effective at a median dose of 35 mg/kg (Figure 9) [102]. R Cl

O N

NH N O

116

F

H N

N N

H2N R

N

N

NH S

N NH N

117 R=3-Cl

119 R=COCH3

118 R=4-Cl

120 R=SO2NH2

Figure 9. Structures of compounds 116–120. Figure 9. Structures of compounds 116–120.

13. The Triazolethione Functional Group 13. The Triazolethione Functional Group Many compounds bearing a triazole moiety were found to possess anticonvulsant properties in 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 various animal models of epilepsy. Therefore, some people want to loop through a combination of triazole-thione compounds to improve the antiepileptic activity. triazole-thione compounds to improve the antiepileptic activity. Luszczki et al., reported the effects of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3HLuszczki et al., reported the effects of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2, 1,2,4-triazole-3-thione (compound 121) and 5-(3-chlorophenyl)-4-(4-methylphenyl)-2,4-dihydro-3H4-triazole-3-thione (compound 121) and 5-(3-chlorophenyl)-4-(4-methylphenyl)-2,4-dihydro-3H-1,2, 1,2,4-triazole-3-thione (compound 122) on the protective action of four classical antiepileptic drugs— 4-triazole-3-thione (compound 122) on the protective action of four classical antiepileptic carbamazepine, phenobarbital, phenytoin and valproate—against MES test in mice (Table 6). Results drugs—carbamazepine, phenobarbital, phenytoin and valproate—against MES test in mice (Table 6). indicated that compound 121 administered intraperitoneally at doses of 75 and 100 mg/kg significantly Results indicated that compound 121 administered intraperitoneally at doses of 75 and 100 mg/kg elevated the threshold for electroconvulsions in mice. Compound 121 (50 mg/kg) significantly significantly elevated the threshold for electroconvulsions in mice. Compound 121 (50 mg/kg) enhanced the anticonvulsant activity of carbamazepine, phenobarbital and valproate. Compound 122 significantly enhanced the anticonvulsant activity of carbamazepine, phenobarbital and valproate. administered intraperitoneally at 10 mg/kg significantly elevated the threshold for electroconvulsions Compound 122 administered intraperitoneally at 10 mg/kg significantly elevated the threshold in mice. Moreover, compound 122 (5 mg/kg) significantly enhanced the anticonvulsant activity of for electroconvulsions in mice. Moreover, compound 122 (5 mg/kg) significantly enhanced the valproate, but not that of carbamazepine, phenobarbital or phenytoin in the MES test in mice. anticonvulsant activity of valproate, but not that of carbamazepine, phenobarbital or phenytoin in the Pharmacokinetic experiments revealed that compound 122 significantly elevated total brain MES test in mice. Pharmacokinetic experiments revealed that compound 122 significantly elevated concentrations of valproate in mice [103,104]. total brain concentrations of valproate in mice [103,104]. Siddiqui al., prepared a various of 3-[4-(substituted phenyl)-1,3-thiazol-2-ylamino]-4-(substituted Molecules 2015, 20,etpage–page phenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones. in vivo anticonvulsant screenings were Table 6. Structures ofTheir compounds 121–126. 6. Structures of compounds performed using the two mostTable adopted seizure models, MES 121–126. and sc-PTZ. Two compounds, 123 and NH 124 (Table 6), showed significantNanticonvulsant activity in both the screenings with ED50 values of S N NH S 23.9 mg/kg and 13.4 mg/kg, respectively, in Rthe MES screen and 178.6 mg/kg and 81.6 mg/kg, 1 N N N S N H R displayed a wide margin of safety respectively, in the sc-PTZ test. They with PI, median hypnotic dose R (HD50) and median lethal Cl dose (LD50) which were much higher than that of the standard drugs [105]. 121-124 125-126 Plech et al., designed and synthesized 4-alkyl-1,2,4-triazole-3-thione derivatives. A group of Compound No. R R R1R1 ReferenceReference Compound No. derivatives showed strong anticonvulsant activity. The characteristic features of the most active 121 -Ph(p-Br) — —the tested compounds, compound 125 121 onset and long -Ph(p-Br) compounds were rapid lasting effects. Among [103,104] [103,104] 122 -Ph(p-CH ) 122 3) —— -Ph(p-CH 3 was assayed for the different PI values at different preprocessing times (Table 6), and the results of 123 n-C6 H13 n-C6H13 1239.7 [106]. —— [105] that were ranging 124 from 2.8 to [105] -Ph(p-F) — 124 -Ph(p-F) — Plech et al., also of 1,2,4-triazole-3-thione features 125reported a synthesis -Ph(o-CH -Cl derivatives. Characteristic [106] 3) 125 a -Ph(p-OCH 3) -Cl-Brlong lasting [106] effects. -Ph(o-CH 126 [107] Compound 126 of all active compounds were rapid onset 3 ) of action and 126 (ED50 = -Ph(p-OCH -Br6) [107]. [107] exhibited the most potent activity 35.2 mg/kg)3)(Table Siddiqui et al., prepared a various of 3-[4-(substituted phenyl)-1,3-thiazol-2-ylamino]-414. The Indoline-2, 3-dione Functional Group (substituted phenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones. Their in vivo anticonvulsant screenings (indoline-2,3-dione), one ofadopted the simplest indole derivatives, has led to Two numerous analogues wereIsatin performed using the two most seizure models, MES and sc-PTZ. compounds, 123 with a wide range of biological properties, including anxiogenic, sedative, anticonvulsant, anticancer and 124 (Table 6), showed significant anticonvulsant activity in both the screenings with ED values 50 15 activities [108,109]. 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, Siddiqui et al., designed various 1-(amino-N-arylmethanethio)-3-(1-substituted-benzyl-2,3dioxoindolin-5-yl) ureas. Their in vivo anticonvulsant 20756 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

Molecules 2015, 20, page–page

Table 6. Structures of compounds 121–126.

Molecules 2015, 20, 20741–20776

N NH

S N NH S R1 N N N S Nwith respectively, in the sc-PTZ test. TheyR displayed a wide margin of safety PI, median hypnotic dose H R (HD50 ) and median lethal Cl dose (LD50 ) which were much higher than that of the standard drugs [105].

125-126 Plech et al., designed and121-124 synthesized 4-alkyl-1,2,4-triazole-3-thione derivatives. A group of Compound No. R R1 Reference derivatives showed strong anticonvulsant activity. The characteristic features of the most active 121and long lasting -Ph(p-Br) — compounds were rapid onset effects. Among the tested compounds, compound [103,104] 122 PI values-Ph(p-CH 3) preprocessing — 125 was assayed for the different at different times (Table 6), and the results 123 — of that were ranging from 2.8 to 9.7 [106]. n-C6H13 [105] 124 -Ph(p-F) — Plech et al., also reported a synthesis of 1,2,4-triazole-3-thione derivatives. Characteristic features 3) -Cllasting effects. [106]Compound 126 exhibited -Ph(o-CH of all active compounds were125 a rapid onset of action and long -Ph(p-OCH 3 ) -Br [107] the most potent activity (ED126 = 35.2 mg/kg) (Table 6) [107]. 50

14. TheIndoline-2, Indoline-2,3-dione Functional Group Group 14. The 3-dione Functional Isatin Isatin (indoline-2,3-dione), (indoline-2,3-dione), one one of of the the simplest simplest indole indole derivatives, derivatives, has has led led to to numerous numerous analogues analogues with a wide range of biological properties, including anxiogenic, sedative, anticonvulsant, with a wide range of biological properties, including anxiogenic, sedative, anticonvulsant, anticancer anticancer activities activities [108,109]. [108,109]. Siddiqui designed various various 1-(amino-N-arylmethanethio)-3-(1-substituted-benzyl-2,31-(amino-N-arylmethanethio)-3-(1-substituted-benzyl-2,3Siddiqui et et al., al., designed dioxoindolin-5-yl) dioxoindolin-5-yl) ureas. ureas. Their Their in in vivo vivo anticonvulsant anticonvulsant screenings screenings were were performed performed by by the the two two most most adopted seizuremodels, models,MES MES sc-PTZ. Atmg/kg, 300 mg/kg, compounds 127 showed and 128 showed adopted seizure andand sc-PTZ. At 300 compounds 127 and 128 significant significant protective effectand on sc-PTZ-induced MES- and sc-PTZ-induced seizures the of lower protective effect on MESseizures (Figure 10). (Figure Even at10). the Even loweratdose 100 dose of compound 100 mg/kg,128 compound exhibited goodonprotection on MES-induced seizure. These two mg/kg, exhibited128 good protection MES-induced seizure. These two compounds compounds exhibited marked protective against in a 6 Hz psychomotor seizure test, exhibited marked protective effect againsteffect seizures in a seizures 6 Hz psychomotor seizure test, and could be and could be used as lead compounds for future investigations [110]. used as lead compounds for future investigations [110]. Prakash al.,prepared prepared a series of 1-(substituted benzylidene)-4-(1-(morpholino/piperidino Prakash etetal., a series of 1-(substituted benzylidene)-4-(1-(morpholino/piperidino methyl)methyl)-2,3-dioxoindolin-5-yl) semicarbazides. The compounds were subjected to in vivo antiepileptic 2,3-dioxoindolin-5-yl) semicarbazides. The compounds were subjected to in vivo antiepileptic evaluation evaluation using using MES MES and and sc-PTZ sc-PTZ test test methods. methods. The neurotoxicity was determined by rotarod test. test. Among the synthesized compounds, 129 129 revealed excellent protection in both models with lower neurotoxicity neurotoxicity (Figure (Figure 10) 10) [111]. [111]. H N R2

H N S

H N

O N

O

O

F

N

H N

H N O

R2=4-OCH3

O N N

R1 127 R1=H

O

O

129

128 R1=2-Cl R2=H

Figure 10. 10. Structures of compounds compounds 127–129. 127–129. Figure Structures of

15. The Cyclopropanecarboxylate Functional Group 15. The Cyclopropanecarboxylate Functional Group He et al., synthesized twenty three 1-(2-arylhydrazinecarboxamido)-2,2-dimethylcyclopropaneHe et al., synthesized twenty three 1-(2-arylhydrazinecarboxamido)-2,2-dimethylcyclopropanecarboxylate derivatives and tested their anticonvulsant activity using the MES, sc-PTZ screens. Their carboxylate 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 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 protection against the MES-induced seizures with ED50 value of 9.8 mg/kg and TD50 value of after i.p. to mice (Figure 11), which provided compound 128 with a PI of 33.9 in the MES test [112]. 332.2 mg/kg after i.p. to mice (Figure 11), which provided compound 128 with a PI of 33.9 in the Zhong et al., reported fourteen ethyl 2,2-dimethyl-1-(2-substituted-hydrazinecarboxamido) MES test [112]. cyclopropanecarboxylate derivatives and tested the anticonvulsant activity using the MES, sc-PTZ Zhong et al., reported fourteen ethyl 2,2-dimethyl-1-(2-substituted-hydrazinecarboxamido) screens. The most active compound 131 showed protection against MES-induced seizures with an cyclopropanecarboxylate derivatives and tested the anticonvulsant activity using the MES, sc-PTZ ED50 value of 9.2 mg/kg and TD50 value of 387.5 mg/kg after i.p. to mice (Figure 11), which provided screens. The most active compound 131 showed protection against MES-induced seizures with an compound 129 with a PI of 42.1 in the MES test [113]. 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]. 16 20757

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O O N N O H HN NH H HN NH O O O Molecules 2015, 20, page–page O O CF3 F N N Molecules 2015, 20, page–page O O H OHN O H OHN NH Molecules 2015, 20, page–pageO NH Cl O O CF3 N N O F O NH O H HN H HN NHO O O O O O N 131 O N CF3 130 F Cl Molecules 2015, 20, page–page O H HN O NH O NH H HN O N O O N O OH NHN Figure H NHN NH CF3 O NH 11. Structures ofOcompounds compounds 130–131. Cl F O O H HN of 130–131. O O H HNFigure NH NH 130 11. Structures 131 O O CF3 F O O CF3 OO OO Cl F 130 131 130–131. Figure 11. Structures O O 16. The Pyrrolidine-2,5-dione Functional Groupof compounds N Cl N 16. The Pyrrolidine-2,5-dione Functional Group O H HN NH H HN NH O Cl 130 11. Structures of compounds131 Figure 130–131. O Derivatives of pyrrolidine-2,5-diones, heterocyclic compounds, have been widely applied O CFas 3 heterocyclic F 16. The Pyrrolidine-2,5-dione Derivatives of pyrrolidine-2,5-diones, as been widely applied 130Functional Group 131compounds, have O 11. Structures O 130 131 Figure compounds 130–131. in medicinal chemistry and synthesis fields. ofThey exhibit numerous bioactivities, especially in medicinal chemistry and synthesis fields. They exhibitcompounds, numerous Clhave bioactivities, especially in 16.inThe Pyrrolidine-2,5-dione Functional Group Figure 11. Structures compounds 130–131. Derivatives of pyrrolidine-2,5-diones, asofheterocyclic been widely applied

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anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient Figure 11. Structures of compounds 130–131. anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new especially and efficient medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, in 16.in The Pyrrolidine-2,5-dione Functional Group strategies for the of multi-substituted pyrrolidine-2,5-diones is also the current hot applied in organic Derivatives ofsynthesis pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely 130multi-substituted 131 strategies for the synthesis of pyrrolidine-2,5-diones is also the current hot in 16. The Pyrrolidine-2,5-dione Functional Group and tyrosinase inhibitory activities. Therefore, development of new and efficient and medical chemistry [114].synthesis in anticonvulsant medicinal chemistry and fields. They exhibit numerous bioactivities, especially in 16. The Pyrrolidine-2,5-dione Functional Group Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied organic and chemistry [114]. 11. Structurespyrrolidine-2,5-diones of compounds 130–131. is also the current hot in organic strategies formedical the synthesis ofFigure multi-substituted Obniska et al., designed and synthesized many series pyrrolidine-2,5-diones (Table 7) efficient and tested Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and in medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in Obniska et al., designed and synthesized many series pyrrolidine-2,5-diones 7)applied and tested Derivatives of pyrrolidine-2,5-diones, as heterocyclic compounds, have been(Table widely applied and medical chemistry [114]. their anticonvulsant activity in the MES and metrazole seizure threshold (sc-Met) tests [115–127]. The in16. medicinal chemistry and synthesis fields. They exhibit numerous bioactivities, especially in strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient their anticonvulsant activity in the MES and metrazole seizure threshold (sc-Met) tests [115–127]. TheObniska Pyrrolidine-2,5-dione Functional Group in medicinal chemistry and synthesis fields. They series exhibitpyrrolidine-2,5-diones numerous bioactivities, especially in et al., designed and synthesized many (Table 7) and tested quantitative evaluation in the MES seizures after oral administration into rats showed that the most anticonvulsant and tyrosinase inhibitory activities. Therefore, new rats and efficient and medical [114]. strategies for chemistry the synthesis of multi-substituted pyrrolidine-2,5-diones is also theofcurrent hot in organic The quantitative evaluation theMES MES seizures after oraldevelopment administration showed that anticonvulsant and tyrosinase inhibitory activities. Therefore, development ofinto new and efficient their anticonvulsant activity inin the metrazole seizure threshold (sc-Met) tests [115–127]. The Derivatives ofdesigned pyrrolidine-2,5-diones, as heterocyclic compounds, have been widely applied active were compound 153 with ED 50 of and 7.4 mg/kg and compound 154 with ED 50 of 26.4 mg/kg. These strategies for the synthesis of multi-substituted pyrrolidine-2,5-diones is also the current hot in organic Obniska et al., and synthesized many series pyrrolidine-2,5-diones (Table 7) and tested and medical chemistry [114]. the most active were compound 153 with ED of 7.4 mg/kg and compound 154 with ED 50oral administration 50 of strategies for the synthesisand of the multi-substituted pyrrolidine-2,5-diones is also the hot in organic quantitative evaluation in MES seizures after ratscurrent showed that most in medicinal chemistry synthesis fields. They exhibit numerous bioactivities, especially in as molecules were more potent and also less neuron-toxicity than that ofinto phenytoin which wasthe used and medical chemistry [114]. their anticonvulsant activity in the MES and metrazole seizure threshold (sc-Met) tests [115–127]. The Obniska et al., designed and synthesized many series pyrrolidine-2,5-diones (Table 7) and tested 26.4 mg/kg. These molecules were more potent and also less neuron-toxicity than thatmg/kg. of phenytoin and medical chemistry [114]. active were compound 153 with ED 50 of 7.4 mg/kg and compound 154 with ED 50 of 26.4 These anticonvulsant and tyrosinase inhibitory activities. Therefore, development of new and efficient reference antiepileptic drug. Although Kaminski et al., had reported several series pyrrolidine-2,5Obniska etevaluation al., designed and synthesized series pyrrolidine-2,5-diones (Table 7)that andthe tested quantitative in the MES seizures after oral administration into rats showed most their anticonvulsant activity in the MES and many metrazole seizure threshold (sc-Met) tests [115–127]. The which was as reference antiepileptic drug. Although Kaminski et al., had reported several Obniska etused al., designed and synthesized many series pyrrolidine-2,5-diones (Table 7) and tested molecules were more potent and also less neuron-toxicity than that of phenytoin which was used as strategies forcompound the synthesis of multi-substituted pyrrolidine-2,5-diones iswith also thecompound current hot in organic diones (Table 7) used for anticonvulsant activity, none exhibited better than 153 [128–132]. their anticonvulsant activity in the MES and metrazole seizure threshold (sc-Met) tests [115–127]. The active were 153 with ED 50 of 7.4 mg/kg and compound 154 ED 50 of 26.4 mg/kg. These quantitative evaluation in the MES seizures after oral administration into(sc-Met) rats showed that better the most series pyrrolidine-2,5-diones (Table 7) used for anticonvulsant activity, none exhibited than their anticonvulsant activity in the MES and metrazole seizure threshold tests [115–127]. The reference antiepileptic drug. Although Kaminski et al., had several seriesthat pyrrolidine-2,5and medical chemistry [114]. quantitative evaluation in the MES seizures after oral administration into rats theused most molecules more potent and also less thanreported that of phenytoin was as active werewere compound 153 with ED 50 of 7.4neuron-toxicity mg/kg and compound 154 with EDshowed 50 ofwhich 26.4 mg/kg. These compound 153 [128–132]. quantitative evaluation in the MES seizures after oral administration into rats showed that the most diones (Table 7) used for anticonvulsant activity, none exhibited better than compound [128–132]. Table 7. Structures of compounds 132–165. Obniska et al., designed and synthesized many series pyrrolidine-2,5-diones (Table 7)153 and tested active were compound 153 with ED 50 of 7.4 mg/kg and compound 154 with ED 50 of 26.4 mg/kg. These reference antiepileptic drug. Although Kaminski et al., had reported several series pyrrolidine-2,5molecules more potent andED also less neuron-toxicity than that of phenytoin which was used as activeanticonvulsant werewere compound 153 with 50 of 7.4 mg/kg and compound 154 with ED50 of 26.4 mg/kg. These their activity in MES and metrazole seizure threshold (sc-Met) tests [115–127]. O the molecules were and also less neuron-toxicity thanreported that of phenytoin which was[128–132]. used The as diones (Table 7)more usedpotent for anticonvulsant activity, none exhibited better than compound 153 Table 7.Kaminski Structures of al., compounds 132–165. reference antiepileptic drug. Although et had several series pyrrolidine-2,5molecules were more potent and also neuron-toxicity phenytoin which wasthe used as O than that Table 7.less Structures of compounds 132–165. R1ofinto R quantitative evaluation in the MES seizures after oral administration rats showed that most reference antiepileptic drug. Although Kaminski etR1al., exhibited had reported series pyrrolidine-2,5diones (Table 7) used for anticonvulsant activity, none betterseveral than 153 [128–132]. O compound N (CH2)n reference antiepileptic drug. Although Kaminski et al., had reported several series pyrrolidine-2,5O ED7. R2154 with ED50 of 26.4 mg/kg. These active(Table were compound 153 with 50 of 7.4 mg/kg compound Table Structures ofand compounds 132–165. N R diones 7) used for anticonvulsant activity, none exhibited better than 153 [128–132]. N compound O R1 than O diones (Table 7) used for anticonvulsant activity, none exhibited better 153 [128–132]. R X Rwhich Ncompound molecules were more potent and also less neuron-toxicity than that of phenytoin was used as R O 1 O O Table of compounds 132–165. (CH7. 2)n Structures 132 N R1=2-CH O 3 n=0 R 2 O R reported N R1 reference antiepileptic drug. Although Kaminski et al., had several series pyrrolidine-2,5R Table 7. Structures of compounds 132–165. N 133 n=1 1=2-Cl ONTable Rof OR 150-165 1 compounds O N X R 135-149 132–165. (CH 2)n 7. Structures =2-OCH n=1 134 R R2 better diones (Table 7) used for anticonvulsant activity, noneONexhibited R1 O than compound 153 [128–132]. O132 R11=2-CH3 3 n=0 R OR N R 1 OO N R(CH OR1 Comp. No. R R2 ON Reference X RX 2)n 133 n=1R 1=2-Cl RR21R O 150-165 ON R 135-149 R1 O R 1 )n 3 n=0 132N R(CH =2-CH O =2-OCH n=1 134 R 2 N 1 1 3 Rof 135 3) -NHPh(p-CH Structures O Table 1 compounds R2 132–165.ON X R (CH2)n7.n=1 N R 133 N R1=2-Cl R2 O 150-165 NR2 Comp. No. R R 1 R Reference 135-149 N R X O-NHPh(o-CF 132 R =2-CH n=0 O X 1 3 136 3 ) =2-OCH n=1 134 R O 1R N RN2 Comp. No. R1 X Reference 3 O R O X [116–118] 133 R =2-Cl n=1 N 132 -NHPh(p-CH R1=2-CH OO 1 O1 150-165 3 n=0 3) R R 135-149 137 Comp.135 No. R R 1 R 2 X Reference -NHPh 132 R =2-CH n=0 O =2-OCH n=1 134 R1 1 (CH )n 3 3 O 133 R1N=2-Cl 2 n=1 3) 135-149 136 -NHPh(o-CF 135 -NHPh(p-CH R2 150-165 133-NHPh(2,4-Cl 3 )n=1 134 R1R=2-OCH 1=2-Cl 135 138 -NHPh(p-CH 150-165 3 n=13) 2) Comp. No. R R 1 N R R 2N X Reference 135-149 [116–118] 134 OR1=2-OCH3 n=1 X R 137 N Comp. No. R-NHPh R1 R X Reference O2 139 [116] -NHPh(m-CH 136 -NHPh(o-CF ) 33)) 3) 136 -NHPh(o-CF 3 135 -NHPh(p-CH 132 R1=2-CH Comp.138 No. R 3 n=0 2) R1 O R2 X Reference [116–118] [116–118] -NHPh(2,4-Cl 135 3 ) -NHPh(p-CH 140 -NHPh(2,4-Cl 2 ) [117] 137 -NHPh 133 R1=2-Cl n=1 136 3) -NHPh(o-CF 137 -NHPh 150-165 135-149 135 3) -NHPh(p-CH [116–118] =2-OCH n=1 134 R 139 [116] -NHPh(m-CH 3) 1 3 141 -Ph(o-OCH 3 ) 136 -NHPh(o-CF 138 -NHPh(2,4-Cl 137 -NHPh 3))32)) [119] 136 -NHPh(o-CF [116–118] 138 -NHPh(2,4-Cl Comp. No. R 2 3) 2) R1 R2 X Reference 140 -NHPh(2,4-Cl [117] 142 -NHPh(4-Cl) [116–118] 137 -NHPh 139 [116] -NHPh(m-CH 138 2) -NHPh(2,4-Cl 137 -NHPh ) 3)3) 135 -NHPh(p-CH 141 -Ph(o-OCH 139 -NHPh(m-CH [116] 138 -NHPh(2,4-Cl 140 -NHPh(2,4-Cl [117] CH323) 23)) 139 [116] -NHPh(m-CH [119] 143 138 2) -NHPh(2,4-Cl 142 -NHPh(4-Cl) 136 3) -NHPh(o-CF 139 [116] -NHPh(m-CH 141 -Ph(o-OCH233))2) 140 -NHPh(2,4-Cl [117] 140 -NHPh(2,4-Cl [117] [120] — — [116–118] 139 [116] -NHPh(m-CH 3) [119] 137 -NHPh CH 140 143 -NHPh(2,4-Cl 2 ) [117] 142 -NHPh(4-Cl) 3 144 N 141 -Ph(o-OCH 3) 141 -Ph(o-OCH 140 -NHPh(2,4-Cl [117] 3 ) 2) [119] CH3 138 -NHPh(2,4-Cl [119] 141 -Ph(o-OCH 3) 2) [120] 142 -NHPh(4-Cl) CH —— — — [119] 143 3 3) 141 -Ph(o-OCH 142 -NHPh(4-Cl) 139 [116] -NHPh(m-CH 3 ) H3C N 142 144 [119] 145 -NHPh(4-Cl) [121] -NHPh CH3 CH33 [120] 142 143 -NHPh(4-Cl) CH — — 140 -NHPh(2,4-Cl 2) [117] CF 3 144 NCH3 143 143 [120] 146 [122] CH3 3) H3C CH3 — — 145 141 [121] -NHPh 143 -Ph(o-OCH [120] CH3 [119] 144 [120] N — — N N 142 -NHPh(4-Cl) CF [120] 3 147 3 ) [123] -Ph(o-CF H C CH — — 145 [121] -NHPh 3 144 N 146 [122] CH3 144 N CH 144 CH3 3 2H4)32N-CH 3 -Ph(m-Cl) [124] -N(C 143 CF H C 145148 3 [121] -NHPh 3 CH3 N N CH3 CH3 3) 146 [122] 147 [123] -Ph(o-CF H C 145 [121] -NHPh 3 [120] — — O CF3 H3-Ph(m-Cl) C CH3 145 [121] N-NHPh 148 2HN 4)2N-CH3 [124] -N(C 146 [122] CH33) 144 147 [123] -Ph(o-CF 149 [125] O N CF3 CH 3 CF CH3 146 [122] 3 NN N N 148 2 H 4 ) 2 N-CH 3 -Ph(m-Cl) [124] -N(C O 146 [122] 147 [123] -Ph(o-CF3) NO-NHPh N CH3 H3C 149 [125] 145 [121] 147 3) [123] -Ph(o-CF N2H4)2NN-CH CH 148 3 -Ph(m-Cl) [124] -N(C 20758 3 147 3) [123] -Ph(o-CF N NO 17 CF CH 148 [124] -N(C 149 [125] O 2H4)2N-CH3 3 3 -Ph(m-Cl) 146 [122] 148 -Ph(m-Cl) [124] -N(C2NH4)2N-CH O 33 N CH 149 [125] O N N O CH3 17 3) 147 [123] -Ph(o-CF N N O 149 [125] O

136 -NHPh(o-CF active were with ED50333))of mg/kg. These 135compound 153 ) 7.4 mg/kg and compound 154 with ED50 of 26.4 -NHPh(p-CH 136 -NHPh(o-CF [116–118] 136 3) -NHPh(o-CF [116–118] 137 -NHPh molecules137 were more potent and also3)less neuron-toxicity than that of phenytoin which was used as 136 -NHPh(o-CF [116–118] -NHPh [116–118] 137 -NHPh 138 2) Kaminski et al., had reported several series pyrrolidine-2,5-NHPh(2,4-Cl reference138 antiepileptic drug. Although 137 -NHPh 2) -NHPh(2,4-Cl 138 -NHPh(2,4-Cl 139 [116] -NHPh(m-CH 3)2) diones (Table anticonvulsant [128–132]. 138 7) used for-NHPh(m-CH 23) activity, none exhibited better than compound 153 -NHPh(2,4-Cl 139 [116] 139 [116] -NHPh(m-CH 140 -NHPh(2,4-Cl 2)3) [117] 139 [116] -NHPh(m-CH -NHPh(2,4-Cl23) [117] Molecules140 2015, 140 20, 20741–20776 -NHPh(2,4-Cl 2) [117] Table 7. of compounds 132–165. 141 -Ph(o-OCH 3)Structures 140 -NHPh(2,4-Cl [117] 141 -Ph(o-OCH3)2) [119] 141 -Ph(o-OCH 3 ) [119] 142 -NHPh(4-Cl) O 141 -Ph(o-OCH 3) [119] 142 -NHPh(4-Cl) 142 -NHPh(4-Cl) R Table 7.OCont. [119] R1 CH R 143 142 -NHPh(4-Cl) 3 1 O N (CH CH2)n 143 3 R2 CH3 N R 143 [120] N CH3 — —R 143 O X— [120] O— R N 144 No. [120] N Comp. R R X Reference — 2 — 1 O 132 R1N =2-CH3 n=0 144 [120] CH3 — — 144 N 133 R1=2-Cl n=1 CH 3 150-165 144 N 135-149CH 3 134 -NHPh R1=2-OCH3 n=1 H3C CH 145 [121] 145 -NHPh 3 H C 145 No. [121][121] -NHPh CH3 3 H C Comp. R R 1 CH3 R 2 X Reference 145 [121] -NHPh 3 CF CH3 H3C 145 [121] -NHPh CF33 146 [122] CH 135 3 ) -NHPh(p-CH CF 3 3 146 [122][122] 146 CF3 146 [122] N N 136 3) -NHPh(o-CF 146 [122] 147 [123] -Ph(o-CF3) N N [116–118] 147 [123] -Ph(o-CF3) N N 147 [123] -Ph(o-CF 137 147 -Ph(o-CF [123] 3 ) 3) 148 2H4)2N N-CH3 -Ph(m-Cl) [124] -N(CN-NHPh 147 3) [123] -Ph(o-CF 148 3 -Ph(m-Cl) [124] -N(C2H4)2N-CH CH 148 2H4)2N-CH -Ph(m-Cl) [124] -N(C 138 2) 33 -NHPh(2,4-Cl CH 148 -N(C -Ph(m-Cl) 2H 4 )42)N-CH 148 2H 2N-CH 33 -Ph(m-Cl) [124][124] -N(C O3 CH 3 OCH 139 [116] -NHPh(m-CH 3 ) 149 [125] O O 3 149 [125] O N N O 2) 140 -NHPh(2,4-Cl [117] 149 [125] O N N 149 [125][125] O 149 N N 3) 141 -Ph(o-OCH N N [119] 17 142 -NHPh(4-Cl) 17 17 150 -Ph(m-CF -Ph(m-CH3 ) CH33) 17-H 143 151

144

-Ph(p-Cl)

152

-Ph(m-CF3 )

153 145

-Ph(p-F) -NHPh

154

-Ph(m-Cl)

155

N-Ph N

146

147 156 148 157

149 158

-H

N

-H CH3

H3C -H CF3

-CH Ph 2H24)2N-CH3 -N(C —

O O -CH 2 CH2 OH N N

-Ph(m-Cl) —

CH3

CH3

-Ph(m-Cl)

N

-Ph(o-Br)

-H

-Ph(o-Br)

-H

-Ph(m-CF3 )

-Ph(o-CF3) -H -Ph(m-Cl)

[120]

—

-Ph(o-Cl)

-H

[121] [122] [123–128]

C O N

159

-CH2 Ph

160

-Ph(p-F)

161

-Ph(m-Cl)

162

-Ph(3,4-Cl2 )

163

-Ph(m-CF3 )

-Ph

-Ph

164

-Ph(3,4-Cl2 )

-H

-CH3

165

-Ph(3,4-Cl2 )

-H

-H

-CH3 17

-Ph

[126–128]

[123] [124]

[129]

[125] [130]

C

[131] N [132] [133]

Rybka et al., reported a synthesis of 22 new N-[(4-phenylpiperazin-1-yl)-methyl]-3-methylpyrrolidine-2,5-dione and pyrrolidine-2,5-dione derivatives. Administration to mice revealed that the most active compounds were compound 164 with ED50 = 16.13 mg/kg (MES), ED50 = 133.99 mg/kg (sc-PTZ) and compound 165 with ED50 = 37.79 mg/kg (MES), ED50 = 128.82 mg/kg (sc-PTZ) (Table 7). Compared with the positive control drugs valproate and ethosuximide, these compounds exhibited more activity and less neurotoxicity [133]. 17. The Imidazoline-2,4-dione Functional Group Imidazoline-2,4-diones, also called hydantoins, a class of cyclic imides, have been demonstrated to possess good anticonvulsant properties [134]. Their substitution products have also been found a number of other pharmacological properties such as antitumor, anti-HIV and antibacterial activities [135–137]. 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

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determined by the rotarod test. The most active of the series was compound 166 (Table 8), which showed a MES ED50 value of 12.5 mg/kg in mice. The TD50 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 ED50 value of 9.2 mg/kg and TD50 value of 421.6 mg/kg after i.p. to mice (Table 8), which provided compound 167 with a protective index (TD50 /ED50 ) of 45.8 in the MES test [139]. Botros et al., designed and synthesized new phenytoin derivatives and tested the anticonvulsant activity. Preliminary anticonvulsant screening was performed using standard MES and sc-PTZ screens in mice. The neurotoxicity was determined by applying the rotarod test. Among these compounds, 168 and 169 showed the highest protection (80%) in the sc-PTZ test at a dose of 100 mg/kg, whereas the compound 170 displayed promising anticonvulsant effect in the MES model (Table 8) [140]. Byrtus et al., prepared a various of N-Mannich bases derived from 5-cyclopropyl-5-phenyland 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-diones. The quantitative evaluation after oral administration in rats showed that the most active was compound 171 with ED50 values of 5.76 mg/kg (MES) and 57.31 mg/kg (sc-PTZ) (Table 8). Compared with the control drugs of ethosuximide and 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 (6-Hz) in mice showed comparable activity to a new generation anticonvulsant-levetiracetam [141]. Dhanawat et al., had reported a synthesis of N-(3)-substituted-2,4-imidazolidine diones and oxazolidinediones derivatives and tested the anticonvulsant activity using the MES test. Compounds 172, 173, 174 and 175 exhibited significant anticonvulsant activity as compared to the standard drug phenytoin (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) [144]. Madaiah et al., demonstrated a synthesis of new 3-[(2,4-dioxo-1,3,8-triazaspiro[4,6]undec-3-yl) methyl]benzonitrile derivatives and evaluated their possible anticonvulsant activity by MES and PTZ tests. Compounds 178, 179, 180 and 181 showed significant and protective effect on seizure when compared with the standard drug valproate (Table 8). These compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug [145]. Madaiah et al., synthesized a series of novel 11 -[2-(difluoromethoxy)benzyl]-21 H,51 Hspiro[8-azabicyclo[3,2,1]octane-3,41 -imidazolidine]-21 ,51 -dione substituted hydantoins. The novel molecules were screened for anticonvulsant activity in mice by MES and sc-PTZ-induced seizure tests. The neurotoxicity was assessed using the rotarod method. Compounds 182, 183, 184, 185 and 186 exhibited anticonvulsant potency against MES-induced seizure and in the sc-PTZ model (Table 8), with lesser neurotoxicity. Some title compounds showed lesser depression on central nervous system compared to phenytoin [146].

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phenytoin, it was more active in the anti-convulsion assays. Additionally compound 171 with ED50 Molecules 20, 20741–20776 of 26.06 2015, mg/kg in a psychomotor seizure test (6-Hz) in mice showed comparable activity to a new generation anticonvulsant-levetiracetam [141]. Table 8. Structures of compounds 166–186.

Table 8. Structures of compounds 166–186. O R2 R1

R N N H

166-167

O O

R1 R2

R N N H

168-177

R

O

O N

N

N

O HN

O 178-181

N

R N N H

O

182-186

F

O F

Comp. R R R1 R2 R2 Reference Comp. No.No. R1 Reference 166 166 3 H -Ph(p-SO 2 CH 3 ) [138] -CH -CH3 H -Ph(p-SO2 CH3 ) [138] -NHCOPh(p-CF -CH3 -CH3 -CH-CH [139] 167 167 3 [139] -NHCOPh(p-CF 3 ) 3) 3 -CH -Ph -Ph-Ph 2 C(O)NNCSH 168 168 -CH 2C(O)NNCSH -Ph 169 -CH2 CONHNHCSNHPh(p-OCH3 ) -Ph -Ph [140] 169 -CH2CONHNHCSNHPh(p-OCH [140] 3) -Ph -Ph 170 -CH2 CONHNHCSNHPh -Ph -Ph 170 171 -CH2CONHNHCSNHPh -Ph -H -Ph -C3 H-Ph [141] 5 171 172 -H 2 )2 Ph -Ph -C53H5 [141] -CH2 N(CH2 CH -Ph -C3 H 173 -CH CONHPh(p-Cl) -Ph -Ph 2 2N(CH2CH2)2Ph 172 -CH -Ph -C3H5 [142] -CH -Ph -Ph-Ph 2 CONHPh(o-Cl) 173 174 2CONHPh(p-Cl) -Ph -CH 175 -CH2 CONHPh(p-OCH3 ) -Ph -Ph [142] 174 176 2CONHPh(o-Cl) -Ph -CH2 -CH CON(CH -Ph -Ph-Ph [143] 2 CH2 )2 Ph(p-NO2 ) 175 -CH 2CONHPh(p-OCH 3) -Ph -Ph -(CH 2 )2 O(CH2 )2 177 -Ph -Ph [144] N(CH 176 -CH 2CON(CH CH2)2Ph(p-NO2) -Ph -Ph [143] 2 CH2 )22Ph(p-Cl) -SO22)Ph(o-F) 177 178 -(CH2)2O(CH 2 N(CH2CH2)2Ph(p-Cl) -Ph -Ph [144] 179 -SO2 Ph(m-F) [145] 178 -SO2Ph(o-F) 180 -CO Ph(m-F) 179 181 -SO 2 Ph(m-F) -CO Ph(p-F) [145] — — 180 182 -CO Ph(m-F) -SO 2 Ph(o-F) -SO-CO 2 Ph(m-F) 181 183 Ph(p-F) 184 -SO2 Ph(o-F) [146] 182 — — -SO2Ph(o-F) 185 -CONHPh 183 186 -SO2Ph(m-F) -CONHPh(m-CH 3) 184 [146] -SO2Ph(o-F) 185 -CONHPh 18. The Oxime Ether Functional Group 186 -CONHPh(m-CH3) Due to the lipophilic aryl portion facilitating penetration of the blood–brain barrier, the introduction of oxime etherreported groups to compounds as a small oxygen functional group had been Dhanawat et al., had a the synthesis of N-(3)-substituted-2,4-imidazolidine diones and studied. Meanwhile, oxime ether alsoanticonvulsant are used as a mechanism for the pro-drug generation [147]. oxazolidinediones derivatives andlinkages tested the activity using MES test. Compounds Karakurt et 175 al., exhibited prepared significant oxime andanticonvulsant oxime ether derivatives of anticonvulsant nafimidone 172, 173, 174 and activity as compared to the standard drug [1-(2-naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the phenytoin (Table 8)[142]. compounds anticonvulsant activities. 187,phenytoin. 188 and 189 (salt) were found Botros etexhibited al., described new bivalent ligandsCompounds derived from Initial anticonvulsant to be active 30 mg/kg at MES the half-hour time point without at the were samefound dose screening was at performed using and PTZ screens in mice. Most ofneurotoxicity the test compounds level (Table 9). Meanwhile, these derivatives exhibited some activity against sc-Met as well as to be effective in at least one seizure model at a dose of 100 mg/kg. Compound 176 exhibited marked MES-induced seizures anticonvulsant activity [148]. in both MES and PTZ screens (Table 8) [143]. Karakurt et established al., reported synthesisofofN-Mannich twenty-three new oxime ester derivatives nafimidone. Byrtus et al., a synthesis from 5-cyclopropyl-5-phenylandof 5-cyclopropylMES and sc-Met tests were employed for their anticonvulsant activities and rotarod testafter for 5-(4-chlorophenyl)-hydantoins and tested their anticonvulsant activity. The quantitative studies 4h neurological deficits.toCompound 190that wasseveral the most active one in sc-Met test at than all dose levels atand oral administration rats showed molecules were more potent phenytoin (Table 9) [149]. ethosuximide which were used as reference antiepileptic drugs. From the whole series, the most et al., synthesized O-alkylated derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone activeBansal was compound 177 with the ED50 value of 5.29 mg/kg in the MES test (Table 8) [144]. oxime as potential of mice with compounds 191 and 192 Madaiah et al.,anticonvulsant demonstrated compounds. a synthesis ofPre-treatment new 3-[(2,4-dioxo-1,3,8-triazaspiro[4,6]undec-3-yl) (30 mg/kg, i.p.) significantly decreased the susceptibility to PTZ-induced seizure by as MES evidenced by methyl]benzonitrile derivatives and evaluated their possible anticonvulsant activity and PTZ delayed onset of clonus and180 mean time ofsignificant extensor phase (Table 8). effect The treatment mice tests. Compounds 178, 179, and onset 181 showed and protective on seizureofwhen with these with compounds show equivalent protection level compared with standard drug to diazepam compared the standard drug valproate (Table 8). as These compounds were found exhibit (0.5 mg/kg, i.p.). Anticonvulsant data showed that compounds 191 and 192 were the most advanced anticonvulsant activity evaluation as well as lower neurotoxicity than the reference drug [145]. active with ED50 values of 46.77 mg/kg and 24.41 mg/kg, respectively [150].

19

20761

Dueof to oxime the lipophilic aryl portion facilitating of the blood–brain barrier,group the introduction Meanwhile, oxime ether linkages alsothe arecompounds used aspenetration a mechanism foroxygen pro-drug generation [147]. groups as aa small functional had been studied. of oxime ether ether groups to theto compounds as a small oxygen functional groupgroup had been of oxime ether groups to the compounds as small oxygen functional had studied. been of oxime ether groups to the compounds as a small oxygen functional group been studied. studied. of oxime etheret groups to the compounds as are aether small oxygen functional group had beenhad studied. Karakurt al., prepared oxime and oxime derivatives of anticonvulsant nafimidone [1-(2Meanwhile, oxime ether linkages also used as a mechanism for pro-drug generation [147]. Meanwhile, oximeoxime ether linkages also are used as a mechanism for pro-drug generation [147]. [147]. Meanwhile, ether linkages also are used as aa mechanism for pro-drug generation Meanwhile, oxime ether linkages also are used as mechanism for pro-drug generation [147]. Meanwhile, oxime etheretlinkages also are usedand as aanticonvulsant mechanism forcompounds. pro-drugofgeneration [147]. naphthyl)-2-(imidozole-1-yl)ethanone] as potential Most of the compounds Karakurt al., prepared oxime ether derivatives anticonvulsant nafimidone Karakurt et al., prepared oximeoxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2- [1-(2Karakurt et al., prepared oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2Karakurt et al., prepared oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2Karakurt et al., prepared oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2exhibitednaphthyl)-2-(imidozole-1-yl)ethanone] anticonvulsant activities. Compounds 187, 188 and 189 (salt) were found to be of active at as potential anticonvulsant compounds. Most the compounds naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the compounds naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the compounds naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the compounds naphthyl)-2-(imidozole-1-yl)ethanone] as potential anticonvulsant compounds. Most of the compounds 30 mg/kgexhibited at the half-hour time pointactivities. without neurotoxicity at187, the 188 same dose level (Table 9).found Meanwhile, anticonvulsant Compounds and 189 (salt) were be active at Molecules 2015, 20, 20741–20776 exhibited anticonvulsant activities. Compounds 187, 188 189 were found to be to active at exhibited anticonvulsant activities. Compounds 187, 188 and 189 (salt) were found to active at exhibited anticonvulsant activities. Compounds 187,and 188 and(salt) 189 (salt) were found to be be exhibited anticonvulsant activities. Compounds 187, 188 and 189 (salt) were found to be active at active at these derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148]. 30 mg/kg at the half-hour time point without neurotoxicity at the same dose level (Table 9). Meanwhile, 30 mg/kg at the half-hour time point neurotoxicity at the same dose level (Table 9). Meanwhile, 30 mg/kg at the timewithout point without neurotoxicity at the same dose level (Table 9). Meanwhile, 30 mg/kg the half-hour half-hour without neurotoxicity at dose the same dose level 9). Meanwhile, 30 mg/kg at the half-hour time pointtime without neurotoxicity at the same level (Table 9). (Table Meanwhile, Karakurt etderivatives al., at reported synthesis ofpoint twenty-three new oxime ester derivatives of nafimidone. MES exhibited some activity against sc-Met as well as MES-induced seizures [148]. these these derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148]. these derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148]. these derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148]. thesesc-Met derivatives exhibited some activity against sc-Met as well as MES-induced seizures [148]. Karakurt et al., synthesized oxime and oxime ether derivatives of [1-(2-naphthyl)-2and tests were employed for their anticonvulsant activities and rotarod test for neurological Karakurt et al., reported synthesis of twenty-three new oxime ester derivatives of nafimidone. Karakurt et al., reported synthesis of twenty-three new oxime ester derivatives of nafimidone. MES MES Karakurt et al., reported synthesis of twenty-three new oxime ester derivatives of nafimidone. MES Karakurt et al., reported synthesis of twenty-three new oxime ester derivatives of nafimidone. Karakurt et al., reported synthesis of twenty-three new oxime derivatives of4 nafimidone. MES (1,2,4-triazol-1-yl)ethanone] as potential anticonvulsant compounds. The most of9)for the series MES deficits. Compound 190 was theemployed most active one in sc-Met test at ester allactivities dose levels atrotarod hactive (Table [149]. and sc-Met tests were for their anticonvulsant and test neurological and sc-Met tests were employed for their anticonvulsant activities and rotarod test for neurological and sc-Met tests were employed for their anticonvulsant activities and rotarod test for neurological and sc-Met tests were for their anticonvulsant activities andtest rotarod test for neurological andwas sc-Met tests were employed for their anticonvulsant activities and at rotarod for neurological compound 193 (Table 8) employed [151]. deficits. Compound 190 was the most active in sc-Met all dose levels 44 hh (Table 9) deficits. Compound 190 was the most active one inone sc-Met test attest all dose levels at 4 h at (Table 9) [149]. deficits. Compound 190 was the most active one in sc-Met test at all dose levels at 9) [149]. [149]. deficits. Compound 190 was the most active one in sc-Met test at all dose levels at h (Table (Table 9. Structures 187–193. deficits. Compound 190 wasTable the most active oneofincompounds sc-Met test at all dose levels at 4 h (Table4 9) [149]. 9) [149]. Table 9. Structures of compounds 187–193.187–193. O of compounds 9. Structures TableTable 9. Structures ofNcompounds 187–193. Table 9. of 187–193. R1 compounds Table 9. Structures Structures of compounds Table 9. Structures of compounds 187–193. 187–193. ON

N

R

R1

O O O RR1 RN N 1 N R11

R

RR R

O

187–193 RR1

Comp. No. R Reference 187–193 187–193 187–193 187–193 187–193 187 3 -CH Comp. R R Reference Comp. No. Comp. R R R111 Reference No. No. R1 Reference Comp. No. R Reference Comp. No. R -CR2H R Comp. R 1 5 Reference 188 No. [148] Reference 187 3 -CH 187 187 -CH3 -CH Molecules 2015, 20, page–page 187 -CH333 187 -CH 187 3 189 -CH-CH 2CHCH 2-C2H5 188 -C H 188 188 [148] [148] 2 H 5 -C 188 [148] Cl -C222H55 188 [148] [148] 188 Group [148] -C2H5-CH 189Functional -CH CHCH 189 2 CHCH 2 19. The Pyridazine 2 2 N 189 189 -CH2CHCH 2 -CH 2CHCH 2 189 -CH 2CHCH 2 Cl 190 [149] 189 -CH2CHCH 2 Cl Cl Cl N Clthe molecular formula (CH)4N2. It contains Pyridazine is190 a heterocyclic organic compound with N N N O N [149] 190 190 [149] [149] 190 [149] O 190 Nnitrogen atoms, [149] a six-membered ring with191 two adjacent and is aromatic [150]. Pyridazine derivatives 190 [149] N N N 3O OO CHO N [150] O O N have various biological applications [152–155]. O O O O Cl 191 O CH 192 191 191 3 191 CH CH 191 Guan et al., synthesized of 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine derivatives. In initial CH33 [150] [150] 191a series O3 3 O O [150] CH O [150] [150] Cl O [150] Cl Cl 192 N screening and quantitative evaluation, compound 194 was the Cl most active agent, exhibiting the 192 192 193 -CH 3 Cl [151] 192 192 N 192 lowest toxicity at the same time (Table N 10). In the anti-MES test, it showed ED50 of 17.3 mg/kg and N N N N 193 -CH3 [151] N 193 -CH 3 -CH3 [151] 193 [151] N N N 193 -CH 3 [151] [151]drugs [156]. TD50 of 380.3 mg/kg, which isN much than PI of the reference 193 PI of 22.0 -CHbetter 3 193 and the -CH N N 3 [151] N N N Bansal et al., synthesized O-alkylated derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone Sivakumar et al., reported synthesis of 1-substituted-1,2-dihydro-pyridazine-3,6-diones as N oxime as potential anticonvulsant compounds. Pre-treatment of mice with 191 andactivity. 192 potential anticonvulsant agents. The compounds were tested in vivo for compounds the anticonvulsant Bansal et al., synthesized O-alkylated derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone BansalBansal et al., et synthesized O-alkylated derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone al., O-alkylated derivatives of Bansal et al., synthesized synthesized O-alkylated derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone Bansal et al., synthesized O-alkylated derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone (30 The mg/kg, i.p.) significantly decreased the susceptibility to PTZ-induced seizure as evidenced by195 compound which have maximum protection against MES-induced seizures was compound oxime as potential anticonvulsant compounds. Pre-treatment of mice with compounds 191 and 192 19. The Functional Group oxime asPyridazine potential anticonvulsant compounds. Pre-treatment of mice with compounds 191 and oxime as potential anticonvulsant compounds. Pre-treatment of mice with 191 and oxime as potential anticonvulsant compounds. Pre-treatment ofThe mice with compounds compounds 191192 and 192 192 oxime as potential anticonvulsant compounds. Pre-treatment of mice with compounds 191 and 192 delayed onset of clonus and mean onset time of extensor phase (Table 8). treatment of mice with with ED 50mg/kg, = 44.7 mg/kg i.p. 4 h (Table 10) [157]. (30 i.p.) significantly decreased the susceptibility to PTZ-induced seizure as evidenced by (30 mg/kg, i.p.) significantly decreased the susceptibility to PTZ-induced seizure as evidenced by (30 mg/kg, i.p.) significantly decreased the susceptibility to PTZ-induced seizure as evidenced by (30i.p.) mg/kg, significantly decreased the susceptibility to PTZ-induced seizure evidenced by Pyridazine is i.p.) a heterocyclic organic compound with molecular formula (CH) It contains (30 mg/kg, significantly decreased theof susceptibility tothe PTZ-induced seizure as evidenced by 4 Ndiazepam 2 .ofas these compounds show equivalent protection level as compared with standard drug Moreau et al., reported a synthesis several 3-substituted pyridazines and a series imidazodelayed onset of clonus and mean onset time of extensor phase (Table 8). The treatment of mice with delayed onset of clonus and mean onset time of extensor phase (Table 8). The treatment of mice with delayed onset of clonus and mean onset time of extensor phase (Table 8). The treatment of mice with delayed onset of clonus and mean onset time of extensor phase (Table 8). The treatment of mice with a six-membered ring with two adjacent nitrogen atoms, and is aromatic [150]. Pyridazine derivatives delayed onset of clonus andand mean onset time of extensor phase (Table 8). MES-induced The of mice with (0.5 mg/kg, i.p.). Anticonvulsant evaluation data showed that compounds 191 treatment and 192 were the most and tested their anticonvulsant activity against seizures in mice. these compounds equivalent protection as compared with standard diazepam thesetriazolopyridazines compounds show show equivalent protection level level as compared with standard drug drug diazepam these compounds show equivalent protection level as compared with standard drug diazepam these compounds show equivalent protection level as compared with standard drug diazepam have various biological applications [152–155]. these compounds show equivalent protection level as compared with standard drug diazepam active with ED 50 values ofAnticonvulsant 46.77 196, mg/kg and 24.41 mg/kg, respectively [150]. The most active derivatives, 197, 198, 199 and 200 with oral ED 50 ranged from 6.2 to 22.0 mg/kg (0.5 mg/kg, i.p.). evaluation data showed that compounds 191 and 192 were the most (0.5 mg/kg, i.p.). Anticonvulsant evaluation data showed that compounds 191 and 192 were the most (0.5 mg/kg, i.p.). Anticonvulsant evaluation data showed that compounds 191 and 192 were the (0.5i.p.). mg/kg, i.p.). Anticonvulsant data showed that compounds 191were and 192 were the most most Guan et al., synthesized aoxime seriesand of evaluation 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine derivatives. In initial (0.5(Table mg/kg, Anticonvulsant evaluation data showed that compounds 191 and 192 the most Karakurt et al., synthesized oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazol10). The compound 200 was also protective in the PTZ-induced seizure test (ED 50 = 76 mg/kg with ED 50 values of 46.77 mg/kg and 24.41 mg/kg, respectively [150]. activeactive with ED 50 values of 46.77 mg/kg and 24.41 mg/kg, respectively [150]. [150]. active with ED 50 values of 46.77 mg/kg and 24.41 mg/kg, respectively active with ED 50 values of 46.77 mg/kg and 24.41 mg/kg, respectively [150]. screeningED and quantitative evaluation, compound 194The was the most active agent, exhibiting the lowest active 50 ofal., 46.77 mg/kg and 24.41 mg/kg, respectively [150]. 1-yl)ethanone] asvalues potential anticonvulsant compounds. most active of the series was 50 = 34.5 mg/kg per os).compound Furthermore, per with os) andKarakurt blocked tonic extensor seizures (ED et synthesized and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazolKarakurt et al.,strychnine-induced synthesized oximeoxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazolKarakurt et al., synthesized oxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazolKarakurt et al., synthesized oxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazoltoxicity at the same time (Table 10). In the anti-MES test, it showed ED of 17.3 mg/kg and TD50 of Karakurt et al., synthesized oxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazol50 193derivative (Table 8) [151]. 200 showed anticonvulsant effects on bicucullineand yohimbine-induced seizure tests in 1-yl)ethanone] as potential anticonvulsant compounds. The most active the series was compound 1-yl)ethanone] as potential anticonvulsant compounds. The most active of theof series was compound 1-yl)ethanone] as potential anticonvulsant compounds. The most active of the series was compound 1-yl)ethanone] as potential anticonvulsant compounds. The most active of the series was compound 380.3 mg/kg, and the PI of 22.0 which is much better than PI of the reference drugs [156]. 1-yl)ethanone] as potential anticonvulsant compounds. The most active of the series was compound mice [158]. 193 8) 193 (Table 8) [151]. 193 (Table (Table 8) [151]. [151]. 193 (Table193 8) (Table [151]. 8) [151]. Table 10. Structures of compounds 194–200. Table 10. Structures 20 of compounds 194–200. R2 R N N

20

N N

NH2 O

194-198

199

RR 2) -OPh(2,4-Cl -OPh(2,4-Cl 2) -CH -CH 3 3 -CH 3 3 -CH -CH3 -CH3 -CH3

-CH3

20 20 20

NH

N N

R1

Comp. No. Comp. No. 194 194 195 196 196 197 197 198 198

20

R11 H H H H H H -NH2 -NH2 -NH2 -NH2

NH2 O HN NH OH

O N NH

200

RR 2 2 Reference Reference HH [156] [156] -CH [157] -CH 2Ph [157] 2 Ph 2 Ph(2,6-Cl -CH-CH 2Ph(2,6-Cl 2) 2 ) -CH2 Ph [158] [158] -CH2Ph -CH2 Ph(2,6-Cl2 ) -CH2Ph(2,6-Cl2)

Sivakumar et Functional al., reported synthesis of 1-substituted-1,2-dihydro-pyridazine-3,6-diones as 20. Miscellaneous Groups potential anticonvulsant agents. The compounds were tested in vivo for the anticonvulsant activity. Sapa et al., which established a synthesisprotection of some novel derivatives and evaluated The compound have maximum againstpyrrolidin-2-one MES-induced seizures was compound 195 their possible anticonvulsant activity by MES and PTZ tests. Compound 201 significantly reduced with ED50 = 44.7 mg/kg i.p. 4 h (Table 10) [157]. the incidence of seizures in the MES test. The compounds 202 and 203 demonstrated activity in the PTZ-induced seizures test [159,160]. 20762 Nevagi et al., demonstrated synthesis of novel thiosemicarbazide derivatives and evaluated their anticonvulsant activity and neurotoxicity. Amongst all the synthesized compounds, compound 204 is a broad-spectrum anticonvulsant agent since it was active in both MES- and PTZ-induced seizure

Molecules 2015, 20, 20741–20776

Moreau et al., reported a synthesis of several 3-substituted pyridazines and a series of imidazo- and triazolopyridazines and tested their anticonvulsant activity against MES-induced seizures in mice. The most active derivatives, 196, 197, 198, 199 and 200 with oral ED50 ranged from 6.2 to 22.0 mg/kg (Table 10). The compound 200 was also protective in the PTZ-induced seizure test (ED50 = 76 mg/kg per os) and blocked strychnine-induced tonic extensor seizures (ED50 = 34.5 mg/kg per os). Furthermore, derivative 200 showed anticonvulsant effects on bicuculline- and yohimbine-induced seizure tests in mice [158]. 20. Miscellaneous Functional Groups Sapa et al., established a synthesis of some novel pyrrolidin-2-one derivatives and evaluated their possible anticonvulsant activity by MES and PTZ tests. Compound 201 significantly reduced the incidence of seizures in the MES test. The compounds 202 and 203 demonstrated activity in the PTZ-induced seizures test [159,160]. Nevagi et al., demonstrated synthesis of novel thiosemicarbazide derivatives and evaluated their anticonvulsant activity and neurotoxicity. Amongst all the synthesized compounds, compound 204 is a broad-spectrum anticonvulsant agent since it was active in both MES- and PTZ-induced seizure models with no neurotoxicity (Figure 12) [161]. Dawidowski et al., synthesized a series of novel diastereomerically pure, monocyclic 2,6-DKP derivatives using a diastereoselective method. In the MES test, some of them showed good or weak antiepileptic activities, however, there was no active compound in the sc-Met screen. The most promising compound 205 exhibited notable action in the 6 Hz test (Figure 12) [162]. Strupinska ´ et al., synthesized a series of benzylamides of isocyclic and heterocyclic acids and tested their anticonvulsant activity. Nearly all synthesized heterocyclic acid derivatives showed anticonvulsant activity. Compound 206 appeared the most promising (Figure 12). It showed in minimal clonic seizure (6 Hz) test (ASP) in rats after i.p. administration: MES ED50 = 36.5 mg/kg, TOX TD50 = 269.75 mg/kg, and PI = 7.39 [163]. Pastore et al., synthesized novel N-derivative-1,2,3-oxathia-zolidine-4-one-2,2-dioxides heterocycles, bioisosteres of trimethadione (TMD, oxazolidine-2,4-dione) and phenytoin. Anticonvulsant screening was performed in mice after intraperitoneal administration in the MES test and sc-PTZ test. Compound 207 (Figure 12), the most active drug obtained, with an ED50 of 60 µg/kg was 10,000 times more active than TMD, the reference compound in this work, and 90 times more active than valproic acid, an anticonvulsant drug presently in use in the clinic [164]. 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]. Guan et al., prepared a variety of N-(2-hydroxyethyl)cinnamamide derivatives and screened their anticonvulsant activities by the MES test and their neurotoxicity was evaluated by the rotarod test. In the anti-MES potency test, compounds 211 and 212 exhibited ED50 dose of 17.7 and 17.0 mg/kg, respectively (Figure 12), and TD50 dose of 154.9 and 211.1 mg/kg, respectively, resulting in a PI of 8.8 and 12.4, respectively, which were much greater than the PI of the market antiepileptic drug carbamazepine [166]. Alswah et al., reported synthesis of some [1,2,4]triazolo[4,3-a]quinoxaline derivatives as novel anticonvulsant agents. The anticonvulsant evaluation was used metrazol-induced convulsion model and phenobarbitone sodium was as a standard. Among this set of tested compounds, two of them (213 and 214) showed the best anticonvulsant activities (Figure 12) [167]. Chen et al., reported synthesis of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazole derivatives. Their anticonvulsant activities were evaluated by the MES test and their neurotoxicity was evaluated by the rotarod test. MES test showed that compound 215 was found to be the most potent with ED50

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value of 8.3 mg/kg and PI value of 5.5, but compound 216 exhibited better PI value of 9.3 (Figure 12), which was greater than PI value of the prototype drug phenytoin [168]. Molecules 2015,much 20, page–page N

N O

N

R1

N H

R2

H N

O

O

206

O H

Br

O

H N

R

N H

HN NH

X

OH

N H

R

210 R=CH(CH3)2 S

NH

N N 213: X=O 214: X=S

211 R=Ph 212 R=CH=CHC6H4(m-F)

O

209 R=C2H5

O O

H

N H

O

208

207

O

205

O N H

H N N H

204

O O S O N

N H

NH

N H

O

201 R1=OH R2=2-OH 202 R1=H R2=2-OMe 203 R1=H R2=2-OEt O

H N

S

S

R

N

O N

N

N

215 R=n-C7H15 216 R=n-C8H17

N

Cl N

O

N N N

R N N

O

N

R

OH

N NH

O

R2

R1

N

N

221 R=n-C6H13 222 R=n-C5H11

O F

223

N H

N

R1=H R1=H R1=H R1=CH3

NH

O

O 224 225 226 227

N

O

EtO2C

N NH N

N

R

N N 220 R=n-C7H15

219

S

O

O

N NH

O

218

217 R=n-C10H21

N N

N

EtO2C R2=4-Hydroxyphenyl R2=Vanilinyl R2=1-Hydroxy-naphthalein-2-yl R2=4-Fluorophenyl

Figure 12. Structures of compounds 201–227. Figure 12. Structures of compounds 201–227.

Pastore et al., synthesized novel N-derivative-1,2,3-oxathia-zolidine-4-one-2,2-dioxides heterocycles, Wang et synthesized(TMD, a series of new purines containing triazole and other heterocycle bioisosteres of al., trimethadione oxazolidine-2,4-dione) and phenytoin. Anticonvulsant screening substituents and inevaluated their preliminary anticonvulsant by using was performed mice after intraperitoneal administration activity in the and MESneurotoxicity test and sc-PTZ test. the MES, sc-PTZ and rotarod tests. Among the compounds studied, compound 217 was the times most Compound 207 (Figure 12), the most active drug obtained, with an ED50 of 60 μg/kg was 10,000 potentactive compound, withthe a ED mg/kg and a high protective index of more after 50 of 23.4 more than TMD, reference compound in this work, and 90 times more activethan than25.6 valproic intraperitoneal administration in mice (Figure 12). Compound 217 showed significant oral activity acid, an anticonvulsant drug presently in use in the clinic [164]. against MES-induced seizures in mice, withsixteen an ED50 of 39.4 mg/kg and a PI above 31.6 [169]. Uysal et al., designed and synthesized 2/3-benzoylaminopropionanilide derivatives. The Shu et al., reported synthesis of 4-(3-alkoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-ones. Allsc-Met target anticonvulsant activity profile of the synthesized compounds was determined by MES and compounds anticonvulsant activity of varying degrees maximal electroshock test. seizure tests.exhibited In the rotarod test, all of them exhibited no toxicity toin thethe nervous system. Compounds Compound 218 was the most promising compound with an ED value of 30.5 mg/kg and a PI 208, 209 and 210 were found to be more potent in the MES or50sc-Met tests (Figure 12). Those of 18.63 (Figure showing a higher safety for than the standard drug[165]. carbamazepine (PI = 6.45). compounds have12), emerged as lead compounds future investigations In addition, the potency of compound 218 against seizures induced pentylenetetrazole and Guan et al., prepared a variety of N-(2-hydroxyethyl)cinnamamidebyderivatives and screened 3-mercaptopropionic acid suggested broad-spectrum [170]. was evaluated by the rotarod their anticonvulsant activities by the its MES test and their activity neurotoxicity Kahveci et al., designed and synthesized a series of new 1,2,4-triazole-3-one derivatives test. In the anti-MES potency test, compounds 211 and 212 exhibited ED 50 dose of 17.7 and 17.0 mg/kg, bearing the salicyl moiety. The anticonvulsant activities of all compounds were evaluated of respectively (Figure 12), and TD50 dose of 154.9 and 211.1 mg/kg, respectively, resulting in a PI by the and Anticonvulsant Screening Program of the greater U.S. National Institutes Health.antiepileptic The most active 8.8 12.4, respectively, which were much than the PI of theofmarket drug carbamazepine [166]. Alswah et al., reported synthesis of some [1,2,4]triazolo[4,3-a]quinoxaline derivatives as novel anticonvulsant agents. The anticonvulsant evaluation was used metrazol-induced convulsion model 20764 and phenobarbitone sodium was as a standard. Among this set of tested compounds, two of them (213 and 214) showed the best anticonvulsant activities (Figure 12) [167].

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compound 219 showed significant anticonvulsant activity with an ED50 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 ED50 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 ED50 value of 12.3 mg/kg, a TD50 value of 73.5 mg/kg, and a PI of 6.0, which was slightly lower than the PI of the prototype drug carbamazepine (ED50 = 8.8, PI = 8.1). In the sc-PTZ test, compound 222 was the most active, with an ED50 value of 19.8 mg/kg, a TD50 value of 80.8 mg/kg and a PI value of 4.1, which are greatly higher than that of carbamazepine (ED50 > 100, PI < 0.72) [173]. Deng et al., synthesized two series of 8-alkoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d] [1,4]thiazepine derivatives. All of the prepared compounds were effective in the MES screens, among which, compound 223 was considered as the most promising one with an ED50 value of 26.3 mg/kg and a superior PI value of 12.6 (Figure 12). The potency of compound 223 against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid and bicuculline was great too [174]. Ulloora et al., synthesized new substituted 1,4-dihydropyridin-4-yl-phenoxyacetohydrazones. The final compounds were screened for their in vivo anticonvulsant activity by MES, sc-PTZ and 6 Hz methods. The active compounds, 224, 225, 226 and 227 exhibited their activities at 4 h after i.p. injection with 100 mg/kg (Figure 12). All these tested compounds exhibited activity in 6 Hz method within 1 h [175]. Siddiqui et al., reported synthesis of various 1-[6-(4-substituted phenyl)-3-cyano-4-(substituted phenyl)-pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acids. Their in vivo anticonvulsant evaluation was performed by MES and sc-PTZ tests. Compounds 228 and 229 displayed comparable anticonvulsant activity to the standard drugs with ED50 values of 13.4 and 18.6 mg/kg in electroshock screen, respectively (Figure 13). The compounds 228 and 229 were also found to have encouraging anticonvulsant activity (ED50 = 86.1 and 271.6 mg/kg, respectively) in sc-PTZ screen. Interestingly, they did not show any sign of motor impairment at the maximum dose administered and were not toxic to the liver [176]. Lee et al., prepared 13 derivatives of N-(biphenyl-41 -yl)methyl-(R)-2-acetamido-3-methoxypropionamide that were tested for anticonvulsant activity at the Anticonvulsant Screening Program (ASP) of the National Institute of Neurological Disorders and Stroke (NINDS) of the U.S. National Institutes of Health. The excellent activities in the MES test (mice, i.p.) of the compound 230 and 231 (ED50 = 9.8 and 12 mg/kg, respectively) coupled with their low neurotoxicities (TD50 = 74 and 86 mg/kg, respectively) provided compounds with notably higher PI (7.6 and 7.2, respectively) (Figure 13) [177]. Siddiqui et al., prepared a series of 4-thiazolidinones bearing a sulfonamide group and tested their anticonvulsant activity utilizing MES and sc-PTZ animal models. Compounds 232, 233 and 234 displayed promising activity and could be considered as leads for further investigations (Figure 13) [178]. Hen et al., synthesized a novel class of 19 carbamates and evaluated their anticonvulsant activity in the rat MES and sc-Met seizure tests and pilocarpine-induced status epilepticus (SE) model. The carbamates 235 (MES ED50 = 64 mg/kg), 236 (MES ED50 = 52 mg/kg) and 237 (MES ED50 = 16 mg/kg) offered an optimal anticonvulsant efficacy and safety profile and consequently are potential candidates for further development as new AEDs (Figure 13) [179].

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Hen et al., synthesized a novel class of aromatic amides composed of phenylacetic acid or branched aliphatic carboxylic acids, with five to nine carbons in their carboxylic moiety, and aminobenzenesulfonamide. The final compounds were screened for their anticonvulsant activity by MES and sc-Met tests. The amides 238, 239 and 240 were the most potent compounds possessing MES-ED50 values of 7.6, 9.9, and 9.4 mg/kg and remarkable PI values of 65.7, 50.5, and 53.2, respectively (Figure 13) [180]. Molecules 2015, 20, page–page O

R1 N

N

O

N H R2=4-Cl NH2 O S O

NH2 O S O

R 232 R=3-OH 233 R=4-Cl 234 R=4-Br

237

R 238 R=CH3 239 R=C2H5

NH O 240

O

235 R=CH3 236 R=C2H5

N

HN O

H2N

OH

O HN

O

S

N O H 230 R=Cl 231 R=Br

229 R1=NO3 R2=H

O

R

O S O O HN N

O

O

R2

NH2

Br O

CN

228 R1=Cl

R

OH

O R 241 R=n-C9H19 242 R=n-C15H31 243 R=n-C17H35

NH

O S N H

O

N O 244

Figure 13. Structures of of compounds compounds 228–244. Figure 13. Structures 228–244.

Lee etet al., prepared 13 aderivatives N-(biphenyl-4′-yl)methyl-(R)-2-acetamido-3-methoxyGuan al., demonstrated synthesis ofofnovel series of N-(2-hydroxyethyl)amide derivatives and propionamide that were tested for anticonvulsant the Anticonvulsant Screening Program screened their anticonvulsant activities by the MESactivity test, andattheir neurotoxicity was evaluated by the (ASP) of the National Institute of Neurological Disorders and Stroke (NINDS) of the U.S. National rotarod test. The MES test showed that compounds 241, 242 and 243 were found to show a better Institutes of Health. Theand excellent activities the MES testthe (mice, i.p.) of the compound 230valproate and 231 anticonvulsant activity also had lowerintoxicity than market anti-epileptic drug (ED50 = 9.8 (Figure 13).and 12 mg/kg, respectively) coupled with their low neurotoxicities (TD50 = 74 and 86 mg/kg, respectively) providedpotency compounds with notably higher PI (7.6 and respectively) (Figure 13) [177]. In the anti-MES test, these compounds exhibited ED7.2, 50 doses of 22.0, 23.3, 20.5 mg/kg, Siddiqui and et al.,TD prepared a series of 4-thiazolidinones bearing a sulfonamide group and tested their respectively, 50 doses of 599.8, >1000, >1000 mg/kg, respectively, resulting in a PI of 27.5, anticonvulsant activity utilizing sc-PTZ animal Compounds 232, 233 and 234 displayed >42.9, >48.8, respectively, whichMES are and much higher than models. valproate (PI = 1.6) [181]. promising activity and could be considered as leads for further investigations (Figure 13) [178]. Senthilraja et al., synthesized a new series of 2-(4-dimethylaminophenyl)-3-substituted Hen et al., synthesized a novel class of 19 carbamates andtitle evaluated their anticonvulsant activity thiazolidin-4-one-5-yl-acetyl acetamides/benzamides. The compounds were investigated for in the rat MES and sc-Met seizure tests and pilocarpine-induced status epilepticus (SE) model. The their anticonvulsant activities, among the test compounds, compound 244 emerged as the most carbamates 235 (MES EDseries 50 = 64 mg/kg), 236 (MESmore ED50 potent = 52 mg/kg) andreference 237 (MES ED50 = 16 mg/kg) active compound of the and as moderately than the standard diazepam offered an (Figure 13)optimal [182]. anticonvulsant efficacy and safety profile and consequently are potential candidates for further development as new AEDs (Figure 13) [179]. 21. Conclusions Hen et al., synthesized a novel class of aromatic amides composed of phenylacetic acid or branched acids, with to nine in this theirreview carboxylic moiety,some and All in aliphatic all, basedcarboxylic on our laboratory work five and the recentcarbons literature, summarized aminobenzenesulfonamide. The final compounds were screened for their anticonvulsant activity significant anticonvulsant compounds which are classified by functional groups and according by to MES obtained and sc-Met The amides in 238, 239 and 240 were mostillustrates potent compounds data by tests. studies designed animal models. Thisthe review the variouspossessing attempts MES-ED values of 7.6,develop 9.9, andantiepileptic 9.4 mg/kg and remarkable PI values of 65.7, 50.5, 53.2, respectively made to 50 discover and compounds with more effective andand selective effects, and (Figure 13) [180]. reduced secondary actions. The extensive work reviewed here may represent a starting point to allow Guan et al., demonstrated a synthesis of novel series of N-(2-hydroxyethyl)amide a better understanding of antiepileptic therapeutic developments as well as to suggest ideasderivatives on design and screened their anticonvulsant activities by the MES test, and their neurotoxicity was evaluated by and synthesis of novel antiepileptic compounds. 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). In the anti-MES potency test, these compounds exhibited ED50 doses of 22.0, 23.3, 20.5 mg/kg, respectively, and TD50 doses of 599.8, >1000, >1000 mg/kg, respectively, resulting in a PI of 27.5, >42.9, 20766 >48.8, respectively, which are much higher than valproate (PI = 1.6) [181]. Senthilraja et al., synthesized a new series of 2-(4-dimethylaminophenyl)-3-substituted thiazolidin4-one-5-yl-acetyl acetamides/benzamides. The title compounds were investigated for their anticonvulsant

Molecules 2015, 20, 20741–20776

Acknowledgments: This work was support by Inner Mongolia Natural Science Foundation (No. 2012MS1165), project in Inner Mongolia autonomous region department of education (No. NJZC13444) and the doctoral scientific research foundation of Inner Mongolia University for the Nationalities (No. BS290). Author Contributions: Cheng-Xi Wei and Ming Bian did equal work on researching the literature and writing the paper. Yue-Hui Bai corrected the manuscript. Guo-Hua Gong directed the work and corrected the manuscript. Conflicts of Interest: This work has been supported by Inner Mongolia University for the Nationalities of the Department of Pharmacology. The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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