Anticonvulsant activity of hydrazones, Schiff and Mannich bases of isatin derivatives.

In the present study, anticonvulsant activity of hydrazones, Schiff and Mannich bases of isatin were evaluated by maximal electroshock method (MES) and metrazol-induced convulsions (MET) at 30, 100 and 300 mg/kg dose levels. Neurotoxicity of the compounds was also assessed at the same dose levels. Eight compounds of the series exhibited significant anticonvulsant activity at 30 mg/kg dose level. 3-(4-chloro-phenylimino)-5-methyl-1,3-dihydro-indol-2-one (compound 10) was found to be the most potent compound of the series with 87% protection at 100 mg/kg and an ED(50) of 53.61 mg/kg (MET). All the compounds exhibited lesser neurotoxicity compared to phenytoin. All the active compounds showed greater protection than sodium valproate. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.     

4-sulphamoylphenyl semicarbazones with anticonvulsant activity

A series of 4-sulphamoylphenyl semicarbazone derivatives were prepared starting from sulphanilamide and screened for anticonvulsant activity. The results indicated that greater protection was obtained in the maximal electroshock screen (MES) and subcutaneous strychnine (scSTY) than the subcutaneous pentylenetetrazole (scPTZ) tests. All the compounds showed low neurotoxicity when compared to the clinically used drugs. Compounds with substituted acetophenone (8-11) showed good activity in the rat oral MES screen. Seven compounds (6, 8-10, 12, 14 and 15) exhibited anticonvulsant activity greater than sodium valproate. Among the new derivatives evaluated, compound 10 emerged as the most active compound as indicated by its protection in the MES and scSTY screens and with low neurotoxicity. Seven compounds possessed sedative-hypnotic activity.     

Synthesis and anticonvulsant activity of 1,2-aminoalkanol derivatives

A series of 1,2-aminoalkanol derivatives were prepared and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (scMet) assays and for neurotoxicity (TOX). Most interesting were the anticonvulsant results of S-(+)-2-amino-1-butanol derivative VIII, which displayed anti-MES activity with a protective index (TD50/ED50) of 4.55 corresponding with that for phenytoin, carbamazepine and valproate.     

Impact of aromatic substitution on the anticonvulsant activity of new N-(4-arylpiperazin-1-yl)-alkyl-2-azaspiro[4,5]decane-1,3-dione derivatives

A series of N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.5]decane-1,3-dione derivatives were synthesized and evaluated for their anticonvulsant and neurotoxic properties. The main modifications to that series of compounds consisted in the introduction of an aromatic area to the cyclohexane ring as a flexible fragment with conformational freedom (1a-h), or as a rigidified skeleton (2a-h). Except for N-[3-(4-phenylpiperazin-1-yl)-propyl]-8-phenyl-2-aza-spiro[4.5]decane-1,3-dione derivative (1e), all the other compounds displayed anticonvulsant activity in the MES test, but some of them (1c, 2f and 2g) were found to be neurotoxic at a dose of 30 mg/kg, irrespective of their activity. The most potent and relatively weakly neurotoxic analogues of that series, i.e. N-[2-{4-(3-chlorophenyl)-piperazin-1-yl}-ethyl]-[7,8-f]benzo-2-aza-spiro[4.5]decane-1,3-dione (2c) and N-[3-{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-propyl]-[7,8-f] benzo-2-aza-spiro[4.5]decane-1,3-dione (2h) had ED50 values of 205 mg/kg (2c) and 23 mg/kg (2h) respectively, in the MES-test in mice, and showed higher protection than magnesium valproate (ED50 = 211 mg/kg), used as a standard substance.     

Synthesis and anticonvulsant activity of some N-(benzoyl)glycinanilide derivatives

Glycine is a major inhibitory neurotransmitter and recent studies have shown that certain lipophilic glycine derivatives demonstrate anticonvulsant activity in animal epilepsy models. On the other hand, anilide is another fruitful structure for designing potential anticonvulsant agents. Ameltolide, ralitoline and some phthalimide derivatives are the examples of anilide analogs with potent anticonvulsant activity. In this study, two key structural pharmacophores were combined and a series of N-benzoylglycinanilide derivatives were designed. Their anticonvulsant activities evaluated against maximal electroshock (MES) and subcutaneous metrazole seizure tests, whereas their neurotoxicity was examined by rotarod test. The preliminary screening results indicated that majority of the compounds were effective in the MES test. None of the compounds showed neurotoxicity according to the rotarod test at studied doses. The most active compound in the series is N-(2-((4-methoxyphenyl)amino)-2-oxoethyl)benzamide (compound 8) which bearing 4-methoxy substituent on the N-phenyl ring.     

Synthesis and Anticonvulsant Activity of N‐(2‐Hydroxy‐ethyl)amide Derivatives

A series novel of N‐(2‐hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N‐(2‐hydroxyethyl)decanamide 1g , N‐(2‐hydroxyethyl)palmitamide 1l , and N‐(2‐hydroxyeth‐yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti‐epileptic drug valproate. In the anti‐MES potency test, these compounds exhibited median effective doses (ED₅₀) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD₅₀) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti‐epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g , 1l , and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3‐mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.     

Synthesis and Anticonvulsant Activity Evaluation of 5‐Phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amines

In the present study we describe the syntheses and anticonvulsant activity evaluation of 5‐phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amine derivatives. Their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock seizure test (MES) and the rotarod test, respectively. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of these compounds, the most promising was compound 8h , which showed an ED₅₀ value of 27.4 mg/kg and a protective index (PI) value of 5.8. These values were superior to those provided by valproate (ED₅₀ and PI values of 272 and 1.6, respectively) in the MES test in mice. As well as its anti‐MES efficacy, the potencies of compound 8h against seizures induced by pentylenetetrazole and thiosemicarbazide were also established, with the results suggesting that the GABAergic system‐mediated mechanisms might be involved in its anticonvulsant activity.     

Synthesis and activity of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines in animal models of epilepsy

A series of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines derivatives was synthesized and evaluated for anticonvulsant activity. The compounds were screened in mice for their ability to antagonize maximal electroshock- and bicuculline-induced seizures; neurotoxicity was evaluated in the rotorod test. The anticonvulsant activity of the most potent compounds in this series was also examined in kindled amygdaloid rats and in photoepileptic Papio papio baboons. Phenobarbital, diphenylhydantoin, carbamazepine, and sodium valproate were used as standard antiepileptic drugs. The structure-activity relationships in this series were examined by either varying the aryl ring in the 6-position of the pyridazine ring or by modifying the 3-amino side chain. Only the compounds with a phenyl ring in the 6-position of the pyridazine ring exhibited appreciable anticonvulsant activity. Furthermore, a 4-hydroxypiperidine side chain in the 3-position of the pyridazine ring appeared essential for anticonvulsant activity. Substituting the phenyl ring with a Cl in the 2-position led to a substantial increase of activity; disubstituting the phenyl ring with a Cl in the 2- and 4-positions yielded the most potent compounds in this series, some of which were as potent or more potent than phenobarbital. Two compounds, 6-(2-chlorophenyl)-3-(4-hydroxypiperidino)pyridazine (2) and 6-(2,4-dichlorophenyl)-3-(4-hydroxypiperidino)pyridazine (3), were selected for further studies. Clinical evaluation of these compounds is in progress.     

Design and synthesis of some new derivatives of 3H-quinazolin-4-one with promising anticonvulsant activity

A new series of 3-substituted (methyl, ethyl or phenyl)-3H-quinazolin-4-one derivatives (4a-l) were synthesized through condensation reaction of their potassium salts (3a-l) with methyl, ethyl and phenylisocyanate. The newly synthesized derivatives (4a-l) were evaluated for anticonvulsant activity. It was found that these compounds showed the highest anticonvulsant activity at low doses (50-100 mg kg(-1)), whereas at doses over 100 mg kg(-1) they showed a stimulant effect on the central nervous system that even potentiated the effect of the convulsive agent, pentylenetetrazole, in mice. A series of halogenated derivatives, 3-methyl, 3-ethyl and 3-phenyl-6-mono and 6,8-disubstituted-3H-quinazolin-4-one derivatives (4m-z) was also synthesized and evaluated for anticonvulsant activity. Reduced anticonvulsant activity was recorded. Phenobarbitone sodium was used as a reference drug.     

Synthesis and anticonvulsant activity of 2-benzylglutarimides

A series of 2-benzylglutarimides (4) and their N-methyl analogues (5) were prepared according to the Topliss scheme for the selection of benzyl substituents to maximize anticonvulsant activity. A total of 22 such compounds were subjected to initial (phase I) screening in mice against seizures induced by maximal electroshock (MES) and pentylenetetrazol (scMet) and in the rotorod assay for neurotoxicity. From this series of test compounds, 10 were advanced to quantitative (phase II) testing. Of these, 2-(4-chlorobenzyl)glutarimide (4b) emerged as the most promising anticonvulsant drug candidate by demonstrating both good anti-scMet and anti-MES activity combined with low neurotoxicity after intraperitoneal administration in mice. In drug differentiation tests, 4b was also effective in nontoxic doses against seizures induced by bicuculline, picrotoxin, and strychnine. When compared with the clinically useful drugs phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide, 4b exhibited an overall pharmacological profile most closely resembling that of valproate.     

Synthesis and Evaluation of 3‐[(2,4‐Dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile Derivatives as Potential Anticonvulsants

New 3‐[(2,4‐dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile derivatives 8 – 37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure–activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11 , 18 , 31 , and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two‐electron donor.     

Synthesis and anticonvulsant activity of 4-(2-phenoxyphenyl)semicarbazones

A new series of 4-(2-phenoxyphenyl)semicarbazones were synthesized as potential anticonvulsant agents. Thus, the reaction of 4-(2-phenoxyphenyl)semicarbazide with various benzaldehydes and acetophenones in ethanol yielded the corresponding semicarbazones 6a–k and 7a–i, respectively. Structures of the synthesized compounds were confirmed by spectral data and elemental analysis. All compounds were evaluated for their anticonvulsant activity in pentylenetetrazole (PTZ)-induced kindling model in adult male Wistar rats. The neurotoxicity of active compounds was also assessed using the rotorod method. The results showed that two compounds (6g and 6i) showed greater protection from seizure than sodium valproate at dose of 100 mg/kg. Compounds 6g and 6i showed no neurotoxicity at the maximum dose administered (300 mg/kg).     

Design, synthesis, and anticonvulsant evaluation of some novel 1, 3 benzothiazol-2-yl hydrazones/acetohydrazones

A series of 2-[2-(substituted)hydrazinyl]-1,3-benzothiazole and 2-(1,3-benzothiazol-2-ylsulfanyl)-N′-(substituted)acetohydrazide were designed and synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The anticonvulsant activity of the titled compounds was assessed using the 6?Hz psychomotor seizure test. The most active compound of the series was 2-(1,3-benzothiazol-2-ylsulfanyl)-N′-[4-(4-bromophenoxy)benzylidene]acetohydrazide BT 15, which showed 75% protection (3/4, 1.0?h) and 50% protection (2/4, 0.5?h) at a dose of 100?mg/kg in mice. A computational study was carried out for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as GABA (A) alpha-1, glutamate, GABA (A) delta receptors and Na/H exchanger, in Lamarckian genetic algorithm-based flexible docking studies.     

Synthesis and anticonvulsant properties of 3-(1,3,4-thiadiazol-2-yl) thiazolidin-4-ones.

A series of 2-substituted 3-(1,3,4-thiadiazol-2-yl)thiazolidin-4-ones were synthesized and evaluated for anticonvulsant activity in a genetic model of reflex epilepsy (sound-induced seizures in DBA/2 mice). The combination of preferred substituents in the 2-position coupled with the introduction of a mercapto group on the thiadiazole moiety led to a number of active compounds. The anticonvulsant activity of most derivatives is better than that of the clinically useful anticonvulsant sodium valproate and some of them appear to possess potencies in the same range as phenytoin and clobazam.     

Novel 1-phenylcycloalkanecarboxylic acid derivatives as potential anticonvulsant agents

A series of analogues based on the anticonvulsant carbetapentane (1, 2-[2-(diethylamino)ethoxy]ethyl 1-phenyl-1-cyclopentylcarboxylate) was prepared as potential novel anticonvulsant drugs. Structure-activity relationships of analogues in which the ester function and cyclopentane moieties were modified have been investigated by evaluating their ability to prevent seizures in the rat maximal electroshock test. These compounds (11, ED50 = 16 mumol/kg; 12, ED50 = 86 mumol/kg, and 23, ED50 = 173 mumol/kg) were effective anticonvulsants. Compound 11, an alkyl ether derivative of 1, was more potent than the parent compound (ED50 = 48 mumol/kg) and also showed a 2-fold increase in potency compared to that of the prototypic anticonvulsant drug diphenylhydantoin.     

Preliminary evaluation of anticonvulsant activity of some 4-(benzyloxy)-benzamides

A series of alkanolamides have been tested for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure treshold (ScMet) assays and for neurotoxicity (TOX) in rodents. Most interesting were the anticonvulsant results of 2N-methylaminoethanol derivative II, which displayed anti-MES activity (mice) with a protective index (TD50/ED50) of 2.536 higher than that for valproate.     

Search for New Anticonvulsant Compounds,Part 2. Structure-Activity Relationship Studies of New N-Substituted Amides of α-Piperazine-γ-Hydroxybutyric Acid as Active Anticonvulsants

In a search for new anticonvulsants, two series of compounds, viz. derivatives of N-benzylamides of α-(4-phenylpiperazine)-γ-hydroxybutyric acid ( A and derivatives of N-benzylamides of α-(4-benzylpiperazine)-γ-hydroxybutyric acid ( B ), were investigated. These amides were obtained by aminolysis of 3-(4-phenyl-, or 4-benzylpiperazine)-tetrahydrofuran-2-one with primary arylalkylamines (i.e. 2-phenylethylamine and 2,3,4-substituted derivatives of benzylamine). Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay were employed. All compounds displayed anticonvulsant activity at range of doses 100–300 mg/kg in the MES screens. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two representative compounds of series A and B .     

Synthesis, anticonvulsant and neurotoxic activity of some new 2,5-disubstituted-1,3,4-oxadiazoles

Two novel series 2a–2d (2Z)-N-[5-(4-substituted)phenyl-1,3,4-oxadiazol-2-yl]-2-[(2Z)-3,7-dimethylocta-2,6-dien-1-ylidene]hydrazinecarboxamide and 1a–1d 5-(4-substituted)phenyl-N-[(1Z,2Z)-3,7-dimethylocta-2,6-dien-1-ylidene]-1,3,4-oxadiazol-2-amine have been synthesized and screened for their anticonvulsant and neurotoxic activity. After i.p. injection to mice at doses of 30, 100 and 300 mg/kg body weight 2,5-disubstituted-1,3,4-oxadiazole analogues were examined in the maximal electroshock induced seizures (MES) and subcutaneous metrazole (ScMET) induced seizure models in mice. Amongst all the compounds, 1a–1d and 2a–2d, one compound 1a exhibited activity at 100 mg/kg body weight at 0.5 and 4 h in ScMET, respectively. Compound 2b showed anticonvulsant activity at 100 mg/kg without activity in ScMET and neurotoxicity. The neurotoxicity was assessed by rotorod method, and all compounds (except 1a) were found to be safe at maximum administered dose.     

Synthesis and reactions of some new substituted pyridine and pyrimidine derivatives as analgesic, anticonvulsant and antiparkinsonian agents

A series of substituted pyridine and pyrimidine derivatives were synthesized as analgesic, anti convulsant, and antiparkinsonian agents by using compounds 1, 2, and 9 as starting materials. Pyr idino-imide derivative 3 was prepared by condensation of 1 with tetrachlorophthalic anhydride and compounds 4 and 5 were also obtained by reaction of compound 1 with 1,2,4,5-benzene-tetra carboxylic dianhydride and 1,4,5,8-naphthalenetetracarboxylic dianhydride, respectively. Similarly, compound 2 was reacted with previous anhydrides to afford the corresponding imide 6 and bis-imide derivatives 7 and 8, respectively. Bis-arylmethylene derivatives 9 were treated with hydrogen peroxide to afford the corresponding bis-oxiranocycloalkanone derivatives 10, which condensed with thiourea to give the corresponding thioxopyrimidine derivatives 11. Treatment of compound 11 with chloroacetic acid in the presence of anhydrous sodium acetate afforded the corresponding thiazolopyrim idine derivative 12 which condensed with aromatic aldehydes in acetic acid/acetic anhydride to give arylmethylene derivative 13. Also, compounds 13 could be prepared by reaction of compounds 11 with chloroacetic acid, aromatic aldehydes, and sodium acetate in a mixture of acetic acid and acetic anhydride. The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Valdecoxib, Carbamazepine, and Benzatropine as reference drugs.     

Structure-based design,synthesis, and anticonvulsant activity of isatin-1-N-phenylacetamide derivatives

In an effort to develop the potent anticonvulsant agents, a series of novel isatin-1-N-phenylacetamide derivatives was synthesized and screened for their in vivo anticonvulsant activity against maximal electroshock test and evaluated for their neurotoxicity by the rotarod test at the same dose levels. Ten compounds exhibited the anticonvulsant activity. 2-(5-Methyl-2,3-dioxoindolin-1-yl)-N-phenylacetamide (4b) was found to be the most potent compound of the series with an ED₅₀ of 91.3 mg/kg, TD₅₀ of >1,000 mg/kg, a higher protective index (PI = TD₅₀/ED₅₀, >11) was gained than the reference drug phenobarbital and carbamazepine. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.