Studies on the Synthesis, Anticonvulsant Activity, and the Structure-Activity Relationships of Phenyl Pyridazinones and their GABA Derivatives

In searching for effective anticonvulsant agents,fourteen 6-aryl-4.5-di- hydro-3(2H)pyridazinones.fifteen 6-aryl-3(2H)pyridazinones,and seventeen 3-GABA derivatives of 6-aryIpyridazines have been synthesized,and evaluated in mice for the ability to antagonize maximal electroshock seizure(MES).The ED_(50) values showed that 6-(2′,4′- dichlorophenyt)-3(2H)pyridazinone was the most potent anticonvulsant among these corn- pounds(ED_(50)=10.15 mg/kg).The structure-activity relationships of the aryl pyridazinones were studied.The result showed that:(1)the higher the value of the hydrophobic parameter л of the substituent on the phenyl ring.the more potent the anticonvulsant activity of the corn- pound.and(2)only the compounds with an electron withdrawing substituent on the phenyl ring exhibited appreciable anticonvulsant activity.

A Study of the Relationship Between the Chemical Structure and the Anticonvulsant Activity of the 3-Pyrazolidinones

The Hansch approach was used in the quantitative structure anticonvulsant activity studies of the previously synthesized 1-substituted-and 1.5-disubstituted-3-pyrazo- lidinones.Correlation analysis predicted that 1.5-disubstituted-3-pyrazoljdinones in which 1- substituent is n-propyl but not benzyl.with the total hydrophobic constant of 1-and 5-sub- stituents(∑л)equals to 4.5(optimum value)will have the most potent activity.On the basis of this analysis eleven 5-substituted and I-n-butyl-5-substituted-3-pyrazolidinones were syn- thesized.Pharmacological tests indicated that the prediction of the Hansch analysis of the 3- pyrazolidinones is correct.The Hansch analysis,by including these 11 compounds,gives an almost identical correlation with that previously obtained.

A novel series of 2,5-disubstituted 1,3,4-thiadiazoles as potential anticonvulsant agent

In pursuit for better antiepileptic drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-thiadiazoles as anticonvulsant pharmacophore, a series of novel N-（{5-[（6-methyl-l-benzofuran-3-yl）methyl]-l,3,4-thiadiazol-2-yl}carba- mothioyl）-2/3/4-substitutedbenzamide were designed, synthesized and evaluated for their anticonvulsant activity. The findings of the present studies confirmed that the pharmacophore model with four binding sites is crucial for anticonvulsant activity. Structure-activity relationships among synthesized compounds were also established.

Studies on the Relationship Between the Structure and Anticonvulsant Activity of Cinnamamides and Their Analogs

On the basis of systematic modification of the structure of componds of antiepilepsirine type, more than 200 cinnamamides were synthesized and tested by animal assay (maximal electroshock seizure, MES). Pharmacological evaluation showed that the configuration and the substituents on the phenyl ring and the nitrogen of amides, and substituents on the double bond displayed an important effect on the anticonvulsant activity.For studying the effect of the modification of structure to anticonvulsant activity, Hansch approach was employed to study the QSAR among 38 cinnamamides, and Hopfinger' s MSA was employed to study the MSA-QSAR among 26 cinnamamides.

Synthesis and anticonvulsant activity of some potent 5,6-bis aryl 1,2,4-triazines

In the present research, a series of 5,6-bis aryl 1,2,4-triazines 5a^5f were synthesized by condensation of various benzils 4a^4f with aminoguanidine bicarbonate and were screened in vivo, for their anticonvulsant and neurotoxicity studies. Compounds 5a, 5b and 5d were found to be potent molecules of this series, when compared with the reference drugs phenytoin sodium, diazepam and lamotrigine. The structures of these compounds were established by IR, 1H NMR, 13C NMR and mass spectroscopic data.

Synthesis and Anticonvulsant Activity of γ-Aminobutyric Acid Derivatives

Under physiological conditions, γ-aminobutyric acid poorly crosses the blood-brain barrier. It is likely that a non-toxic derivative of γ-aminobutyric acid which enters the brain easily will have useful anticonvulsant activity. 16 derivatives of γ-aminobutyric acid with an imine link to a lipophilic carrier were prepared and tested for anticonvulsant activity; six compounds show anticonvulsant activity.

Evaluation of the Anticonvulsant Activity of the Leaf Methanol Extract of Crassula arborescens （Mill.） Willd. （Crassulaceae） in Mice

Crassula arborescens （Mill.） Willd. subsp. Arborescens is widely used for the treatment of various ailments including diarrhoea, corns, epilepsy and as a purgative. However, no information exists in any literature to verify the acclaimed effectiveness of C. arborescens in the treatment of the various ailments. The study, therefore, intended to investigate the anticonvulsant activity of the leaf methanol extract of C. arborescens in mice. Acute toxicity study and phytochemical qualitative analysis of the plant extracts were also carried out. Chemically-induced convulsion methods were used to assess the anticonvulsant activity of C. arborescens. Standard methods were used for the acute toxicity study and phytochemical analysis of the chemical components of the plant extract. PTZ （pentylenetetrazole）, bicuculline, picrotoxin, NMDLA （N-methyl-DL-aspartic acid） or strychnine produced tonic convulsions in all the mice used. Leaf methanol extract of Crassula arborescens, muscimol, phenobarbitone or diazepam significantly antagonised PTZ, bicuculline or picrotoxin-induced convulsion. C. arborescens or LY233053 significantly antagonised NMDLA-induced tonic convulsion. C. arborescens or phenobarbitone significantly antagonised strychnine-elicited tonic convulsion. Phenytoin or DMSO （dimethylsulfoxide） did not significantly affect the tonic convulsion produced by PTZ, bicuculline, picrotoxin, NMDLA or strychnine. The LDso value obtained from intraperitoneal administration of C. arborescens was 781.6 mg/kg while that following oral administration of the plant extract was over 4,000 mg/kg. The phytochemical qualitative analysis done showed the presence of flavonoids, tannins, reducing sugar, saponins and triterpene steroids. The data obtained in the study show that the leaf methanol extract of Crassula arborescens has anticonvulsant activity which may be underpinned by GABAergic, glutaminergic and glycinergic mechanisms. The high LDso value obtained following the oral administration of the plant extract shows that the leaf methanol extract is non-toxic to animals.

Synthesis, Characterization and Antiepileptic Activity of Some New N-Substituted Phthalimide Analogs

The present study was designed to investigate the anticonvulsant effect of series phthalimides possessing an N-aromatic amines moiety substituted at position 2 （2-7）. The compounds synthesized using phthalic anhydride and various amines in reflux synthesizer. The chemical structures of the titled compound were confirmed by physical and spectra analysis. All the synthesized compounds were evaluated in vivo for antiepileptic activity by using standard experimental models. Compounds： 2-（3H-1, 2, 4-Triazole-3-y） isoindoline-1, 3-dione （2）, Ethyl-4（1, 3-dioxoisoindoline-2-yl） benzoate 3 and 2-（4-nitrophenyl） isoindoline-1,3dione （7） were found significantly （P 〈 0.01-0.00001） delayed the onset and antagonized picrotoxin-induced seizures.

Crystal Structure of 3- (4-Methoxyphenyl )- 1-methylpyrrolo [2, 1-b] benzothiazole

The crystal structure of 3-(4-methoxyphenyl)- l-methyl-pyrrolo[2,1-b] benzothiazole (C18H15NOS, Mr = 293. 38) has been determined. The title com-pound crystallizes in monoclinic space group P21/n with cell dimensions a= l. 3308(4)'b=0. 8403(2), c= l. 4l47 (4)nm, β= 68. 08(2)°, V= 1. 4676(5)nm3, Z= 4, Dc=1. 328g. cm-3, F(000) = 6l6,μ= l8. 18cm-l, CuKa(η= O. 154l8nm). The struc-ture was solved by direct methods and refined by full matrix least-Squares. The finaldiscrepancy factor is 0. 053 for 1522 observed reflections. The molecular backbone is anearly planar tricyclic system.

p-TSA-catalyzed one-pot synthesis and docking studies of some 5H-indeno[ 1,2-b]quinoline-9,11 (6H,10H)-dione derivatives as anticonvulsant agents

The present work describes a facile, one-pot three component environment friendly, green synthesis of a series of 5-（4-methoxyphenyl）-7,7-dimethyl-10-phenyl-7,8-dihydro-SH-indeno[ 1,2-b]quinoline- 9,11 （6H,10H）-dione derivatives 8（a-n）. 1,3-indanedione, awl-aldehyde and enaminone was thoroughly ground in the presence of catalytic amount of p-toluene sulfonic acid （p-TSA） to give the titled compounds in good yields. All the synthesized derivatives were evaluated for their anticonvulsant activity using the maximal electroshock （MES） method with phenytoin as a standard drug along with their neurotoxicity effect. Derivatives 8b, 8e and 8k exhibited significant anticonvulsant activity （P 〈 0.001）. The neurotoxicity study clearly revealed that all the tested compounds are non-toxic at a dose of 40 mg/kg. The molecular modeling studies also predicted good binding interactions of most active molecules with the serotonin 5-HT2A receptor. Therefore, it can be safely concluded that synthesized derivatives 8（a-n） would represent useful leads for further investigation in the development of a new class of anticonvulsant agents.

Synthesis, potential anticonvulsant and antidepressant effects of 2-(5-methyl-2,3-dioxoindolin-1-yl)acetamide derivatives

A new series of 2-(5-methyL2,3-dioxoindolin-1 y)acetamide derivatives were synthesized and evaluated for their anticonvulsive activity in a pentylenetetrazole (PTZ)-evoked convulsion model and antidepressant activity in the forced swimming test (FST) model. Eleven synthesized compounds were found to he protective against PTZ-induced seizure and showed the anticonvulsant activity. In addition, four of the synthesized compounds (41, 4m, 4p and 4q) showed potent antidepressant-like activity. Among these compounds, compound 41 was found to have the most potent antidepressant-like activity, and significantly reduced the duration of immobility time at 100 mg/kg dose level when compared to the vehicle control, which is similar to the reference drug lluoxetine. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical. Sciences. Production and hosting by Elsevier BAT. This is an open access article under the CC BY-NC-ND licenses (http://creativecommons.org/licenses/by-nc-nd/4.0/).