Synthesis and Anticonvulsant Activity of Some New Hexahydropyrimidine-2,4-dione Derivatives

Abstract

In this study, twelve new hexahydropyrimidine-2,4-dione derivatives were synthesized and screened for their anticonvulsant activities. All the compounds (7a−l) which have 6-arylhexahydropyrimidine-2,4-dione and N,N-disubstituted dithiocarbamate structures were prepared by the reaction with appropriate 3-(2-chloroethyl)-6-arylhexahydropyrimidine-2,4diones and the corresponding N,N-disubstituted dithiocarbamate potassium salts. The structure of the synthesized compounds was confirmed by UV, IR, 1 H-NMR and elemental analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous pentetrazol (metrazol, scMet) and ro-Zusammenfassung Synthese und Bewertung der antikonvulsiven Wirkung von neuen Hexahydropyrimidin-2,4-dionen In dieser Arbeit wurden zwölf neue Derivate von Hexahydropyrimidin-2,4dion hergestellt und auf antikonvulsive Wirkung untersucht. Alle Substanzen mit 6-Arylhexahydropyrimidin-2,4-dion und N,N-disubstituiertem Dithiocarbamat (7a−7l) wurden durch Reaktion mit 3-(2-Cloroethyl)-6-arylhexahydropyrimidin-2,4-dion und den entsprechenden N,N-disubstituierten Dithiocarbamat-Kaliumsalzen gewonnen. Die Strukturaufklärung der synthetisierten Verbindungen erfolgte mittels UV, IR, 1 H-NMR-Spektroskopie sowie durch Elementaranalyse. Die antikonvulsive Wirkung wurde in torod toxicity tests for neurological deficits. According to the activity studies, 6-(4-chlorophenyl)hexahydropyrimidine-2,4-dione derivatives (7e−h) were found to be highly protective against MES and scMet. Neurotoxicity was not observed in any of the tested compounds. MES-(Maximal ElectroshockSeiture), scMet-(subkutanes Pentetrazol, Metrazol) und Drehstab-Toxizitätstests bestimmt. Die 6-(4-Chlorophenyl)hexahydropyrimidin-2,4-dion-Derivate (7e−h) waren im MES-und scMet-Test hochwirksam. Eine Neurotoxizität wurde bei keiner der untersuchten Verbindungen beobachtet. Key words Antiepileptic drugs 6-Arylhexahydropyrimidine-2,4-diones, anticonvulsant activity, S-alkylation, synthesis Carbamodithioic acid esters Arzneim.-Forsch./Drug Res. 55, No. 5, 259−264 (2005) Arzneim.-Forsch./Drug Res. 55, No. 5, 259−264 (2005) Septioglu et al. − Hexahydropyrimidine-2,4-dione derivatives

Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole

“…The compoundsw eree valuated fort heiranticonvulsantactivity byt wom odels,namelyMES-and scPTZ-induced seizure threshold tests.The acuteneurologicaltoxicity wasdetermined in the rotarod test.Phenytoin (PHT),carbamazepine (CBZ)and sodiumvalproate( NaV)wereused ast he standardd rugsfor comparison [33].All thesetests werep erformed in male mice according tothe phase-Itests of the AntiepilepticD rugDevelopment(ADD)programwhichweredeveloped bythe National Institutesof Health( NIH) [24].Thisprogramwasu sed for screening of manycompoundsin various previous studies [25][26][27].Stimulator(Grass S88,A stro-Med.Inc.Grass Instru-mentDivision,W .Warwick,R I, USA),c onstantcurrentu nit (Grass CCU1A, Grass MedicalInstrument,Q uincy,M A, USA), and cornealelectrodeswereused forthe evaluation of anticonvulsantactivity in the MES-induced seizuretest.All synthesized compoundsw eresuspended in 30 %aqueous of PEG 400 and administered tothe micei ntraperitoneally(i. p.) in avolume of 0.01ml/gatbodyw eight.TwelveSwiss albino male mice weighing 20 -2gwereused foreachcompound (micep urchased from the HacettepeUniversity AnimalFarm) according tothe ADD-NINDS program [24].All the animalswereacclimatized foraweek beforeuse. The animalsw erem aintained in colonycagesu ndera12h-light-and-12h-darkcycle and kept unders tandard( hygienic)conditionsatatemperatureo f22°C (± 3)and atarelativeh umidity between 50t o60 %and fed a standardl aboratory diet.Food and waterw asprovided adl ibitum exceptatt he time theyw erebroughtout of the cage.…”

“…Anticonvulsantactivity of the synthesized compounds wasexamined byMES-and scPTZ-induced seizure tests.The acuten eurologicaltoxicity wasdetermined in the rotarod test.All thesetests werep erformed with Swiss albino male miceaccording tothe phase-Itests of the AntiepilepticD rugDevelopment(ADD)p rogram developed byt he NationalInstitutesof Health( NIH) [24].Thisprogramwasu sed fort he screening of many compoundsin various previous studies [25][26][27].…”