Synthesis and anticonvulsant properties of new acetamide derivatives of phthalimide, and its saturated cyclohexane and norbornene analogs

• Published in: European journal of medicinal chemistry 2011-09, Vol.46 (9), p.4634-4641
• Main Authors: Kamiński, Krzysztof, Obniska, Jolanta, Wiklik, Beata, Atamanyuk, Dmytro
• Format: Article
• Language: English
• Subjects: 4-Azatricyclo[5.2.1.0 2,6]dec-8-ene-3,5-dione; Acetamides - chemistry; Animals; Anticonvulsant activity; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Boron Compounds - chemistry; Cyclohexanes - chemistry; Dose-Response Relationship, Drug; Electric Stimulation; Hexahydro-1 H-isoindole-1,3(2 H)-dione; In vivo studies; Magnetic Resonance Spectroscopy; Male; Medical sciences; Mice; Neuropharmacology; Pharmacology. Drug treatments; Phthalimide (isoindoline-1,3-dione); Phthalimides - chemical synthesis; Phthalimides - chemistry; Phthalimides - pharmacology; Rats; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.07.043

The synthesis and anticonvulsant properties of new piperazine or morpholine acetamides derived from 2-(1,3-dioxoisoindolin-2-yl)-, 2-(1,3-dioxo-3a,4,5,6,7,7a-hexahydroisoindol-2-yl-) and (3,5-dioxo-4-azatricyclo[5.2.1.0 2,6]dec-8-en-4-yl)-acetic acid were described. Initial anticonvulsant screening was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole ( scPTZ) seizures tests. The neurotoxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective in the MES screen. The most active was 2-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}isoindoline-1,3-dione ( 12) that revealed protection in the electrically induced seizures at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration in mice respectively. This molecule given orally in rats at a dose of 30 mg/kg was more potent than reference anticonvulsant – phenytoin. [Display omitted] ► Library of 25 new compounds as potential anticonvulsants have been synthesized. ► Anticonvulsant screening was performed using in vivo MES and scPTZ seizures tests. ► The most active compound showed comparable activity to model anticonvulsants.