Enaminones 12. An explanation of anticonvulsant activity and toxicity per Linus Pauling’s clathrate hypothesis

• DOI: 10.1016/j.ejmech.2012.02.003
• Publication Date: 2012-02-10T04:45:56Z
• Authors: Patrice L. Jackson; Clive D. Hanson; Alanna K. Farrell; Raymond J. Butcher; James P. Stables; Natalie D. Eddington; K.R. Scott
• Keywords: Male; Mice; Structure-Activity Relationship; Hydrocarbons, Fluorinated; Cyclohexanones; Animals; Anticonvulsants; Amides; 01 natural sciences; Rats; 0104 chemical sciences; 3. Good health

The x-ray crystal structure of 3-((5-methylisoxazol-3-yl)amino)-5-methylcyclohex-2-enone (12b) and 3-((5-methylisoxazolyl-3-yl)amino)-5,5-dimethylcyclohex-2-enone (12c) were determined and correlated to their anticonvulsant activity in mice and rats. A hypothesis for the toxicity of the analogs are advanced. In addition, a series of 5-methyl-N-(3-oxocyclohex-1-enyl)-isoxazole-3-carboxamides were synthesized and evaluated for anticonvulsant activity. These compounds were compared to the activity of the corresponding amino and aminomethyl enaminones. Additional investigation involved the synthesis and evaluation of a trifluoromethyl analog of the active isoxazole tert-butyl 4-(5-methisoxazol-3-yl-amino)-6-methyl-2-oxo-cyclohex-3-ene carboxylate (4f).