title: Enaminones 12. An explanation of anticonvulsant activity and toxicity per Linus Pauling's clathrate hypothesis.
abstract: 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).
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, 1 Backbone Rd., Princess Anne, MD 21853, USA. pljackson@umes.edu
authors.forename: Patrice L
authors.initials: PL
authors.lastname: Jackson
authors.forename: Clive D
authors.initials: CD
authors.lastname: Hanson
authors.forename: Alanna K
authors.initials: AK
authors.lastname: Farrell
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Butcher
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Eddington
authors.forename: K R
authors.initials: KR
authors.lastname: Scott
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry; D008297:Male; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000927:Anticonvulsants; D003512:Cyclohexanones; D006845:Hydrocarbons, Fluorinated; C029999:fluoromethane