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

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).

Graphical abstractClathrate formation of the anticonvulsant active dimethyl enaminone isoxazole analog (12c), assembled as a head-to-tail dimer.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A novel series of carboxamide isoxazole enaminones were synthesized. ► All analogs reported were evaluated for anticonvulsant activity. ► X-ray crystal data proves formation of a clathrate, seen in compound 12c. ► The clathrate formation blocks access to the proposed active site.