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

• Published in: European journal of medicinal chemistry Vol. 51; pp. 42 - 51
• Main Authors: Jackson, Patrice L., Hanson, Clive D., Farrell, Alanna K., Butcher, Raymond J., Stables, James P., Eddington, Natalie D., Scott, K.R.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.05.2012; Elsevier
• Subjects: Amides - chemistry; Animals; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants - toxicity; Biological and medical sciences; Chemistry, Medicinal; Clathrate; Cyclohexanones - chemistry; Cyclohexanones - pharmacology; Cyclohexanones - toxicity; GABA; Hydrocarbons, Fluorinated - chemistry; Isoxazole enaminones; Life Sciences & Biomedicine; Male; Medical sciences; MES; Mice; Miscellaneous; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; scPTZ; Structure-Activity Relationship; ADD; RAJYEVUWOYRVOS-UHFFFAOYSA-N; scPTZ; Isoxazole enaminones; ip; Clathrate; TD50; NINDS; GABA; PI; MES; ED50; Tox; ASP; SUBSTITUTED VINYLIC BENZAMIDES; GABA(A) RECEPTOR; ANTIEPILEPTIC DRUGS; THIP; AGONISTS; BRAIN
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.02.003

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). Clathrate formation of the anticonvulsant active dimethyl enaminone isoxazole analog (12c), assembled as a head-to-tail dimer. [Display omitted] ► 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.