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...
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Published in | European journal of medicinal chemistry Vol. 51; pp. 42 - 51 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
ISSY-LES-MOULINEAUX
Elsevier Masson SAS
01.05.2012
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | NIH RePORTER |
ISSN: | 0223-5234 1768-3254 |
DOI: | 10.1016/j.ejmech.2012.02.003 |