Abstract
Enaminone derivatives have been widely studied as potential anticonvulsant agents to treat epilepsy. Our research group is focused on evaluating the anticonvulsant activities of cyclic enaminones connected to a substituted aromatic ring via a sp2 hybridized linker. We herein report our lead optimization efforts and the subsequent synthesis of the target fluorinated N-benzamide enaminone analog N-(3-oxo-5-(trifluoromethyl) cyclohex-1-en-1-yl)-4-(trifluoromethyl) benzamide (compound 7) from fluorinated intermediates, and its bioevaluation in acute seizure rodent models. The synthesis of the fluorinated cycloalkyl intermediates, 5-(trifluoromethyl) cyclohexane-1,3-dione (compound 5) and 3-amino-5-(trifluoromethyl) cyclohex-2-en-1-one (compound 6) were derived from an improve method of a one-pot hydrolysis and acid catalyzed decarboxylation of 4-carbo-tert-butoxy-5-trifluoromethylcyclohexane-1,3-dione (compound 4). Compound 7 produced pharmacological response at a higher dose of 300 mg/kg with only 25% protection observed, when compared to our previous lead compound THA40 in the 6 Hz 44 mA animal model. In the maximal electroshock (MES) model, compound 7 showed moderate activity at 100 mg/kg with 25% after 2 h. At a higher dose of 300 mg/kg, 25% of the animals were protected both at 0.5 h and 2 h. Although compound 7 did not produce the expected results, it allowed for a new avenue to investigate during our lead optimization studies.
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