Design and development of trifluoromethylated enaminone derivatives as potential anticonvulsants

• Published in: Journal of fluorine chemistry 2021-11, Vol.251, p.109886, Article 109886
• Main Authors: Amaye, Isis J., Harper, Tawes, L Jackson-Ayotunde, Patrice
• Format: Article
• Language: English
• Subjects: 1, 3-cyclohexanedione; Anticonvulsant; Diketo-ester; Enaminone benzamide; Trifluoromethyl
• ISSN: 0022-1139; 1873-3328
• DOI: 10.1016/j.jfluchem.2021.109886

•Successful introduction of trifluoromethyl functionality to the enaminone scaffold.•Improved reaction conditions for fluorinated enaminone building blocks.•Successful synthesis of a novel enaminone benzamide and anticonvulsant evaluation 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. [Display omitted]