Design, synthesis and evaluation of some trifluoromethylated cyclic enaminones as anticonvulsant agents

John Apraku, Tennessee State University


Epilepsy is one of the most ubiquitous neurological disorders, affecting about 1% of the world's population. The currently available anticonvulsant drugs are effective in reducing the severity and number of seizures in less than 70 % of patients. Moreover, their usage is associated with undesirable side effect profiles, ranging from gingival hyperplasia to life threatening hepatotoxicity. Thus, the continued search for more potent, safer and selective antiepileptic drugs (AEDs) has prompted us to synthesize a series of fluorinated cyclic enaminones, whose biological activity have been evaluated. To the best of our knowledge enaminones containing a trifluoromethyl group on the six-membered cycloalkane framework have not been studied. The fluorine atom is endowed with unique properties, such as electron-withdrawing, lipophilicity, hydrogen bond acceptor ability and blockade of metabolic sites. We hypothesize that the introduction of a trifluoromethyl group gamma to the basic nitrogen will enhance in vitro potency, affect off-target selectivity, and modulate the pka of basic moieties. The above are expected to improve the overall affinity for the putative target. Cyclic fluorinated enaminone derivatives were synthesized using three methods as shown in scheme 1 -4. Each derivative was prepared by condensing 5-trifluoromethyl-1,3-cyclohexanedione 1 with substituted phenyl, benzylamine and heteroaromatic amines, respectively. These series of novel fluorinated cyclic enaminone derivatives have been evaluated as potential anticonvulsants in four animal models of epilepsy, MES, ScPTZ, rotorod neurotoxicity and 6 Hz assay. Phase I screening test data indicated significant anticonvulsant activity for compounds 2a, 4a, 4b, 7 and 8. Except for 2a and 4c all the above compounds showed protection with no observed neurotoxicity. Compound 8 exhibited continuous protection at four tested time in the 6 Hz assay with no overt toxicity.

Subject Area

Organic chemistry

Recommended Citation

John Apraku, "Design, synthesis and evaluation of some trifluoromethylated cyclic enaminones as anticonvulsant agents" (2013). ETD Collection for Tennessee State University. Paper AAI1552436.