Synthesis of Methyl Substituted Enaminones as Potential Anticonvulsant Agents

Epilepsy is the second most prevalent neurological disorder affecting more than 3 million individuals in the United States and 50 million individuals worldwide. Studies show that current medications are useful in treating 60-70% of patients with epilepsy; however problems arise in the various side effects and resistance to current medications. Therefore, more potent, selective and safer anticonvulsant agents are needed.;Enaminones are chemical compounds consisting of an amino group linked through a C=C bond to a keto group have been identified for use in anticonvulsant therapy and as potential P-glycoprotein (P-gp) inhibitors. P-glycoproteins are a group of transmembrane proteins responsible for transporting drugs. These proteins may influence the transport of enaminones at the Blood Brain Barrier (BBB) contributing to the effective treatment of epilepsy. The primary aim of this research was the design, synthesis, and pharmacological evaluation of 2, 5-dimethyl enaminone derivatives. Completion of this study answered several questions: 1) is the vinyl proton essential for anticonvulsant activity, 2) why is the vinyl proton required for activity, and 3) can we substitute any further?;The substituted enaminone compounds were evaluated for anticonvulsant activity in five different seizure models by the National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Health (NIH). For anticonvulsant studies, the enaminone moiety was thought to impart physiological activity and we anticipated that the methyl substituted enaminones would be inactive in anticonvulsant evaluation. Later the compounds would undergo testing to investigate their activity as P-glycoprotein (P-gp) inhibitors. In this study, three novel series of sixteen substituted enaminones have been successfully synthesized with average yields of 24% (1), 25% (2), and 18% (3) with each having undergone anticonvulsant evaluation. Three compounds, 3-(4-chlorophenyl-amino)-2,5-dimethylcyclohex-2-enone ( 14i) ADD 421104, 3-((4-trifluromethoxy) phenylamino)-2,5-dimethylcyclohex-2-enone (14l) ADD 427037 and 2,5,5-trimethyl-1,3-(phenylamino)cyclohex-2-enone (14q) ADD 427031, were the most active and 14i and 14l were further examined by X-ray and computational analysis. The outcome of this structure activity relationship study of methyl substituted enaminones has provided insight in how to continue anticonvulsant studies.*;*Please refer to dissertation for diagrams.