The synthesis of a novel series of N-benzenesulfonamide enaminones as potential anticonvulsant agents

Epilepsy is one of the most frequent neurological afflictions world-wide. Due to the vast complications with current treatment, there is a high demand for more effective and safer antiepileptic drugs. In this study, three novel series of para-substituted N-benzenesulfonamide enaminones have been successfully synthesized with average yields of 24% (1), 23% (2), and 35% (3), and each analogue has undergone anticonvulsant evaluation. We anticipated the sulfonamide group to be an interesting bioisosteric replacement for the previously active vinylic benzamides ( 4). The N-benzenesulfonamide enaminones were synthesized by N-deprotonation of the respective vinylogous amide, followed by sulfonylation of the amino-anion with the corresponding para-substituted benzene sulfonyl chlorides. The substitutents at the para position (R1) of the aromatic ring are varied based upon their electronic (sigma), lipophilicity (pi), and steric properties. Our compounds were subsequently evaluated for anticonvulsant activity in three different seizure models by the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH). Several analogues tested exhibited activity against the MES, scPTZ (only 3-[(4'-methyl)benzenesulfonylamino]-5-methylcyclohex-2-enone, 11l, ADD 363053), and/or the 6-Hz (psychomotor seizure) seizure test models, with no sign of neurotoxicity. The most active compound to date 3-[(4'-bromo)benzenesulfonylamino]-cyclohex-2-enone 11i, (ADD 404075), was protective against MES for 3 out of 4 mice at 100 and 300 mg/kg at 2 hours with no sign of neurotoxicity, and in phase VIA, in the rat, the compound showed protection at 0.25 h after dosing at 75 mg/kg. A common trend with the activity of the compounds is those active against the MES and scPTZ test are inactive in the 6-Hz model, with the exception to 3-[(4'-chloro)benzenesulfonylamino]-5-methylcyclohex-2-enone, 11r (ADD 403054), while on the other hand, analogs effective in the 6-Hz seizure model are ineffective in the MES and scPTZ test with the exception to compound ADD 403054. This same trend was also seen with known antiepileptic drugs (Barton et al. 2001). This phenomenon in anticonvulsant activity has not been observed in previously synthesized enaminone derivatives. The outcome of this structure-activity relationship study of para -substituted benzenesulfonamide enaminones has provided further insight into the structural and electronic requirements for anticonvulsant activity for these classes compounds.*;*Please refer to dissertation for diagrams.