Synthesis of N-1′, N-3′-disubstituted spirohydantoins and their anticonvulsant activities in pilocarpine model of temporal lobe epilepsy

[Display omitted] Herein we report the synthesis and anticonvulsant activity of a library of eighteen new compounds that are structural mimics of phenytoin. These class of compounds contain a N-1′, N-3′-disubstituted spirohydantoin scaffold, where the N-1′ and N-3′ positions are modified with an alkyl group or aryl group. Of the eighteen compounds synthesized and tested, compound 5c showed the best anticonvulsant activity. It completely prevented the precursor events of motor seizure in the pilocarpine model of temporal lobe epilepsy. Additionally, ten of the analogs were more effective than phenytoin when compared using the Racine’s score in the pilocarpine model. Based on the structure activity relationship (SAR), we concluded that alkyl groups (ethyl, propyl or cyclopropyl) at N-3′ position and 4-nitro phenyl group at N-1′ position are desirable.