Structure-activity study of 5-substituted 1-carbobenzoxy-2-iminohydantoins as potential anticonvulsant agents.

Abstract

On the basis of our previous findings, a series of 5-substituted 2-iminohydantoins has been synthesized and tested for anticonvulsant activity to better understand the SAR of 2-iminohydantoins. Among the compounds tested, (S)-(+)-1-carbobenzoxy-2-iminohydantoin analogs with ethyl (6)-, n-propyl (7a)-, isopropyl (8)-, allyl (9)-, and sec-butyl (11)-substituted groups at the C5 of the iminohydantoin ring provided the best activities against the MES test with ED50 values in the range of 52-74 mg/kg. All of the above compounds except 8 also showed activity against the scMET test with ED50 values in the range of 141-223 mg/kg. All significantly active compounds (1, 6, 7a, 8, 9, and 11) possessed aliphatic hydrocarbon side chains of two- to three-carbon lengths at the C5 position. All of the compounds with no or minimal activity had either shorter or longer side chains. The compounds substituted at the C5 position by aryl groups, arylalkyl groups, or alkyl and arylalkyl groups containing heteroatoms also showed no activity against the MES and scMET tests. The results suggested that the C5 side chain with the correct stereochemistry in 2-iminohydantoins provides optimal anticonvulsant activity when the side chains are aliphatic hydrocarbons with the length, ignoring branching, of two to three carbons.