Synthesis and anticonvulsant activity of 2-iminohydantoins.
Iminohydantoins selectively substituted at position C-5 and their 1-carbobenzoxy derivatives have been synthesized, and their anticonvulsant activity was evaluated in mice. In general, the more lipophilic 1-carbobenzoxy iminohydantoins were more potent than the unsubstituted counterparts. Evaluation of the individual enantiomers of the chiral iminohydantoins showed that the anticonvulsant activity resided primarily in the S isomers. In this study, (S)-(+)-1-carbobenzoxy-5-isobutyl-2-iminohydantoin (9a) was the most active member. This compound was not nearly as active as phenytoin against electrically induced convulsions, but was also active against pentylenetetrazole-induced seizures, suggesting a broader clinical potential. The closest analogue of phenytoin, viz., 5,5-diphenyl-2-iminohydantoin (1), failed to show any significant activity. Methylation on N-3 or the imino nitrogen of 1 also did not provide a compound with substantial activity. 2-Thiophenytoin was not active against electroshock seizures and showed only a weak activity against pentylenetetrazole. This study suggested that the structure-activity relationship of 2-iminohydantoins was quite different from that of 2-hydantoins.
Kwon
C H
CH
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439.
Iqbal
M T
MT
Wurpel
J N
JN
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis; D004305:Dose-Response Relationship, Drug; D006827:Hydantoins / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D006827:Hydantoins