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.

Synthesis and structure activity study of N‐1 substituted (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins as potential anticonvulsant agents

“…All compounds were made from the corresponding L-amino acid, i.e., L-norvaline. f Previously synthesized and published data [Sun et al, 1994]. The succinimide esters were then coupled with excess cyanamide in the presence of sodium hydroxide to produce the corresponding N-protected aminoacylcyanamides.…”

“…Briefly, Nprotected amino acids were allowed to react initially with dicyclohexylcarbodiimide (DCC) and then with Nhydroxysuccinimide to form the activated succinimide esters. Previously synthesized and published data [Sun et al, 1994]. The acylcyanamides, which are usually unstable, underwent intramolecular cyclization spontaneously under acidic condition or by heat treatment to form the corresponding N-1-substituted 5-n-propyl-2-iminohydantoins.…”

“…Maximal activity against the maximal electroshock seizure (MES) test results when two phenyl groups are placed in the C-5 position of the hydantoin ring, viz, phenytoin. 1) was one of the most active members of the series [Sun et al, 1994]. The closest analog of phenytoin, 5,5-diphenyl-2iminohydantoin, failed to show any significant activity.…”

“…In general, at least one aromatic group, e.g., phenyl or thienyl, is essential for the anticonvulsant activity of the hydantoins [Kupferberg, 1995]. However, the structure-activity relationship (SAR) of 2-iminohydantoins was found to be quite differ-ent from that of hydantoins [Kwon et al, 1991;Sun et al, 1994]. However, the structure-activity relationship (SAR) of 2-iminohydantoins was found to be quite differ-ent from that of hydantoins [Kwon et al, 1991;Sun et al, 1994].…”

Design, synthesis, and anticonvulsant activity of new N-Mannich bases derived from spirosuccinimides and spirohydantoins

“…doi:10.1016/j.bmc.2010.06.064 (unsubstituted or with electron-withdrawing Cl, F atoms or CF 3 group), benzyl-piperazine, 2-hydroxyethyl-piperazine or morpholine. On the other hand, taking into account well documented anticonvulsant properties many of hydantoins [15][16][17] and spirohydantoins, 18-20 as a second step of our investigation, we have synthesized a series of analogues 5a-h in which the succinimide core fragment has been changed into the hydantoin ring (7a-h). Such modification enabled the evaluation of the role of mentioned heterocyclic rings for the anticonvulsant activity.…”