Effect of Structural Modification of the Hydantoin Ring on Anticonvulsant Activity

• Published in: Journal of medicinal chemistry Vol. 28; no. 5; pp. 601 - 606
• Main Authors: Cortes, Sergio, Liao, Zeng-Kun, Watson, Darrell, Kohn, Harold
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.05.1985
• Subjects: Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - toxicity; Biological and medical sciences; Dose-Response Relationship, Drug; Electroshock; General pharmacology; Hydantoins - chemical synthesis; Hydantoins - pharmacology; Hydantoins - toxicity; Male; Medical sciences; Mice; Motor Activity - drug effects; Pentylenetetrazole; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Postural Balance - drug effects; Structure-Activity Relationship; Diamine; Five membered ring; Structure activity relation; Nitrogen heterocycle; Aminoacid; Ureas; Anticonvulsant
• DOI: 10.1021/jm50001a012
• ISSN: 0022-2623

Selectively substituted hydantoins 1 (15 examples), 4-hydroxy-2-imidazolidinones 2 (13 examples), 2-imidazolones 3 (10 examples), 2-imidazolidinones 4 (four examples), vicinal diamines 5 (two examples), and simple amino acid derivatives 6 (four examples) have been prepared and evaluated in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole seizure threshold (sc Met), and rotorod (Tox) tests. The medium effective doses (ED50) and the medium toxic dose (TD50) for the most active compounds are reported. In general, the most pronounced activity was observed for hydantoins 1 and protected amino acids 6. Within each series of compounds, enhanced anticonvulsant activity was often noted for compounds containing an aromatic group one carbon removed from a nitrogen atom. Among the most active compounds observed were the amino acid derivative N-acetyl-D,L-alanine benzylamide (6d) and the two 2-imidazolones 4-methyl-1-(phenylmethyl)-1,3-dihydro-2H-imidazol-2-one (3e) and 1-phenyl-1,3-dihydro-2H-imidazol-2-one (3g). Compound 6d proved to be slightly more potent in the MES test than phenacemide.