Conformational analysis of clinically active anticonvulsant drugs

Abstract

A series of ureides active against grand mal epilepsy have been studied by using classical potential energy calculations. The series includes phenyl ethyl and diphenyl derivatives of hydantoins, succinimides, glutarimides, oxazolidine-2,4-diones, pyrimidine-2,6-diones, barbituric acids, and phenacemide. A thorough examination of the conformational possibilities did not reveal an exclusive conformation that could account for their activity. However, comparisons with diazepam and other benzodiazepines known to have the ability to competitively bind with drugs such as diphenylhydantoin at some sites show that there is a distinct conformational preference that may well account for their activity against grand mal epilepsy. The conformational studies led to the proposal of a general model for anticonvulsant activity comprising two aromatic rings or their equivalent in a favored orientation and a third region, usually a cyclic ureide, comprising a number of hydrogen-bond-forming functional groups. The specific placement of hydrogen-bonding groups in this region appears to be of less importance than the correct conformational arrangement of the hydrophobic elements.

Synthesis and anticonvulsant activity of new N-mannich bases derived from benzhydryl- and isopropyl-pyrrolidine-2,5-dione

“…Likewise, nine substances 5, 6, 7, 10, 11, 15, 17, 19, and 28 were effective only in the scPTZ test. Derivatives 5,7,9,11,12,13,15,17,19, and 28 showed protection at the dose of 100 mg/kg after 4 h. It is a better protection at thse same time point than the result of ethosuximide, recognized as the model antiepileptic drug effective in the scPTZ test. Especially interesting seem to be compounds 11 and 12, which revealed activity at the dose of 100 mg/kg not only after 4 h, but also after 0.5 h. The other compounds have demonstrated protection at the dose of 300 mg/kg after 4 h (6 and 10), and 0.5 h (compound 9).…”

“…Compounds 5,7,11,12,13,15, and 17, as well as ethosuximide and valproic acid compared with the vehicle-treated group, prolonged in a dose-dependent manner the latency time to first seizure episode. Compounds 5,7,11,12,13, and 17 at doses 100 and 150 mg/kg significantly prolonged latency time to the first seizure episode by 99-142% and 119-176%, respectively. Compound 15 at the dose of 150 mg/kg lengthened latency time to the first seizure episode by 128%, in a statistically significant manner, whereas reference compounds significantly prolonged latency time to the first seizure episode starting at the dose of 120 mg/kg (ethosuximide) or 250 mg/kg (valproic acid).…”

“…All compounds (5,7,9,11,12,13,15, and 17) showed higher potency in the scPTZ tests in comparison with the reference drugs -ethosuximide and valproic acid. Moreover, all these molecules demonstrated lower rotarod toxicity than phenytion, ethosuximide, and valproic acid, what resulted in more favorable protection indexes.…”

“…As a result, it is well established that one of the important core fragments is defined by a nitrogen heteroatomic system, usually cyclic imide, with at least one carbonyl group and phenyl or alkyl groups attached to the heterocyclic system [6][7][8] . The examples of the above-mentioned structures are pyrrolidine-2,5-dione, pyrrolidin-2-one or imidazolidine-2,4-dione.…”

Synthesis and Evaluation of Some Novel Semicarbazones Based Benzimidazole Derivatives as Anticonvulsant Agent

“…The conformational studies of the existing anticonvulsant drugs such as phenytoin, carbamazepine, lamotrigine, rufinamide and phenobarbitone has led to the proposal of a model for anticonvulsant activity [6] (Fig. 1).…”