Abstract
| - Phenylmethylenehydantoins (PMHs) and their des-phenyl analogues were synthesized andevaluated for anticonvulsant activity using the maximal electroshock seizure (MES) assay.The phenyl rings of PMHs were substituted with a wide spectrum of groups, and the selectionof substituents was guided by Craig's plot. Phenylmethylenehydantoins substituted with alkyl(2, 3, 5, 6, 12, 14), halogeno (35, 38, 41), trifluoromethyl (11), and alkoxyl (23) groups at thephenyl ring were found to exhibit good anticonvulsant activity with EDMES(2.5) ranging from 28to 90 mg/kg. Substitution of polar groups such as −NO2, −CN, and −OH was found to be lessactive or inactive on PMHs. Replacement of the phenyl ring with heteroaromatic rings reducedor caused the loss of anticonvulsant activity. The study identified two PMHs, 14 (EDMES(2.5) =28 ± 2 mg/kg) and 12 (EDMES(2.5) = 39 ± 4 mg/kg), to be the most active candidates of theseries, which are comparable to phenytoin (55, EDMES(2.5) = 30 ± 2 mg/kg) in their protectionagainst seizure. Multivariate analysis performed on the whole series of 54 PMHs furthersupported the finding that the alkylated phenylmethylenehydantoins are the best actingcompounds. The SAR model derived on the basis of 12 of the most active phenylmethylenehydantoins demonstrated good predicting ability (root-mean-square error of prediction(RMSEP) = 0.134; RMSEE = 0.057) and identified LUMO energy and the log P as criticalparameters for their anticonvulsant activity.
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