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Anticonvulsant Activity of Phenylmethylenehydantoins: A Structure−Activity Relationship Study
journal contribution
posted on 2004-03-11, 00:00 authored by Jeyanthi Chinnappa Thenmozhiyal, Peter Tsun-Hon Wong, Wai-Keung ChuiPhenylmethylenehydantoins (PMHs) and their des-phenyl analogues were synthesized and
evaluated 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 selection
of 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 the
phenyl ring were found to exhibit good anticonvulsant activity with EDMES(2.5) ranging from 28
to 90 mg/kg. Substitution of polar groups such as −NO2, −CN, and −OH was found to be less
active or inactive on PMHs. Replacement of the phenyl ring with heteroaromatic rings reduced
or 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 the
series, which are comparable to phenytoin (55, EDMES(2.5) = 30 ± 2 mg/kg) in their protection
against seizure. Multivariate analysis performed on the whole series of 54 PMHs further
supported the finding that the alkylated phenylmethylenehydantoins are the best acting
compounds. 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 critical
parameters for their anticonvulsant activity.