Anticonvulsant activity of phenylmethylenehydantoins: a structure-activity relationship study.
Phenylmethylenehydantoins (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 ED(MES(2.5)) ranging from 28 to 90 mg/kg. Substitution of polar groups such as -NO(2), -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 (ED(MES(2.5)) = 28 +/- 2 mg/kg) and 12 (ED(MES(2.5)) = 39 +/- 4 mg/kg), to be the most active candidates of the series, which are comparable to phenytoin (55, ED(MES(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.
Department of Pharmacy, National University of Singapore, Block S4, 18, Science Drive 4, Singapore-117543, Singapore.
Jeyanthi Chinnappa
JC
Thenmozhiyal
Peter Tsun-Hon
PT
Wong
Wai-Keung
WK
Chui
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004597:Electroshock; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015999:Multivariate Analysis; D021281:Quantitative Structure-Activity Relationship; D012640:Seizures / Q000188:drug therapy / Q000209:etiology
D000927:Anticonvulsants; D006827:Hydantoins