title: ortho Substituent effects on the anticonvulsant properties of 4-hydroxy-trifluoroethyl phenols.
abstract: 2,6-Dialkylphenols with isopropyl and sec-butyl substituent are well known anesthetic compounds. The 4-substitution with 1-hydroxy-2,2,2-trifluoroethyl (4-HTFE) group in these compounds led to the discovery of compounds with anticonvulsant activity in the 6 Hz (32 mA) model of partial epilepsy. In the present study a series of 2-alkyl-4-HTFE phenols with the 6-position being replaced with either hydrogen and bromine were designed, synthesized and tested to evaluate the effect of ortho-substitution on the anticonvulsant property. The studies show that 2-substituted branched alkyl chain (iso-propyl and sec-butyl) is necessary for the anti-seizure effect. Phenols with 2-substituted linear alkyl groups (methyl, ethyl and n-propyl) having no substitution at 6-position were found to be devoid of antiseizure effects. The 6-substitution with bromine moderately reduces the anticonvulsant effect in the compounds with branched alkyl chains, but led to enhanced anticonvulsant effect in the compound with a linear alkyl chain. This study shows that 4-HTFE phenols having isopropyl or sec-butyl ortho groups produce good antiseizure protection in the 6 Hz therapy-resistant mouse model.
authors: Department of Anesthesia, Carver College of Medicine, University of Iowa, Iowa City, IA, United States. Mishra@Tansna.com
authors: Rajesh K
authors: RK
authors: Mishra
authors: Max T
authors: MT
authors: Baker
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy*; D054879:Halogenation; D008297:Male; D051379:Mice; D010636:Phenols / Q000737:chemistry* / Q000627:therapeutic use*; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D010636:Phenols