title: Synthesis and anticonvulsant activity of enaminones. 4. Investigations on isoxazole derivatives.
abstract: Due to the exceptional anticonvulsant activity displayed by substituted aniline enaminones, related pyridine derivatives and phenothiazines synthesised in our laboratories, the further investigation of various aromatic heterocycles was undertaken. Condensation of cyclic 1,3-diketo esters with 3-, and 5-aminoisoxazole derivatives led to a series of potent anti-maximal electroshock (MES) analogues, three of which occurred in the 3-amino series: ethyl ester (10), orally (po) active in rats [ED(50) 68.9 mg kg(-1), TD(50) > 500 mg kg(-1), protective index (PI = TD(50)/ED(50)) > 49.6]; methyl ester (9), ED(50) 68.9 mg kg(-1) intraperitoneally (ip) in mice, TD(50) > 500 mg kg(-1), PI > 7.3, and tert-butyl ester (8), ED(50) 28.1 mg kg(-1) po in rats, TD(50) > 500 mg kg(-1), PI > 17.8. Sodium channel binding studies, as well as evaluations against pentylenetetrazol, bicuculline, and picrotoxin on isoxazole 10 were all negative, leading to an unknown mechanism of action. X-ray diffraction patterns of a representative of the 3-amino series (isoxazoles 6-11) unequivocally display the existence of intramolecular hydrogen bonding of the nitrogen to the vinylic proton in the cyclohexene ring, providing a pseudo three ring structure which was also shown previously with the vinylic benzamides. Physicochemical-permeability across the BBB suggested an efflux mechanism for the previously synthesised aniline enaminones, but not with isoxazole 10.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201-4403, USA.
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Eddington
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Roberts
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Butcher
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Edafiogho
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
authors.forename: Neville
authors.initials: N
authors.lastname: Cooke
authors.forename: Angela M
authors.initials: AM
authors.lastname: Goodwin
authors.forename: Carlynn A
authors.initials: CA
authors.lastname: Smith
authors.forename: K R
authors.initials: KR
authors.lastname: Scott
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D018360:Crystallography, X-Ray; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009498:Neurotoxins / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000927:Anticonvulsants; D007555:Isoxazoles; D009498:Neurotoxins; D015222:Sodium Channels