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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
chemistry
Synthesis and anticonvulsant activity of enaminones. 4. Investigations on isoxazole derivatives
European Journal of Medicinal Chemistry, Volume 37, No. 8, Year 2002
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Description
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 [ED50 68.9 mg kg-1, TD50>500 mg kg-1, protective index (PI=TD50/ED50)>49.6]; methyl ester (9), ED50 68.9 mg kg-1 intraperitoneally (ip) in mice, TD50>500 mg kg-1, PI>7.3, and tert-butyl ester (8), ED50 28.1 mg kg-1 po in rats, TD50>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. © 2002 Published by Éditions scientifiques et médicales Elsevier SAS.
Authors & Co-Authors
Eddington, Natalie D.
United States, Baltimore
University of Maryland School of Pharmacy
Cox, Donna S.
United States, Wilmington
Dupont
Roberts, Ralph R.
United States, Saint Paul
3m Usa
Butcher, Ray Jay
United States, Washington, D.c.
Howard University
Edafiogho, Ivan Ogheneochuko
Kuwait, Kuwait City
Kuwait University
Stables, James P.
United States, Bethesda
National Institute of Neurological Disorders and Stroke
Cooke, Neville
United States, Washington, D.c.
Howard University
Goodwin, Angela M.
United States, Washington, D.c.
Howard University
Smith, Carlynn A.
United States, Washington, D.c.
Howard University
Scott, Kenneth R.
United States, Washington, D.c.
Howard University
Statistics
Citations: 98
Authors: 10
Affiliations: 6
Identifiers
Doi:
10.1016/S0223-5234(02)01377-6
ISSN:
02235234