Quantitative structure-activity analyses of novel hydroxyphenylurea derivatives as antioxidants.
A series of substituted hydroxyphenylureas was synthesized, the chemical structure of which was designed based on structures of natural antioxidants, vitamin E (alpha-tocopherol) and uric acid. They exhibited high inhibitory activity against lipid peroxidation. In order to gain an insight into the mechanism of the inhibition reaction, we analyzed their structure-activity relationships quantitatively. Electronic and steric effects of substituents on the phenolic hydroxyl group were shown to be of importance in governing the inhibitory potency. An increase in the electron donating property of substituents toward the phenolic hydroxyl group enhanced the antioxidative activity by the stabilization of an electron-deficient radical-type transition state. The steric shielding by ortho-substituents stabilized the phenoxy radicals formed following the transition state. Derivatives having the carboxyl group were only weakly active presumably because of an intermolecular ion-dipole interaction of the phenolic hydroxyl group with the carboxylate anion which could retard the formation of the transition state.
Nakao
K
K
Lead Generation Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Shimizu
R
R
Kubota
H
H
Yasuhara
M
M
Hashimura
Y
Y
Suzuki
T
T
Fujita
T
T
Ohmizu
H
H
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008968:Molecular Conformation; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011789:Quantum Theory; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D013329:Structure-Activity Relationship
D000975:Antioxidants; D010671:Phenylurea Compounds