QUANTITATIVE STRUCTURE-ACTIVITY ANALYSES OF NOVEL HYDROXYPHENYLUREA DERIVATIVES AS ANTIOXIDANTS

A series of substituted hydroxyphenylureas was synthesized, the chemic al structure of which was designed based on structures of natural anti oxidants, vitamin E (alpha-tocopherol) and uric acid. They exhibited h igh inhibitory activity against lipid peroxidation, In order to gain a n insight into the mechanism of the inhibition reaction, we analyzed t heir structure-activity relationships quantitatively. Electronic and s teric effects of substituents on the phenolic hydroxyl group were show n 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 stabilizati on 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-d ipole interaction of the phenolic hydroxyl group with the carboxylate anion which could retard the formation of the transition state. (C) 19 98 Elsevier Science Ltd, All rights reserved.