The structure-activity relationship of 9-(X-phenyl)guanine inhibitors of xanthine oxidase.

A correlation analysis of the structure-activity relationship in the 9-(X-phenyl)guanine inhibitors of xanthine oxidase has been made. The following equation (see article) has been formulated for 30 derivatives having substituents in the 2-, 3- and 4-positions of the 9-phenyl moiety. C in this expression is the molar concentration of inhibitor causing 50% inhibition of xanthine oxidase. MR-3,4 is the combined molecular refractivity of substituents in the 3- and 4-positions. Molar refractivity is a measure of the polarizability of the substituents; it is assumed in the present instance to be a measure of the dispersion forces between the substituent and the enzyme. The positive coefficient with this term roughly indicates that the greater the number of electrons and the greater their polarizability in the substituent, the more inhibitory are the substituents. Es-2 and Es-4 are Taft steric parameters for functions in the ortho and para positions. The positive coefficients with these two terms indicate that bulky groups in the 2- and 4-positions do not make good inhibitors. This is a proximity effect and is related to the enzymic region near the ortho and para positions. No sigma term occurs in this equation which indicates the lack of importance of the electronic effect of substituents on the phenyl ring as it pertains to inhibitory power. Since the hydrophobic parameter pi was not found to be important, it is assumed that these inhibitors are not binding to hydrophobic space in or on the enzyme; rather, they are interacting with polar space. The implications of this equation for the design of better inhibitors are discussed.