Structure-activity correlations between hydroxamic acids and their inhibitory powers on urease activity. I. A quantitative approach to the effect of hydrophobic character of acyl residue.

Abstract

Regression analyses were made in the study of structure-activity relationship between hydroxamic acids and their inhibitory powers on urease activity according to the Hansch and Fujita's method. It was found that the primary effect of acyl residues in altering the inhibitory power of hydroxamic acid is associated with the hydrophobic character of the acyl residues. That is, the inhibitory power, pI50, of the series of congeners such as n-aliphatic, m-substituted benzo-, and p-substituted benzohydroxamic acids vary parabolically with the hydrophobic parameter, π, of acyl residues and substituents. The optimal hydrophobic parameter, π0, for acyl residue of n-aliphatic hydroxamic acid, which gives theoretically the strongest inhibitory power, was calculated to be 2.543. The results presented here suggest that hydrophobic character of acyl residue of hydroxamic acids plays two kinds of roles in urease inhibition ; the role in the random walk process of hydroxamic acids to the active site ; the other in the stereospecific hydrophobic bonding at the active site. On the other hand, electronic effect of acyl residues does not play a significant role in their inhibitory power on urease activity. Furthermore, it is assumed that in a series of araliphatic hydroxamic acids, the remarkable decrease in the inhibitory power of α-substituted derivatives is due to a steric effect of the bulky phenyl group in the α-position preventing the hydroxamic acid from proper fit on the active site of urease.