Quantitative structure-activity studies. I. Parameters relating to hydrophobicity.

Abstract

The logarithm of partition coefficient between octanol and water, log P, widely used in structure-activity studies as a hydrophobic parameter was factored into two intrinsic components, free molecular volume and hydrophilic effect of polar group. Among those additive parameters relating to molecular volume as parachor, molar refraction, diamagnetic susceptibility, molar attraction constant, and Exner's molar volume, Quayle's atomic parachor, Pr, showed the best correlation with observed log P for apolar compounds. The hydrophilic group effect, Ew, was estimated as a correction term in the evaluation of log P for polar compounds by using a linear relation of log P to Pr obtained for apolar molecules. The parameters Pr and Ew could be satisfactorily applied to the regression analysis of water-solubility of 156 organic liquids and frog muscle narcosis of 39 drugs. These artificial parameters have a great advantage in drug design because they can be evaluated for a wide variety of classes of compounds before the molecules are even synthesized.