Studies on quantitative structure-activity relationships. IV. Usefulness of the novel substituent entropy constant .SIGMA.s and the sign of the enthalpy parameter.

Abstract

Biological response (BR) can be expressed by the equation BR=α (σso)2+bσso+cσi+dσx+e for quantitative structure-activity relationships (QSAR) analyses. The values of σi and σx originally take+or-sign depending on the electronic character of the substituent group and can be used to describe strong drug-site interactions. On the contrary, original chemical significance is lost in |σi| and |σx|, which can be applied to weak drug-site interaction, where dipole-dipole or dispersion interaction could be predominant. The coefficient c of the BR equation becomes the same in meta- and para-substituted benzene series. When σx is real, σx/m+σx/p gives a better result than σx/m, p, while on the other hand, when σx is absolute, |σx|/m, p gives a good result. As regards the entropy term a (σso)2+bσso, the ortho-substituted benzene series requires the+sign for a and the-for b, whereas for meta-and para-substituted series, this is reversed. When the relative weight of the entropy term decreases and the contribution of the enthalpy term becomes predominant, the quantum chemical index could often be used as an effective scale for BR.