Parachors in drug design.

Parachor has been used extensively in physical organic chemistry for structure determination. It has rarely been used as a parameter for the correlation of structure and biological activity. We have reexamined the parachor concept for structure-activity correlations of some closely related analogs. Parachor is an additive and constitutive molecular parameter consisting of two physical properties, molar volume and surface tension, factors which appear to be important in the passage of a drug or hormone from the site of administration or synthesis to the site of action. Correlations between parachor values and biological activities for a number of drug classes have been examined. Good correlations were obtained for three classes: thyromimetic activity of 3'-substituted thyroxine analogs, blood clotting inhibitory activity of 5-substituted pentylamines, and local anesthetic activity of the paracaines. Correlations with parachor are comparable to those obtained with the Hansch hydrophobic constant π for six more drug classes: antibiotic activity of penicillins; fibrinolytic activity of 2,4-substituted benzole acids; parasympatholytic activity of 2-alkyl-diphenhydramines; beta-receptor activity of sympathomimetics; fibrinolytic activity of 5-substituted salicylic acids; and isohemolytic concentrations for n-alcohols. The relative merits of parachor and partition coefficients in predicting biological activities are discussed. When data are available for both parameters, both correlations appear to be equally useful. Because the parachor is a truly additive and constitutive property and involves no new experimental measurements, its predictive usefulness in drug design deserves further evaluation.