Formulation of de novo substituent constants in correlation analysis: inhibition of dihydrofolate reductase by 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines.

A correlation equation based solely on de novo constants was formulated for 105 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines acting as inhibitors of dihydrofolate reductase. An equation with seven indicator variables gives a correlation with a correlation coefficient of 0.903 and a standard deviation of 0.229. The technique used is a modification of the Free-Wilson approach. The results indicate that correlation equations with fewer parameters than the theoretical required to account for all molecular changes may often be encountered. It is also shown that cross-product terms can be used to establish the significance of cooperative substituent effects.