DIHYDROFOLATE-REDUCTASE INHIBITION BY 2,4-DIAMINOTRIAZINES - STRUCTURE-ACTIVITY STUDY

Quantitative structure-activity relationships have been formulated for the inhibition of dihydrofolate reductase from bovine and rat liver by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-X-phenyl)-s-triazines. The best correlations are: bovine, log 1 C = 1.05π3 - 1.21 log (β·10π + 1) + 6.64, where log β = -0.736 and r = 0.955 for 28 congeners; rat, log 1 C = 1.12π3 - 1.34 log (β·10π + 1) + 6.29, where log β = -0.978 and r = 0.977 for 18 congeners. In these expressons C is the molar concentration of inhibitor producing 50% inhibition of the enzyme, π3 is the octanol/water hydrophobic parameter for the 3-X-phenyl substituent, β is an iteratively derived coefficient, and r is the multiple least squares correlation coefficient. The implications of these bilinear models are discussed and compared with earlier work by B. R. Baker. © 1979.