Crystallography, quantitative structure-activity relationships, (QSAR) and molecular graphics in a comparative analysis of the inhibition of dihydrofolate reductase from chicken liver and Lactobacillus casei by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines

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Abstract
The inhibition of dihydrofolate reductase [DHFR] from chicken liver and from L. casei was studied with 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines. For the chicken enzyme, inhibitor potency for 101 triazines was correlated by the following equation: log 1/Kiapp = 0.85 .SIGMA. .pi.'' -1.04 log (.beta. .cntdot. 10 .SIGMA..pi.'' + 1) + 0.57.sigma. + 6.36. The parameter .pi.'' indicates that for certain substituents, .pi. = 0. In the case of the L. casei DHFR results, meta and para derivatives could not be included in the same equation. For 38 meta-substituted compounds, log 1/Kiapp = 0.38.pi.''3 -0.91 log (.beta. .cntdot. 10.pi.''3 + 1) + 0.71I + 4.60 and for 32 para-substituted phenyltriazines log 1/Kiapp = 0.44.pi.''4 - 0.65 log (.beta..pi.''4 + 1) -0.90 .nu. + 0.699I + 4.67. In the L. casei equation, I is an indicator variable for substituents of the type CH2ZC6H4-Y and ZCH2C6H4-Y, where Z = O, NH, S, or Se. The parameter .nu. is Charton''s steric parameter, which is similar to Taft''s Es. The mathematical models obtained from correlation analysis are compared wih stereo color graphics models.

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