Analogs of tetrahydrofolic acid. XXXI. Hydrophobic bonding to dihydrofolic reductase. III. Further observations on conformational aspects of hydrophobic bonding with some 5‐alkyl‐2,4‐diamino‐6‐pyrimidinols

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Abstract
Thirteen 5‐alkyl ‐ 2, 4 ‐diamino ‐ 6 ‐ pyrimidinols have been compared as inhibitors of dihydrofolic reductase in an attempt to delineate some of the conformational requirements for hydrophobic bonding to the enzyme; definite conformational limitations were observed. For example, cyclohexyl and trans‐crotyl side‐chains gave inhibitors that were as effective as the n‐butyl‐6‐pyrimidinol, whereas, isoamyl was better than all three; these results indicate that the n‐butyl group complexes in a near‐staggered conformation and additional hydrophobic bonding can be obtained by branching at C3 of the butyl group. Methyl branching at C2 of the n‐butyl group also gave a better inhibitor than n‐butyl, but the 2‐methylbutyl side‐chain was only half as effective as isoamyl; in contrast, the 1‐methylbutyl side‐chain gave an inhibitor only one‐half as effective as n‐butyl. That the amount of hydrophobic bonding was simply an “extraction process” dependent upon the size of the hydrocarbon group was unequivocally eliminated.