Analogs of tetrahydrofolic acid. XXX. Inhibition of dihydrofolic reductase by some 6‐substituted 2,4‐diamino‐s‐triazines

Four different routes to 6‐alkyl‐, 6‐aryl‐, and 6‐aralkyl‐2,4‐diamino‐ s ‐triazines were investigated. The most convenient was reaction of an ester with biguanide in methanol at room temperature. Seven of these 6‐substituted 2,4‐diamino‐ s ‐triazines were investigated as inhibitors of dihydrofolic reductase. As a class they were weaker inhibitors than the corresponding 2,4‐diamino‐6‐substituted pyrimidines, this difference being attributed to the weaker basicity of the former class. Although hydrophobic bonding by 6‐alkyl and 6‐aralkyl groups on 2 the 4‐diamino‐ s ‐triazine system could be detected, the extent of hydrophobic bonding was much weaker than that previously seen with 2,4‐diaminopyrimidine containing a 5‐alkyl or 5‐aralkyl group or 1‐alkyl‐ and 1‐aralkyl‐2,4‐diamino‐1,2‐dihydro‐2,2‐dimethyl‐ s ‐triazines.