Analogs of tetrahydrofolic acid. XXIII. 1‐(ω‐phenylalkyl)‐4,6‐diamino‐1,2‐dihydro‐s‐triazines as inhibitors of dihydrofolic reductase

A series of 1‐(ω‐phenylalkyl)‐4,6‐diamino‐1, 2‐dihydro‐s‐triazines was synthesized by acid catalyzed condensation of 1‐(ω‐phenylalkyl)biguanides with acetone, aromatic aldehydes and ω‐phenylalkyl aldehydes; the intermediate biguanides were prepared by fusion of ω‐phenylalkylamines with cyanoguanidine at 150°. 4, 6‐Diamino‐1, 2‐dihydro‐2,2‐dimethyl‐1‐(4‐phenylbutyl)‐ and 1‐(3‐phenylpropyl)‐s‐triazines (Xe and Xd) were potent inhibitors of dihydrofolic reductase, being complexed with the enzyme about two hundred times better than the substrate, dihydrofolic acid; further Xd and Xe were about 15‐fold better inhibitors of dihydrofolic reductase than the earlier investigated 1‐(p‐chlorophenyl)‐4, 6‐diamino‐1,2‐dihydro‐2,2‐dimethyl‐s‐triazine, the antimalarial drug. When the 2,2‐dimethyl group was replaced by p‐acetamidophenyl (IX) or phenyl (VIII), in inhibitors such as Xd and Xe, activity was reduced only 5‐30 fold; the corresponding change in 1‐(m‐chlorophenyl)‐4, 6‐diamino‐1,2‐dihydro‐2, 2‐dimethyl‐s‐triazine (V) gave a 19,000‐fold reduction in activity with the 2‐(p‐acetamidophenyl) analog (VII) and a 550‐fold decrease in activity with the 2‐phenyl analog. These decreases in activity are attributed to a combination of intramolecular steric effects, intermolecular (enzymeinhibitor) steric inhibition of binding, and inductive effects. By evaluation of suitable candidate compounds, these effects were partially separated for individual study.