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Analogs of tetrahydrofolic acid. XXIII. 1‐(ω‐phenylalkyl)‐4,6‐diamino‐1,2‐dihydro‐ s ‐triazines as inhibitors of dihydrofolic reductase
Author(s) -
Baker B. R.,
Ho BengThong
Publication year - 1965
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570020113
Subject(s) - chemistry , steric effects , stereochemistry , reductase , medicinal chemistry , enzyme , organic chemistry
Abstract 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.