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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
Author(s) -
Baker B. R.,
Lourens Gerhardus J.
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.5570020404
Subject(s) - chemistry , alkyl , side chain , branching (polymer chemistry) , hydrophobic effect , stereochemistry , reductase , organic chemistry , medicinal chemistry , enzyme , polymer
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 C 3 of the butyl group. Methyl branching at C 2 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.