Abstract
6-Substituted 2,4-diaminoquinazolines ( 1) are good inhibitors of dihydrofolate reductase (DHFR) and effective as growth inhibitors of intact bacterial cells in vitro. The most potent compounds in the in vitro tests were, however, ineffective against a systemic murine infection. Quantitative correlations were obtained between DHFR inhibition and the substituent constant molar refractivity (MR) for 3 of the 4 enzymes studied ( Escherichia coli, Streptococcus faecalis, and bovine liver DHFR); for the fourth enzyme ( Staphylococcus aureus DHFR) the best correlation was obtained with a combination of MR and the lipophilic parameter π. The recognition that the conformational properties of the 6-substituent may play a vital role in mediating the binding of 1 to DHFR prompted the synthesis of novel analogues specifically designed to test this hypothesis. From these results it was possible to construct a simple schematic model of the binding site occupied by the 6-substituents; a subsequent molecular modelling study agreed with the features of this model.
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