2,4-Diamino-5-benzylpyrimidines and analogs as antibacterial agents. 6. A one-step synthesis of new trimethoprim derivatives and activity analysis by molecular modeling

Abstract

A new route to 2,4-diamino-5-(4-hydroxybenzyl)pyrimidines was developed that involves the condensation of 2,4-diamino-5-(hydroxymethyl)pyrimidine with phenols in acidic medium. The use of phenol and its 2,6-dialkyl derivatives produces 5-(4-hydroxybenzyl)pyrimidines exclusively. 2,6-Dimethoxyphenol produces a mixture of 5-(3-hydroxy-2,4-dimethoxybenzyl)- and 5-(4-hydroxy-3,5-dimethoxybenzyl)pyrimidines. The phenolic condensation was used to prepare a series of alkyl-substituted 5-(4-hydroxybenzyl)- and 5-(4-alkoxybenzyl)pyrimidines. The use of 1,2,3-trimethoxybenzene in place of a phenol produces 2,4-diamino-5-(2,3,4-trimethoxybenzyl)pyrimidine, a trimethoprim isomer with low antibacterial activity. The use of molecular models of several of the new o-substituted derivatives in the active site of dihydrofolate reductase provided a rational explanation for their activities relative to trimethoprim.