2,4-diamino-5-benzylpyrimidines and analogues as antibacterial agents. 6. A one-step synthesis of new trimethoprim derivatives and activity analysis by molecular modeling.
A new route to 2,4-diamino-5-(4-hydroxybenzyl)pyrimidines has been 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. However, 2,6-dimethoxyphenol produces a mixture of 5-(3-hydroxy-2,4-dimethoxybenzyl)- and 5-(4-hydroxy-3,5-dimethoxybenzyl)pyrimidines. The phenolic condensation has been 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 ortho-substituted derivatives in the active site of dihydrofolate reductase has provided a rational explanation for their activities relative to trimethoprim.
D000900:Anti-Bacterial Agents; D001665:Binding Sites; D004926:Escherichia coli / Q000201:enzymology; D005493:Folic Acid Antagonists; D008958:Models, Molecular; D008961:Models, Structural; D014295:Trimethoprim / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D014295:Trimethoprim