42310-33-8Relevant academic research and scientific papers
2,4-Diamino-5-benzylpyrimidines and Analogues as Antibacterial Agents. 9. Lipophilic Trimethoprim Analogues as Antigonococcal Agents
Roth, B.,Baccanari, D. P.,Sigel, C. W.,Hubbell, J. P.,Eaddy, J.,et al.
, p. 122 - 129 (2007/10/02)
Lipophilic analogues of trimethoprim (1) bearing 3,5-dialkyl-4-hydroxy substituents in the benzene ring are much more active in vitro against Neisseria gonorrhoeae than is 1.The 3,5-diisopropyl-4-hydroxy derivative (2) was selected as a candidate for clinical evaluation as an antigonococcal agent, and as part of the preliminary evaluation it was submitted to extended pharmacokinetic and metabolism studies in dogs.Although the compound was not extensively conjugated by metabolic enzymes, one of the methyl groups was metabolized to produce a 3-isopropyl-4-hydroxy-5-(α-carboxyethyl)benzyl derivative (43), which was rapidly excreted.Related analogues were likewise extensively metabolized.
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
Stuart,Paterson,Roth,Aig
, p. 667 - 673 (2007/10/02)
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 orthosubstituted derivatives in the active site of dihydrofolate reductase has provided a rational explanation for their activities relative to trimethoprim.
