Structural studies on bio-active compounds. Part 16. Synthesis and properties of sterically-constrained analogues of methylbenzoprim, a new dihydrofolate reductase inhibitor.

The new lipophilic dihydrofolate reductase inhibitor methylbenzoprim is a flexible substituted 2,4-diamino-5-arylpyrimidine bearing an ortho-disposed aromatic nitro group and an N-methylbenzylamine residue. Molecular modelling studies indicate that modifications which incorporate these structural features into a planar benzazole or benzazole-N-oxide arrangement could mimic the overall geometry of methylbenzoprim. Target compounds were synthesized by exploiting known reaction pathways involving ortho-interactions between diazonium-, azido- or nitro-substituents and the adjacent substituted amino group: these syntheses proceeded without detrimental effect on the diaminopyrimidine residue. None of the heterocyclic analogues were more potent than the lead molecule methylbenzoprim.