title: Structural studies on bio-active compounds. Part 16. Synthesis and properties of sterically-constrained analogues of methylbenzoprim, a new dihydrofolate reductase inhibitor.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Aston University, Birmingham, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: M F
authors.initials: MF
authors.lastname: Stevens
authors.forename: C E
authors.initials: CE
authors.lastname: Sansom
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D014230:Triazoles; C064625:methylbenzoprim