title: Synthesis and testing of 5-benzyl-2,4-diaminopyrimidines as potential inhibitors of leishmanial and trypanosomal dihydrofolate reductase.
abstract: Dihydrofolate reductase is a drug target that has not been thoroughly investigated in leishmania and trypanosomes. Work has previously shown that 5-benzyl-2,4-diaminopyrimidines are selective inhibitors of the leishmanial and trypanosome enzymes. Modelling predicted that alkyl/aryl substitution on the 6-position of the pyrimidine ring should increase enzyme activity of 5-benzyl-2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Various compounds were prepared and evaluated against both the recombinant enzymes and the intact organisms. The presence of a substituent had a small or negative effect on activity against the enzyme or intact parasites compared to unsubstituted compounds.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
authors.forename: Shafinaz F
authors.initials: SF
authors.lastname: Chowdhury
authors.forename: Ramon Hurtado
authors.initials: RH
authors.lastname: Guerrero
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruiz-Perez
authors.forename: Dolores Gonzalez
authors.initials: DG
authors.lastname: Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007893:Leishmania donovani / Q000201:enzymology*; D017737:Macrophages, Peritoneal / Q000469:parasitology; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D005493:Folic Acid Antagonists; D011743:Pyrimidines; D014344:Trypanocidal Agents; D013762:Tetrahydrofolate Dehydrogenase