title: 2,4-Diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase.
abstract: This paper describes the synthesis of 4'-substituted and 3',4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, CF10 3XF Cardiff, UK.
authors.forename: Didier
authors.initials: D
authors.lastname: Pez
authors.forename: Isabel
authors.initials: I
authors.lastname: Leal
authors.forename: Fabio
authors.initials: F
authors.lastname: Zuccotto
authors.forename: Cyrille
authors.initials: C
authors.lastname: Boussard
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruiz Perez
authors.forename: Dolores
authors.initials: D
authors.lastname: Gonzalez Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects; D018320:Leishmania major / Q000201:enzymology*; D017737:Macrophages, Peritoneal / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000166:cytology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D013762:Tetrahydrofolate Dehydrogenase