title: Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase.
abstract: This paper concerns the design, synthesis, and evaluation of inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Initially study was made of the structures of the leishmanial and human enzyme active sites to see if there were significant differences which could be exploited for selective drug design. Then a series of compounds were synthesized based on 5-benzyl-2, 4-diaminopyrimidines. These compounds were assayed against the protozoan and human enzymes and showed selectivity for the protozoan enzymes. The structural data was then used to rationalize the enzyme assay data. Compounds were also tested against the clinically relevant forms of the intact parasite. Activity was seen against the trypanosomes for a number of compounds. The compounds were in general less active against Leishmania. This latter result may be due to uptake problems. Two of the compounds also showed some in vivo activity in a model of African trypanosomiasis.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, UK.
authors.forename: S F
authors.initials: SF
authors.lastname: Chowdhury
authors.forename: V B
authors.initials: VB
authors.lastname: Villamor
authors.forename: R H
authors.initials: RH
authors.lastname: Guerrero
authors.forename: I
authors.initials: I
authors.lastname: Leal
authors.forename: R
authors.initials: R
authors.lastname: Brun
authors.forename: S L
authors.initials: SL
authors.lastname: Croft
authors.forename: J M
authors.initials: JM
authors.lastname: Goodman
authors.forename: L
authors.initials: L
authors.lastname: Maes
authors.forename: L M
authors.initials: LM
authors.lastname: Ruiz-Perez
authors.forename: D G
authors.initials: DG
authors.lastname: Pacanowska
authors.forename: I H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D018314:Leishmania infantum / Q000187:drug effects / Q000201:enzymology; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology; D017737:Macrophages, Peritoneal / Q000469:parasitology; D051379:Mice; D008958:Models, Molecular; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D005493:Folic Acid Antagonists; D014344:Trypanocidal Agents; D013762:Tetrahydrofolate Dehydrogenase