title: Trypanocidal activity of melamine-based nitroheterocycles.
abstract: A series of nitroheterocyclic compounds were designed with linkages to melamine or benzamidine groups that are known substrates of the P2 aminopurine and other transporters in African trypanosomes of the brucei group. Several compounds showed in vitro trypanotoxicity with 50% inhibitory concentrations in the submicromolar range. Although most compounds interacted with the P2 transporter, as judged by their ability to inhibit adenosine transport via this carrier, uptake through this route was not necessary for activity since TbAT1-null mutant parasites, deficient in this transporter, retained sensitivity to these drugs. One compound, a melamine-linked nitrofuran, also showed pronounced activity against parasites in mice. Studies into the mode of action of this compound indicated that neither reductive, nor oxidative, stress were related to its trypanocidal activity ruling out a genotoxic effect in T. brucei, distinguishing it from some other, mammalian cell toxic, trypanocidal nitroheterocycles.
authors.affiliation: Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
authors.forename: Mhairi L
authors.initials: ML
authors.lastname: Stewart
authors.forename: Gorka Jimenez
authors.initials: GJ
authors.lastname: Bueno
authors.forename: Alessandro
authors.initials: A
authors.lastname: Baliani
authors.forename: Burkhard
authors.initials: B
authors.lastname: Klenke
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Janice M
authors.initials: JM
authors.lastname: Brock
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
mesh_terms: D000117:Acetylglucosamine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D016503:Drug Delivery Systems; D005260:Female; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D009574:Nitro Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014227:Triazines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects
chemical_list: D006571:Heterocyclic Compounds; D009153:Mutagens; D009574:Nitro Compounds; D014227:Triazines; D014344:Trypanocidal Agents; C011907:melamine; D000117:Acetylglucosamine