title: In vitro and in vivo trypanosomicidal activity of pyrazole-containing macrocyclic and macrobicyclic polyamines: their action on acute and chronic phases of Chagas disease.
abstract: The in vitro and in vivo anti- Trypanosoma cruzi activity of the pyrazole-containing macrobicyclic polyamine 1 and N-methyl- and N-benzyl-substituted monocyclic polyamines 2 and 3 was studied. Activity against both the acute and chronic phases of Chagas disease was considered. The compounds were more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, but 1 and 2 were especially effective, where cryptand 1 was the most active, particularly in the chronic phase. The activity results found for these compounds were complemented and discussed by considering their inhibitory effect on the iron superoxide dismutase enzyme of the parasite, the nature of the metabolites excreted after treatment, and the ultrastructural alterations produced. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug and that 1 and 2 exhibited lower levels of damage than 3.
authors.affiliation: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. msanchem@ugr.es
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
authors.forename: Laurent
authors.initials: L
authors.lastname: Lamarque
authors.forename: Enrique
authors.initials: E
authors.lastname: García-España
authors.forename: Carlos
authors.initials: C
authors.lastname: Miranda
authors.forename: Oscar
authors.initials: O
authors.lastname: Huertas
authors.forename: Francisco
authors.initials: F
authors.lastname: Olmo
authors.forename: Fernando
authors.initials: F
authors.lastname: Gómez-Contreras
authors.forename: Javier
authors.initials: J
authors.lastname: Pitarch
authors.forename: Francisco
authors.initials: F
authors.lastname: Arrebola
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008099:Liver / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology; D014709:Vero Cells
chemical_list: D004791:Enzyme Inhibitors; D011073:Polyamines; D011720:Pyrazoles; D014344:Trypanocidal Agents; D013482:Superoxide Dismutase