title: Scorpiand-like azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model.
abstract: Chagas disease is today one of the most important neglected diseases for its upcoming expansion to non-endemic areas and has become a threat to blood recipients in many countries. In this study, the trypanocidal activity of ten derivatives of a family of aza-scorpiand like macrocycles is evaluated against Trypanosoma cruzi in vitro and in vivo murine model in which the acute and chronic phases of Chagas disease were analyzed. The compounds 4, 3 and 1 were found to be more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, 4 being the most active compound, particularly in the chronic phase. While all these compounds showed a remarkable degree of inhibition of the Fe-SOD enzyme of the epimastigote forms of T. cruzi, they produced a negligible inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli. The modifications observed by (1)H NMR and the amounts of excreted catabolites by the parasites after treatment suggested that the mechanism of action could be based on interactions of the side chains of the compounds with enzymes of the parasite metabolism. The ultrastructural alterations observed in treated epimastigote forms confirmed that the compounds having the highest activity are those causing the largest cell damage. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug.
authors.affiliation: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Olmo
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.forename: M Paz
authors.initials: MP
authors.lastname: Clares
authors.forename: Salvador
authors.initials: S
authors.lastname: Blasco
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Albelda
authors.forename: Conxa
authors.initials: C
authors.lastname: Soriano
authors.forename: Ramón
authors.initials: R
authors.lastname: Gutiérrez-Sánchez
authors.forename: Francisco
authors.initials: F
authors.lastname: Arrebola-Vargas
authors.forename: Enrique
authors.initials: E
authors.lastname: García-España
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002908:Chronic Disease / Q000517:prevention & control; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D006801:Humans; D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D014709:Vero Cells
chemical_list: D000981:Antiprotozoal Agents; D001372:Aza Compounds; D008024:Ligands; D047028:Macrocyclic Compounds; D013482:Superoxide Dismutase
keywords: In vivo activity; Synthetic aza-scorpiand; Trypanocidal activity; Trypanosoma cruzi