title: An in vitro iron superoxide dismutase inhibitor decreases the parasitemia levels of Trypanosoma cruzi in BALB/c mouse model during acute phase.
abstract: In order to identify new compounds to treat Chagas disease during the acute phase with higher activity and lower toxicity than the reference drug benznidazole (Bz), two hydroxyphthalazine derivative compounds were prepared and their trypanocidal effects against Trypanosoma cruzi were evaluated by light microscopy through the determination of IC50 values. Cytotoxicity was determined by flow cytometry assays against Vero cells. In vivo assays were performed in BALB/c mice, in which the parasitemia levels were quantified by fresh blood examination; the assignment of a cure was determined by reactivation of blood parasitemia levels after immunosuppression. The mechanism of action was elucidated at metabolic and ultra-structural levels, by (1)H NMR and TEM studies. Finally, as these compounds are potentially capable of causing oxidative damage in the parasites, the study was completed, by assessing their activity as potential iron superoxide dismutase (Fe-SOD) inhibitors. High-selectivity indices observed in vitro were the basis of promoting one of the tested compounds to in vivo assays. The tests on the murine model for the acute phase of Chagas disease showed better parasitemia inhibition values than those found for Bz. Compound 2 induced a remarkable decrease in the reactivation of parasitemia after immunosuppression. Compound 2 turned out to be a great inhibitor of Fe-SOD. The high antiparasitic activity and low toxicity together with the modest costs for the starting materials render this compound an appropriate molecule for the development of an affordable anti-Chagas agent.
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Olmo
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Kristína
authors.initials: K
authors.lastname: Urbanová
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Rosales
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Martín-Escolano
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology*; D003520:Cyclophosphamide / Q000633:toxicity; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018512:Parasitemia / Q000188:drug therapy*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D007166:Immunosuppressive Agents; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D003520:Cyclophosphamide; D013482:Superoxide Dismutase; C009999:benzonidazole
keywords: Anti-chagasic; Chemotherapy; Hydroxyphthalazine derivatives; Trypanosomiasis