Olmo, FranciscoUrbanová, KristínaRosales, Maria JoseMartín-Escolano, RubenSánchez-Moreno, ManuelMarín, Clotilde2016-01-142016-01-142015-06-20Olmo F, Urbanová K, Rosales MJ, Martín-Escolano R, Sánchez-Moreno M, Marín C. An in vitro iron superoxide dismutase inhibitor decreases the parasitemia levels of Trypanosoma cruzi in BALB/c mouse model during acute phase. Int J Parasitol Drugs Drug Resist. 2015 ; 5(3):110-6http://hdl.handle.net/10668/2129Journal Article;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.enAnti-chagasicChemotherapyTrypanosomiasisHydroxyphthalazine derivativesAntiparasitariosEnfermedad de chagasCitometría de flujoConcentración 50 inhibidoraImagen por resonancia magnéticaRatones consanguíneos BALB CMicroscopíaParásitosCélulas veroMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiparasitic AgentsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Cercopithecidae::Cercopithecinae::Cercopithecus::Cercopithecus aethiopsMedical Subject Headings::Diseases::Parasitic Diseases::Protozoan Infections::Euglenozoa Infections::Trypanosomiasis::Chagas DiseaseMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cell Separation::Flow CytometryMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Magnetic Resonance ImagingMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred BALB CMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::MicroscopyMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Nitro Compounds::NitroimidazolesMedical Subject Headings::Diseases::Parasitic Diseases::ParasitemiaMedical Subject Headings::Organisms::Eukaryota::Animals::Invertebrates::ParasitesMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Superoxide DismutaseMedical Subject Headings::Organisms::Eukaryota::Euglenozoa::Kinetoplastida::Trypanosomatina::Trypanosoma::Trypanosoma cruziMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Vero Cellsresearch article26236582open access10.1016/j.ijpddr.2015.05.0022211-3207PMC4501536