title: In vivo trypanosomicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against acute and chronic phases of Chagas disease.
abstract: The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 and of the new related pyrazole-based compounds 5 and 6 has been studied in both the acute and chronic phases of Chagas disease. As a rule, compounds 1-6 were more active and less toxic than benznidazole in the two stages of the disease, and the monosubstituted derivatives 2, 4, and 6 were more effective than their disubstituted analogs. Feasible mechanisms of action of compounds 1-6 against the parasite have been explored by considering their inhibitory effect on the Fe-SOD enzyme, the nature of the excreted metabolites and the ultrastructural alterations produced. A complementary histopathological analysis has confirmed that the monosubstituted derivatives are less toxic than the reference drug, with the behavior of the imidazole-based compound 4 being especially noteworthy.
authors.affiliation: Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain. msanchem@ugr.es
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sanz
authors.forename: Fernando
authors.initials: F
authors.lastname: Gómez-Contreras
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ramírez-Macias
authors.forename: María Jose
authors.initials: MJ
authors.lastname: Rosales
authors.forename: Francisco
authors.initials: F
authors.lastname: Olmo
authors.forename: Isabel
authors.initials: I
authors.lastname: Garcia-Aranda
authors.forename: Lucrecia
authors.initials: L
authors.lastname: Campayo
authors.forename: Carmen
authors.initials: C
authors.lastname: Cano
authors.forename: Francisco
authors.initials: F
authors.lastname: Arrebola
authors.forename: María J R
authors.initials: MJ
authors.lastname: Yunta
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D002522:Chlorocebus aethiops; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D046529:Microscopy, Electron, Transmission; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000648:ultrastructure; D014709:Vero Cells
chemical_list: D007093:Imidazoles; D010793:Phthalazines; D011720:Pyrazoles; D014344:Trypanocidal Agents; D013482:Superoxide Dismutase