title: New potent 5-nitroindazole derivatives as inhibitors of Trypanosoma cruzi growth: synthesis, biological evaluation, and mechanism of action studies.
abstract: New 5-nitroindazole derivatives were developed and their antichagasic properties studied. Eight compounds (14-18, 20, 26 and 28) displayed remarkable in vitro activities against Trypanosoma cruzi (T. cruzi). Its unspecific cytotoxicity against macrophages was evaluated being not toxic at a concentration at least twice that of T. cruzi IC(50), for some derivatives. The electrochemical studies, parasite respiration studies and ESR experiment showed that 5-nitroindazole derivatives not be able to yield a redox cycling with molecular oxygen such as occurs with nifurtimox (Nfx). The study on the mechanism of action proves to be related to the production of reduced species of the nitro moiety similar to that observed with benznidazole.
authors.affiliation: Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Chile.
authors.forename: Jorge
authors.initials: J
authors.lastname: Rodríguez
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
authors.forename: Lucía
authors.initials: L
authors.lastname: Boiani
authors.forename: Claudio
authors.initials: C
authors.lastname: Olea-Azar
authors.forename: María Laura
authors.initials: ML
authors.lastname: Lavaggi
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Juan Diego
authors.initials: JD
authors.lastname: Maya
authors.forename: Catalina
authors.initials: C
authors.lastname: Carrasco-Pozo
authors.forename: Hernán Speisky
authors.initials: HS
authors.lastname: Cosoy
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy* / Q000235:genetics; D018360:Crystallography, X-Ray; D016054:DNA, Protozoan / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000493:pharmacokinetics / Q000506:poisoning*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D016054:DNA, Protozoan; D007191:Indazoles; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C530840:5-nitroindazole; C009999:benzonidazole