title: Aryl- or heteroaryl-based hydrazinylphthalazine derivatives as new potential antitrypanosomal agents.
abstract: A series of twenty phthalazinyl-hydrazones were synthesized and tested as potential anti-Trypanosoma cruzi agents. The phthalazines containing 5-nitroheteroaryl moiety 3l and 3m displayed an excellent in vitro antitrypanosomal profile, exhibiting low micromolar EC50values against proliferative epimastigote of T. cruzi and minimal toxicity toward Vero cells. These derivatives were more potent than the reference drug benznidazole against the epimastigote stage of the parasite. Structure-property analysis indicates that the highly conjugated 5-nitroheteroaryl moiety connected to the phthalazin scaffold play an important role in the antichagasic activity of these phthalazines. The decrease on the mitochondrial dehydrogenase activity and significant ROS production found for the parasites treated with 3l and 3m suggest that both nitro-derivatives can act through an oxidative stress mechanism.
authors.affiliation: Laboratorio de Química Medicinal y Heterociclos, Departamento de Química, Universidad Simón Bolívar, Valle de Sartenejas, Baruta, Caracas 1080-A, Venezuela. Electronic address: angel.romero12@ucv.ve.
authors.forename: Angel H
authors.initials: AH
authors.lastname: Romero
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rodríguez
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Yael
authors.initials: Y
authors.lastname: García-Marchan
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Jacques
authors.initials: J
authors.lastname: Leañez
authors.affiliation: Laboratorio de Biología y Quimioterapia de Parasitosis Tropicales, Área de Salud, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Xenón
authors.initials: X
authors.lastname: Serrano-Martín
authors.affiliation: Laboratorio de Química Medicinal y Heterociclos, Departamento de Química, Universidad Simón Bolívar, Valle de Sartenejas, Baruta, Caracas 1080-A, Venezuela. Electronic address: slopez@usb.ve.
authors.forename: Simón E
authors.initials: SE
authors.lastname: López
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D010793:Phthalazines; C043388:phthalazine
keywords: Epimastigotes; Mitochondrial dehydrogenase; Nitroheterocycle; Phthalazine; Trypanosoma cruzi