title: Synthesis and evaluation of in vitro and in vivo trypanocidal properties of a new imidazole-containing nitrophthalazine derivative.
abstract: A series of new phthalazine derivatives (1-4) containing imidazole rings and functionalized with nitro groups in the benzene ring of the phthalazine moiety were prepared and identified on the basis of their MS, elemental analyses and bidimensional (1)H and (13)C NMR data, and their trypanocidal activity was tested. The 8-nitrosubstituted compound (3) was more active in vitro against Trypanosoma cruzi and less toxic against Vero cells than the reference drug benznidazole, and showed a SI value that was 47-fold better than the reference drug in amastigote forms. It also remarkably reduced the infectivity rate in Vero cells and decreased the reactivation of parasitemia in immunodeficient mice. Ultrastructural alterations found in epimastigotes treated with 3 confirmed extensive cytoplasm destruction in the parasites, whereas histopathological analysis of the hearts of mice infected and treated with 3 resulted in a decrease in cardiac damage. Biochemical markers showed that livers, hearts, and kidneys of treated mice were substantially unaffected by the administration of 3, despite the presence of the potentially toxic nitro group. It was also found that this compound selectively inhibited the antioxidant parasite enzyme Fe-superoxide dismutase (Fe-SOD) in comparison with human CuZn-SOD, and molecular modeling suggested interaction with the H-bonding system of the iron-based moiety as a feasible mechanism of action against the enzyme.
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria, Hospitales Universitarios de Granada, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Olmo
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain. Electronic address: fercon@ucm.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Gómez-Contreras
authors.affiliation: Instituto de Química Médica, Centro de Química Orgánica M. Lora-Tamayo, CSIC, E-28006 Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria, Hospitales Universitarios de Granada, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain.
authors.forename: María J R
authors.initials: MJ
authors.lastname: Yunta
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cano
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain.
authors.forename: Lucrecia
authors.initials: L
authors.lastname: Campayo
authors.affiliation: Departamento de Biología Celular, Facultad de Ciencias, Universidad de Granada, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Martín-Oliva
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria, Hospitales Universitarios de Granada, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Rosales
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria, Hospitales Universitarios de Granada, Universidad de Granada, E-18071 Granada, Spain. Electronic address: msanchem@ugr.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology; D014709:Vero Cells
chemical_list: C000610703:1-(2-(imidazol-4-yl)ethylamino)-4-chloro-8-nitrophthalazine; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010793:Phthalazines; D014344:Trypanocidal Agents; C029899:imidazole; D013482:Superoxide Dismutase
keywords: Alkylaminonitrophthalazines; Chagas acute and chronic phases; Fe–SOD inhibition; Histopathological analysis; Imidazole; Trypanocidal activity