title: Phthalazine derivatives containing imidazole rings behave as Fe-SOD inhibitors and show remarkable anti-T. cruzi activity in immunodeficient-mouse mode of infection.
abstract: A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.
authors.affiliation: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. msanchem@ugr.es
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
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: Francisco
authors.initials: F
authors.lastname: Olmo
authors.forename: María J R
authors.initials: MJ
authors.lastname: Yunta
authors.forename: Ana María
authors.initials: AM
authors.lastname: Sanz
authors.forename: María José
authors.initials: MJ
authors.lastname: Rosales
authors.forename: Carmen
authors.initials: C
authors.lastname: Cano
authors.forename: Lucrecia
authors.initials: L
authors.lastname: Campayo
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D002522:Chlorocebus aethiops; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D018512:Parasitemia / Q000209:etiology / Q000517:prevention & control*; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014709:Vero Cells
chemical_list: C577945:1,4-bis(2-(imidazol-4-yl)ethylamino)phthalazine; C577947:1,4-bis(3-(imidazol-1-yl)propylamino)phthalazine; C577946:1-(3-(imidazol-1-yl)propylamino)-4-chlorophthalazine; D007093:Imidazoles; D010793:Phthalazines; D014344:Trypanocidal Agents; C043388:phthalazine; D013482:Superoxide Dismutase