title: Imidazole-containing phthalazine derivatives inhibit Fe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis.
abstract: The in vitro leishmanicidal activity of a series of imidazole-containing phthalazine derivatives 1-4 was tested on Leishmania infantum, Leishmania braziliensis and Leishmania donovani parasites, and their cytotoxicity on J774·2 macrophage cells was also measured. All compounds tested showed selectivity indexes higher than that of the reference drug glucantime for the three Leishmania species, and the less bulky monoalkylamino substituted derivatives 2 and 4 were clearly more effective than their bisalkylamino substituted counterparts 1 and 3. Both infection rate measures and ultrastructural alterations studies confirmed that 2 and 4 were highly leishmanicidal and induced extensive parasite cell damage. Modifications to the excretion products of parasites treated with 2 and 4 were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds 2 and 4 were potent inhibitors of iron superoxide dismutase enzyme (Fe-SOD) in the three species considered, whereas their impact on human CuZn-SOD was low. Molecular modelling suggests that 2 and 4 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the antioxidant features of the enzyme.
authors.affiliation: Departamento de Parasitología,Facultad de Ciencias,Universidad de Granada,E-18071 Granada,Spain.
authors.forename: M
authors.initials: M
authors.lastname: Sánchez-Moreno
authors.affiliation: Departamento de Química Orgánica,Facultad de Química,Universidad Complutense,E-28040 Madrid,Spain.
authors.forename: F
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: P
authors.initials: P
authors.lastname: Navarro
authors.affiliation: Departamento de Parasitología,Facultad de Ciencias,Universidad de Granada,E-18071 Granada,Spain.
authors.forename: C
authors.initials: C
authors.lastname: Marín
authors.affiliation: Departamento de Parasitología,Facultad de Ciencias,Universidad de Granada,E-18071 Granada,Spain.
authors.forename: I
authors.initials: I
authors.lastname: Ramírez-Macías
authors.affiliation: Departamento de Parasitología,Facultad de Ciencias,Universidad de Granada,E-18071 Granada,Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Rosales
authors.affiliation: Departamento de Química Orgánica,Facultad de Química,Universidad Complutense,E-28040 Madrid,Spain.
authors.forename: L
authors.initials: L
authors.lastname: Campayo
authors.affiliation: Departamento de Química Orgánica,Facultad de Química,Universidad Complutense,E-28040 Madrid,Spain.
authors.forename: C
authors.initials: C
authors.lastname: Cano
authors.affiliation: Departamento de Química Orgánica,Facultad de Química,Universidad Complutense,E-28040 Madrid,Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Sanz
authors.affiliation: Departamento de Química Orgánica,Facultad de Química,Universidad Complutense,E-28040 Madrid,Spain.
authors.forename: M J R
authors.initials: MJ
authors.lastname: Yunta
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology; D007892:Leishmania braziliensis / Q000187:drug effects / Q000201:enzymology; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology; D018314:Leishmania infantum / Q000187:drug effects / Q000201:enzymology; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D008264:Macrophages; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D010793:Phthalazines / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D010793:Phthalazines; C029899:imidazole; C043388:phthalazine; D013482:Superoxide Dismutase
keywords: Leishmania braziliensis; Leishmania donovani; Leishmania infantum; imidazole; iron superoxide dismutase; phthalazine derivatives