title: In vitro leishmanicidal activity of pyrazole-containing polyamine macrocycles which inhibit the Fe-SOD enzyme of Leishmania infantum and Leishmania braziliensis species.
abstract: The in vitro leishmanicidal activity and cytotoxicity of pyrazole-containing macrocyclic polyamines 1-4 was assayed on Leishmania infantum and Leishmania braziliensis species. Compounds 1-4 were more active and less toxic than glucantime and both infection rates and ultrastructural alterations confirmed that 1 and 2 were highly leishmanicidal and induced extensive parasite cell damage. Modifications in the excretion products of parasites treated with 1-3 were also consistent with substantial cytoplasm alterations. Compound 2 was highlighted as a potent inhibitor of Fe-SOD in both species, whereas its effect on human CuZn-SOD was poor. Molecular modelling suggested that 2 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the enzyme`s antioxidant features.
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: M
authors.initials: M
authors.lastname: Sánchez-Moreno
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 Química Inorgánica,Instituto de Ciencia Molecular, Universidad de Valencia,E-46980 Paterna (Valencia),Spain.
authors.forename: E
authors.initials: E
authors.lastname: García-España
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: F
authors.initials: F
authors.lastname: Olmo
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: F
authors.initials: F
authors.lastname: Gómez-Contreras
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
authors.affiliation: Departamento de Estadística. Facultad de Ciencias,Universidad de Granada,E-18071 Granada,Spain.
authors.forename: R
authors.initials: R
authors.lastname: Gutierrez-Sánchez
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006801:Humans; D007892:Leishmania braziliensis / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D018314:Leishmania infantum / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology; D015800:Protozoan Proteins / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D047028:Macrocyclic Compounds; D011073:Polyamines; D015800:Protozoan Proteins; D011720:Pyrazoles; C031280:pyrazole; D013482:Superoxide Dismutase