title: In vitro leishmanicidal activity of 1,3-disubstituted 5-nitroindazoles.
abstract: The antiprotozoal activity of some indazole-derived amines (2, 3, 5-8) as well as that of some simple structurally related 3-alkoxy-1-alkyl-5-nitroindazoles (1, 4) against promastigote and amastigote forms of Leishmania infantum and Leishmania braziliensis is reported. In some cases, these compounds showed in vitro activities against the different morphological forms of Leishmania similar to or higher than those of the reference drug glucantime; this fact, along with low unspecific cytotoxicities against macrophages shown by some of them, led to good selectivity indexes (SI). The high efficiency of some 5-nitroindazoles against the mentioned protozoa was confirmed by further in vitro studies on infection rates. Complementary analyses by (1)H NMR of the changes on the metabolites excreted by parasites after treatment with the more active indazole derivatives in many cases showed the decreased excretion of succinate and increased levels of acetate, lactate and alanine, as well as, in some cases, the appearance of glycine and pyruvate as new metabolites. Damage caused by indazoles at the glycosomal or mitochondrial level are consistent with these metabolic changes as well as with the huge ultrastructural alterations observed by transmission electron microscopy (TEM), especially affecting the mitochondria and other cytoplasmic organelles.
authors.affiliation: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.affiliation: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ramírez-Macías
authors.affiliation: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Rosales
authors.affiliation: Instituto de Química Médica (IQM), CSIC, c/Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Muro
authors.affiliation: Instituto de Química Médica (IQM), CSIC, c/Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Reviriego
authors.affiliation: Instituto de Química Médica (IQM), CSIC, c/Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
authors.affiliation: Instituto de Química Médica (IQM), CSIC, c/Juan de la Cierva 3, E-28006 Madrid, Spain. Electronic address: vjaran@iqm.csic.es.
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
authors.affiliation: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. Electronic address: msanchem@ugr.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
mesh_terms: D000085:Acetates / Q000378:metabolism; D000409:Alanine / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism; D066298:In Vitro Techniques; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D007892:Leishmania braziliensis / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018314:Leishmania infantum / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007898:Leishmaniasis, Visceral; D008264:Macrophages / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D015388:Organelles / Q000187:drug effects / Q000648:ultrastructure; D019289:Pyruvic Acid / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D000085:Acetates; D000981:Antiprotozoal Agents; D007191:Indazoles; C530840:5-nitroindazole; D019344:Lactic Acid; D019289:Pyruvic Acid; D019802:Succinic Acid; D000409:Alanine; D005998:Glycine
keywords: Cytotoxicity; In vitro assay; Leishmania; Metabolite excretion; Nitroindazole; Ultrastructural alteration