title: In vitro and in vivo activities of three acridine thioethers against Leishmania donovani.
abstract: The lack of definitive chemotherapeutic agents to fight against visceral leishmaniasis has lead to the testing of numerous compounds. In the present work, we carry out an in-depth study of the activity against Leishmania donovani of three acridine derivatives both in vitro and in vivo. These compounds have proven to be highly effective at medium and high concentrations of 10 microg/ml, against both flagellate and nonflagellate forms of the parasite, which, though obtained in vitro, closely resemble natural intracellular amastigotes. The in vivo assays showed a significant reduction in the percentage of parasitation versus control, for all the compounds tested. In addition, we have studied the possible mechanism by which these acridine derivatives act: they displayed a greater inhibitory effect against macromolecule synthesis in treated flagellates, yet alterations are also caused in the production of end metabolites and in the activity of different enzymes. The data obtained indicate that the acridine derivatives had several targets, one of them is the synthesis of nucleic acids and proteins, while the second one might be interaction with the carbohydrate and energy-production processes in the parasite. This conclusion is consistent with our observations concerning the ultrastructural changes induced in the parasite by these compounds principally at the mitochondrial level.
authors.affiliation: Departamento de Biología Aplicada, Facultad de Ciencias, Universidad de Almería, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Mesa
authors.forename: Nieves
authors.initials: N
authors.lastname: Rodriguez-Cabezas
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Castilla
authors.forename: Valentín
authors.initials: V
authors.lastname: Moraleda-Lindez
authors.forename: Jacques
authors.initials: J
authors.lastname: Barbe
authors.forename: Manuel
authors.initials: M
authors.lastname: Sanchez-Moreno
authors.forename: Antonio
authors.initials: A
authors.lastname: Osuna
mesh_terms: D000085:Acetates / Q000378:metabolism; D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D007930:Leucine / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008854:Microscopy, Electron; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000469:parasitology; D013329:Structure-Activity Relationship; D019802:Succinic Acid / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium; D014529:Uridine / Q000378:metabolism
chemical_list: D000085:Acetates; D000166:Acridines; D000981:Antiprotozoal Agents; C464848:BG-203; C464849:BG-237; C464847:BG-289; D011773:Pyruvates; D014316:Tritium; D019344:Lactic Acid; D000431:Ethanol; D019802:Succinic Acid; D007930:Leucine; D013936:Thymidine; D014529:Uridine