title: In vitro activity of C20-diterpenoid alkaloid derivatives in promastigotes and intracellular amastigotes of Leishmania infantum.
abstract: The in vitro anti-proliferative effects are described of several atisine-type diterpenoid alkaloids against the protozoan parasite Leishmania infantum, which causes human visceral leishmaniasis and canine leishmaniasis in the Mediterranean basin, as well as human cutaneous leishmaniasis throughout the Mediterranean region. From a total of 43 compounds tested, including C19- and C20-diterpene alkaloids from several chemical classes, only 15,22-O-diacetyl-19-oxo-dihydroatisine, azitine and isoazitine were highly active against cultures of the parasite (promastigote form) with IC50 values within the range of the reference drug pentamidine-isothionate (7.39-12.80 mg/L for the test compounds, 11.32 mg/L for the positive control). These compounds were not toxic to the host cell. When treated with a dosage of 5 microg/mL of the active compounds (half of their IC50), the promastigote forms lost 80% of their infection capacity and the multiplication of extracellular forms of L. infantum was severely affected. The study showed that atisine-type C20-diterpenoid alkaloids exhibited promising anti-leishmanial properties with strong molecular selectivity. These might have implications for other intracellular pathogens- or phylogenetically related parasites, such as Trypanosoma spp.
authors.affiliation: Departamento de Parasitología, Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, C/ Severo Ochoa s/n, 18071 Granada, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: González
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez-González
authors.forename: Ana B
authors.initials: AB
authors.lastname: Hitos
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Rosales
authors.forename: Matías
authors.initials: M
authors.lastname: Reina
authors.forename: Jesús G
authors.initials: JG
authors.lastname: Díaz
authors.forename: Azucena
authors.initials: A
authors.lastname: González-Coloma
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002460:Cell Line; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development* / Q000648:ultrastructure; D007898:Leishmaniasis, Visceral / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D021261:Parasitic Sensitivity Tests; D051381:Rats
chemical_list: D000470:Alkaloids; D000981:Antiprotozoal Agents; D004224:Diterpenes; C414609:isoazitine