title: Activities of naphthylisoquinoline alkaloids and synthetic analogs against Leishmania major.
abstract: The current treatments for leishmaniasis are unsatisfactory due to their toxic side effects, high costs, and increasing problems with drug resistance. Thus, there is an urgent need for alternative drugs against leishmaniasis. Different approaches have been used to identify novel pharmacophores against Leishmania sp. parasites, and one strategy has been the analysis of naturally occurring plant-derived compounds, including naphthylisoquinoline alkaloids. In the present study, we examined the abilities of these alkaloids to inhibit the growth of Leishmania major promastigotes and evaluated their effects on macrophages, dendritic cells, and fibroblasts. Furthermore, we determined the efficacy of selected compounds in decreasing the infection rate of macrophages and regulating their production of cytokines and nitric oxide. Our results demonstrate that the naphthylisoquinoline alkaloids ancistrocladiniums A and B (compounds 10 and 11) and the synthetic isoquinolinium salt (compound 14) were effective against intracellular amastigotes in the low submicromolar range, while toxicity against mammalian cells was observed at concentrations that were significantly higher than those needed to impair parasite replication. The activities of compounds 11 and 14 were mainly directed against the amastigote stage of L. major. This effect was not associated with the stimulation of host macrophages to produce nitric oxide or secrete cytokines relevant for the leishmanicidal function. In conclusion, our data suggest that ancistrocladiniums A and B (compounds 10 and 11) and the synthetically prepared isoquinolinium salt (compound 14) are promising candidates to be considered as lead compounds for leishmanicidal drugs.
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
authors.forename: Johan H
authors.initials: JH
authors.lastname: Faber
authors.forename: Tanja
authors.initials: T
authors.lastname: Gulder
authors.forename: Inga
authors.initials: I
authors.lastname: Kajahn
authors.forename: Sarah E H
authors.initials: SE
authors.lastname: Pedersen
authors.forename: Martina
authors.initials: M
authors.lastname: Schultheis
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018320:Leishmania major / Q000187:drug effects* / Q000469:parasitology; D007896:Leishmaniasis / Q000188:drug therapy / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009569:Nitric Oxide / Q000378:metabolism; D021261:Parasitic Sensitivity Tests
chemical_list: D000470:Alkaloids; D000981:Antiprotozoal Agents; D016207:Cytokines; D007546:Isoquinolines; D009569:Nitric Oxide