title: Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N,C-coupled arylisoquinolinium salts.
abstract: Alternative drugs against leishmaniasis are desperately needed. Antimonials, the main chemotherapeutic tool, cause serious side effects and promote chemoresistance. We previously demonstrated that representatives of N,C-linked arylisoquinolines are promising leishmanicidal drug candidates. We now performed structure-activity relationship studies varying the aryl portion of our lead substrate. The new series of compounds show an enhanced selectivity against Leishmania major in comparison to their major host cell, the macrophage. Our results suggest that the arylisoquinolinium salts decrease the macrophage infection rate acting directly on the intracellular parasites. However, the activity of the 4'-i-propyl derivative might also involve the modulation of cytokine and nitric oxide production by host macrophages. Additionally, this isoquinoline acts synergistically with amphotericin B and does not interact with drug-metabolizing cytochrome P450 enzymes involved in the metabolism of antileishmanial drugs. The results demonstrate that the newly synthesized structurally simplified N,C-coupled arylisoquinolinium salts are promising candidates to be considered as leishmanicidal pharmacophores.
authors.affiliation: Institute of Molecular Infection Biology, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
authors.forename: Tanja
authors.initials: T
authors.lastname: Gulder
authors.forename: Annemarie
authors.initials: A
authors.lastname: Wegehaupt
authors.forename: Christoph
authors.initials: C
authors.lastname: Albert
authors.forename: Carina
authors.initials: C
authors.lastname: Rikanović
authors.forename: Leonhard
authors.initials: L
authors.lastname: Schaeflein
authors.forename: Andreas
authors.initials: A
authors.lastname: Frank
authors.forename: Martina
authors.initials: M
authors.lastname: Schultheis
authors.forename: Matthias
authors.initials: M
authors.lastname: Unger
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D018320:Leishmania major / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007546:Isoquinolines; D000666:Amphotericin B