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Título : Structure-Activity Relationship and Studies on the Molecular Mechanism of Leishmanicidal N,C-Coupled Arylisoquinolinium Salts
Autor : Ponte-Sucre, Alicia
Gulder, Tanja
Wegehaupt, Anne
Albert, Christian
Rikanović, Carina
Schaeflein, Leonhard
Frank, Andreas
Schultheis, Martina
Unger, Mathias
Holzgrabe, Ulrike
Bringmann, Gerhard
Moll, Heidrun
Palabras clave : N,C-coupled arylisoquinolinium salts
structure-activity relationship
Leishmania major
combination therapy
molecular mechanism
Fecha de publicación : 7-Aug-2012
Citación : Journal of Medicinal Chemistry;52:626-36, 2009
Resumen : 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.
ISSN : 0022-2623 1520-4804
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