Synthesis and antileishmanial activities of 4,5-di-substituted acridines as compared to their 4-mono-substituted homologues.
Newly synthesized 4,5-di-substituted acridines were assessed for in vitro antileishmanial activities as compared to those of their 4-mono-substituted homologues. Mono-substituted acridines exhibited a weak specificity for Leishmania parasites. Di-substituted acridines, on the contrary, displayed interesting amastigote-specific activities through a mechanism of action that might not involve intercalation to DNA. This antileishmanial property, associated with a low antiproliferative activity towards human cells, led to the identification of a new class of promising acridine derivatives such as 4,5-bis(hydroxymethyl)acridine with a nonclassical mechanism of action based on the inhibition of Leishmania internalization within macrophages. In the meantime, the effects of experimental lighting on the biological properties of acridines were assessed: experimental lighting did not significantly improve the antileishmanial activity of the compounds since it produced a greater toxicity against human cells.
Carole
Di Giorgio
DG
Laboratoire de Parasitologie, Hygiène et Zoologie, Faculté de Pharmacie, 27 Bd. Jean Moulin, 13385 Marseille Cedex 05, France. carole.digiorgio@pharmacie.univ-mrs.fr
Michel
De Méo
DM
Julien
Chiron
C
Florence
Delmas
D
Anna
Nikoyan
N
Séverine
Jean
J
Gérard
Dumenil
D
Pierre
Timon-David
TD
Jean-Pierre
Galy
G
D000166:Acridines / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D013045:Species Specificity
D000166:Acridines