Antimalarial, antitrypanosomal, and antileishmanial activities and cytotoxicity of bis(9-amino-6-chloro-2-methoxyacridines): influence of the linker.
Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and tested for their in vitro activity upon the erythrocytic stage of Plasmodium falciparum, trypomastigote stage of Trypanosoma brucei, and amastigote stage of Trypanosoma cruzi and Leishmania infantum as well as for their cytotoxic effects upon MRC-5 cells. Results clearly showed the importance of the nature of the linker and of its side chain for antiparasitic activity, cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at 25 microM upon MRC-5 cells, one displayed IC(50) values ranging from 8 to 18 nM against different P. falciparum strains while three others totally inhibited T. brucei at 1.56 microM.
Girault
S
S
UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447, 59021 Lille, France.
Grellier
P
P
Berecibar
A
A
Maes
L
L
Mouray
E
E
Lemière
P
P
Debreu
M A
MA
Davioud-Charvet
E
E
Sergheraert
C
C
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018314:Leishmania infantum / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
D000166:Acridines; D000962:Antimalarials; D014344:Trypanocidal Agents