Synthesis and antiplasmodial activity of new N-[3-(4-{3-[(7-chloroquinolin-4-yl)amino]propyl}piperazin-1-yl)propyl]carboxamides.
The parallel acylation of N-{3-[4-(3-aminopropyl)piperazin-1-yl]propyl}-7-chloroquinolin-4-amine with polymer-bound carboxylic acids opened straightforward access to novel aminoquinolines with activity against Plasmodium falciparum strains in vitro. Using this amino scaffold prepared in solution and polymer-bound carboxylic, we have synthesized a series of 29 new compounds in good to excellent yield and purity. Biological evaluation included determination of the activity against a chloroquine (CQ) sensitive strain and a CQ resistant mutant. Most of the novel structures presented here displayed activity against both strains in the lower nanomolar range, four compounds showed an at least fourfold increase in the ratio of inhibition of CQ resistant to sensitive strains over CQ itself. These results suggest that this derivatization technique is a useful method to speed up structure-activity relationship studies on aminoquinolines toward improved activity versus CQ resistant strains of P. falciparum in vitro.
Freitag
Marcus
M
Institute of Pharmacy, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Strasse 17, 17487 Greifswald, Germany.
Kaiser
Marcel
M
Larsen
Tim
T
Zohrabi-Kalantari
Vida
V
Heidler
Philipp
P
Link
Andreas
A
D000215:Acylation; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D002855:Chromatography, Thin Layer; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
D000962:Antimalarials; D007202:Indicators and Reagents; D010879:Piperazines; D002738:Chloroquine