Aminoquinolines that circumvent resistance in Plasmodium falciparum in vitro.
Aminoquinoline (AQ) resistance is one of the most important factors in the worldwide resurgence of malaria due to Plasmodium falciparum. We synthesized a series of AQs to define the structure-activity relationships responsible for AQ action against chloroquine-susceptible and -resistant P. falciparum. The AQs with ethyl, propyl, isopropyl, butyl, pentyl, isopentyl (chloroquine), hexyl, octyl, decyl, or dodecyl side chains were equally active against chloroquine-susceptible P. falciparum (50% inhibitory concentrations [IC50s] = 5-15 nM). The AQs with ethyl, propyl, isopropyl, decyl, or dodecyl side chains were also active against chloroquine-, mefloquine- and multiply-resistant P. falciparum (IC50s = 5-20 nM). Verapamil, which enhances the activity of chloroquine against chloroquine-resistant parasites, had no effect on the activity of AQs that were active against resistant parasites. These results indicate that AQs with 2-12 carbon side chains are as active as chloroquine against chloroquine-susceptible P. falciparum, and that AQs with side chains shorter or longer than chloroquine are often active against chloroquine-, mefloquine-, and multiply-resistant P. falciparum.
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Department of Tropical Medicine, Tulane University, New Orleans, Louisiana, USA.
Krogstad
F M
FM
Cogswell
F B
FB
Krogstad
D J
DJ
D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology
D000634:Aminoquinolines; D000962:Antimalarials; D002121:Calcium Channel Blockers; D014700:Verapamil