A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum.
A class of hybrid molecules which we term 'reversed chloroquines' (RCQs) was designed, and a prototype molecule, N'-(7-chloroquinolin-4-yl)-N-[3-(10,11-dihydrodibenzo[b,f]azepin-5-yl)propyl]-N-methylpropane-1,3-diamine (1), was synthesized and tested against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. An in vitro assay against the two strains indicated that 1 was effective at low-nM concentrations against both strains. A preliminary study in mice demonstrated oral efficacy against P. chabaudi and the absence of obvious toxicity. The RCQ approach therefore appears to be feasible.
Burgess
Steven J
SJ
Department of Chemistry, Portland State University, P.O. Box 751, Portland, Oregon 97207-0751, USA.
Selzer
Audrey
A
Kelly
Jane Xu
JX
Smilkstein
Martin J
MJ
Riscoe
Michael K
MK
Peyton
David H
DH
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003984:Dibenzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D016788:Plasmodium chabaudi; D010963:Plasmodium falciparum / Q000187:drug effects*
D000962:Antimalarials; D003984:Dibenzazepines; C514071:N'-(7-chloroquinolin-4-yl)-N-(3-(10,11-dihydrodibenzo(b,f)azepin-5-yl)propyl)-N-methylpropane-1,3-diamine; D002738:Chloroquine