title: 4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum.
abstract: We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.
authors.affiliation: Pharma Division, F. Hoffmann-La Roche, Ltd., Basel, Switzerland. robert_g.ridley@roche.com
authors.forename: R G
authors.initials: RG
authors.lastname: Ridley
authors.forename: W
authors.initials: W
authors.lastname: Hofheinz
authors.forename: H
authors.initials: H
authors.lastname: Matile
authors.forename: C
authors.initials: C
authors.lastname: Jaquet
authors.forename: A
authors.initials: A
authors.lastname: Dorn
authors.forename: R
authors.initials: R
authors.lastname: Masciadri
authors.forename: S
authors.initials: S
authors.lastname: Jolidon
authors.forename: W F
authors.initials: WF
authors.lastname: Richter
authors.forename: A
authors.initials: A
authors.lastname: Guenzi
authors.forename: M A
authors.initials: MA
authors.lastname: Girometta
authors.forename: H
authors.initials: H
authors.lastname: Urwyler
authors.forename: W
authors.initials: W
authors.lastname: Huber
authors.forename: S
authors.initials: S
authors.lastname: Thaithong
authors.forename: W
authors.initials: W
authors.lastname: Peters
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002738:Chloroquine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D010967:Plasmodium yoelii / Q000187:drug effects; D051381:Rats; D013047:Specific Pathogen-Free Organisms
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D002738:Chloroquine; C001920:4-aminoquinoline