8-Aminoquinolines active against blood stage Plasmodium falciparum in vitro inhibit hematin polymerization.
From the Walter Reed Army Institute of Research (WRAIR) inventory, thirteen 8-aminoquinoline analogs of primaquine were selected for screening against a panel of seven Plasmodium falciparum clones and isolates. Six of the 13 8-aminoquinolines had average 50% inhibitory concentrations between 50 and 100 nM against these P. falciparum clones and were thus an order of magnitude more potent than primaquine. However, excluding chloroquine-resistant clones and isolates, these 8-aminoquinolines were all an order of magnitude less potent than chloroquine. None of the 8-aminoquinolines was cross resistant with either chloroquine or mefloquine. In contrast to the inactive primaquine prototype, 8 of the 13 8-aminoquinolines inhibited hematin polymerization more efficiently than did chloroquine. Although alkoxy or aryloxy substituents at position 5 uniquely endowed these 13 8-aminoquinolines with impressive schizontocidal activity, the structural specificity of inhibition of both parasite growth and hematin polymerization was low.
Vennerstrom
J L
JL
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha 68198-6025. jvenners@mail.unmc.edu
Nuzum
E O
EO
Miller
R E
RE
Dorn
A
A
Gerena
L
L
Dande
P A
PA
Ellis
W Y
WY
Ridley
R G
RG
Milhous
W K
WK
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015767:Mefloquine / Q000494:pharmacology; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*
D000962:Antimalarials; D011804:Quinolines; D006427:Hemin; D002738:Chloroquine; D015767:Mefloquine