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.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha 68198-6025. jvenners@mail.unmc.edu
J L
JL
Vennerstrom
E O
EO
Nuzum
R E
RE
Miller
A
A
Dorn
L
L
Gerena
P A
PA
Dande
W Y
WY
Ellis
R G
RG
Ridley
W K
WK
Milhous
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