Quinoline Antimalarials Containing a Dibemethin Group are Active against Chloroquinone-Resistant Plasmodium falciparum and Inhibit Chloroquine Transport via the P. falciparum Chloroquine- Resistance Transporter (PfCRT)
Date
2011
Authors
Zishiri, Vincent K
Joshi, Mukesh C
Hunter, Roger
Chibale, Kelly
Smith, Peter J.
Summers, Robert
Martin, Rowena
Egan, Timothy J.
Journal Title
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Volume Title
Publisher
American Chemical Society
Abstract
A series of 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains were shown to inhibit synthetic hemozoin formation. These compounds were equally active against cultures of chloroquine-sensitive (D10) and chloroquine-resistant (K1) Plasmodium falciparum. The most active compound had an IC50 value comparable to that of chloroquine, and its potency was undiminished when tested in three additional chloroquine-resistant strains. The three most active compounds exhibited little or no cytotoxicity in a mammalian cell line. When tested in vivo against mouse malaria via oral administration, two of the dibemethin derivatives reduced parasitemia by over 99%, with mice treated at 100 mg/kg surviving the full length of the experiment. Three of the compounds were also shown to inhibit chloroquine transport via the parasite's chloroquine-resistance transporter (PfCRT) in a Xenopus oocyte expression system. This constitutes the first example of a dual-function antimalarial for which the ability to inhibit both hemozoin formation and PfCRT has been demonstrated directly.
Description
Keywords
Keywords: 4 amino 7 chloroquinoline derivative; antimalarial agent; chloroquine; dibemethin derivative; hemozoin; multidrug resistance protein; Plasmodium falciparum chloroquine resistance transporter; quinoline derivative; unclassified drug; animal experiment; ani
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Source
Journal of Medicinal Chemistry
Type
Journal article
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DOI
10.1021/jm2009698
Restricted until
2037-12-31