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)

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 compo...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-10, Vol.54 (19), p.6956-6968
Main Authors: Zishiri, Vincent K, Joshi, Mukesh C, Hunter, Roger, Chibale, Kelly, Smith, Peter J, Summers, Robert L, Martin, Rowena E, Egan, Timothy J
Format: Article
Language:English
Subjects:
Animals
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Biological Transport
Cell Survival - drug effects
Chloroquine - pharmacology
CHO Cells
Cricetinae
Cricetulus
Crystallography, X-Ray
Female
Malaria - drug therapy
Membrane Transport Proteins - metabolism
Mice
Molecular Structure
Oocytes - metabolism
Parasitemia - drug therapy
Parasitemia - parasitology
Parasitic Sensitivity Tests
Plasmodium berghei
Plasmodium falciparum - drug effects
Plasmodium falciparum - metabolism
Protozoan Proteins - antagonists & inhibitors
Protozoan Proteins - metabolism
Structure-Activity Relationship
Xenopus laevis
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Summary: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 parasiteʼs 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm2009698