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)

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2009698

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.