Zishiri, Vincent KJoshi, Mukesh CHunter, RogerChibale, KellySmith, Peter J.Summers, RobertMartin, RowenaEgan, Timothy J.2015-12-100022-2623http://hdl.handle.net/1885/51809A 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.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; ani201110.1021/jm20096982016-02-24