ContrastingEx VivoEfficacies of “Reversed Chloroquine” Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates
Wirjanata G., Sebayang BF., Chalfein F., Prayoga None., Handayuni I., Noviyanti R., Kenangalem E., Poespoprodjo JR., Burgess SJ., Peyton DH., Price RN., Marfurt J.
<jats:title>ABSTRACT</jats:title><jats:p>Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance<jats:italic>ex vivo</jats:italic>. Between March to October 2011 and January to September 2013, two “reversed chloroquine” (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content>(<jats:italic>n</jats:italic>= 41) and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium vivax</jats:named-content>(<jats:italic>n</jats:italic>= 45) in Papua, Indonesia, using a modified<jats:italic>ex vivo</jats:italic>schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>field isolates. For<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>, the median 50% inhibitory concentrations (IC<jats:sub>50</jats:sub>s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (<jats:italic>P</jats:italic>< 0.001 and<jats:italic>P</jats:italic>= 0.036, respectively). The corresponding values for<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>were 19.0, 60.0, and 60.9 nM (<jats:italic>P</jats:italic>< 0.001 and<jats:italic>P</jats:italic>= 0.018, respectively). There was a significant correlation between IC<jats:sub>50</jats:sub>s of CQ and PL69 (Spearman's rank correlation coefficient [<jats:italic>r</jats:italic><jats:sub>s</jats:sub>] = 0.727,<jats:italic>P</jats:italic>< 0.001) and PL106 (<jats:italic>r<jats:sub>s</jats:sub></jats:italic>= 0.830,<jats:italic>P</jats:italic>< 0.001) in<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>but not in<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>. Both RCQs were equally active against the ring and trophozoite stages of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>, but in<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>, PL69 and PL106 showed less potent activity against trophozoite stages (median IC<jats:sub>50</jats:sub>s, 130.2 and 172.5 nM) compared to ring stages (median IC<jats:sub>50</jats:sub>s, 17.6 and 91.3 nM). RCQ compounds have enhanced<jats:italic>ex vivo</jats:italic>activity against CQ-resistant clinical isolates of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium</jats:named-content>species.</jats:p>