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<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>&lt; 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>&lt; 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>&lt; 0.001) and PL106 (<jats:italic>r<jats:sub>s</jats:sub></jats:italic>= 0.830,<jats:italic>P</jats:italic>&lt; 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>

Original publication

DOI

10.1128/aac.01048-15

Type

Journal article

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

09/2015

Volume

59

Pages

5721 - 5726