ABSTRACT
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
ex vivo
. 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
Plasmodium falciparum
(
n
= 41) and
Plasmodium vivax
(
n
= 45) in Papua, Indonesia, using a modified
ex vivo
schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant
P. falciparum
and
P. vivax
field isolates. For
P. falciparum
, the median 50% inhibitory concentrations (IC
50
s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (
P
< 0.001 and
P
= 0.036, respectively). The corresponding values for
P. vivax
were 19.0, 60.0, and 60.9 nM (
P
< 0.001 and
P
= 0.018, respectively). There was a significant correlation between IC
50
s of CQ and PL69 (Spearman's rank correlation coefficient [
rs
] = 0.727,
P
< 0.001) and PL106 (
r
s
= 0.830,
P
< 0.001) in
P. vivax
but not in
P. falciparum
. Both RCQs were equally active against the ring and trophozoite stages of
P. falciparum
, but in
P. vivax
, PL69 and PL106 showed less potent activity against trophozoite stages (median IC
50
s, 130.2 and 172.5 nM) compared to ring stages (median IC
50
s, 17.6 and 91.3 nM). RCQ compounds have enhanced
ex vivo
activity against CQ-resistant clinical isolates of
P. falciparum
and
P. vivax
, 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
Plasmodium
species.