ACS Medicinal Chemistry Letters
Letter
susceptibility determined for the C4Dd2 parasites. As shown in
Figure 3A, there was a strong positive correlation between the
ability to inhibit PfCRTCQR-mediated CQ transport in oocytes
and the restoration of CQ accumulation in erythrocytes
infected with C4Dd2 parasites (R2 = 0.94, P = 0.0064). Likewise,
the IC50 values for PfCRTCQR inhibition were strongly
correlated with the CQ RMI values derived for C4Dd2 parasites
(Figure 3B; R2 = 0.869, P = 0.0067). These analyses indicate
that the degree of anti-PfCRTCQR activity exhibited by a CQ
resistance-reverser is an important determinant of its in vitro
chemosensitization activity. While the number of compounds
compared here was small, these findings suggest that the extent
to which a compound inhibits PfCRT-mediated CQ transport
in the oocyte system is a relatively reliable indicator of its ability
to inhibit PfCRTCQR in situ.
Author Contributions
§K.J.D. and R.L.S. contributed equally to this work. R.A.B. and
R.E.M. are cosenior authors. All authors contributed to the
writing of the manuscript.
Funding
This work was supported by the Australian National Health and
Medical Research Council (NHMRC; grant 1007035 to
R.E.M.) and the Research School of Chemistry, ANU. R.E.M.
was supported by NHMRC fellowships 520320 and 1053082
́
and the L’Oreal Australia For Women in Science program.
A.M.L. was supported by an NHMRC Overseas Biomedical
Fellowship [585519]. K.J.D. was supported by a Rod Rickards
scholarship.
Notes
The authors declare no competing financial interest.
In summary, a library of CP analogues was produced, and all
of these molecules were shown to be inhibitors of PfCRTCQR in
the oocyte system. The most active of these compounds carried
a 3-chlorophenyl group in place of the 4-chlorophenyl group of
CP and had in vitro resistance-reversing activity similar to that
of CP. Within this series of analogues, the extent of PfCRTCQR
inhibition observed in the oocyte system was found to correlate
well with the compound’s ability to modulate the CQ-
susceptibility of CQR parasites. This finding indicates that
the degree of anti-PfCRT activity exhibited by a resistance-
reverser is an important determinant of its in vitro chemo-
sensitization activity in CQR parasites. Moreover, the oocyte
system was able to detect relatively small differences in the
inhibitory activities of the 24 CP analogues, indicating that this
ACKNOWLEDGMENTS
We are grateful to the Canberra Branch of the Australian Red
Cross Blood Service for the provision of blood.
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ABBREVIATIONS
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CQ, chloroquine; CP, chlorpheniramine; CQR, chloroquine-
resistant; CQS, chloroquine-sensitive; PfCRT, Plasmodium
falciparum chloroquine resistance transporter; PQ, primaquine;
PZ, promethazine; VP, verapamil
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ASSOCIATED CONTENT
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* Supporting Information
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compounds, the full spectral data, the in vitro assay conditions,
and Figure S1. This material is available free of charge via the
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AUTHOR INFORMATION
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Corresponding Authors
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dx.doi.org/10.1021/ml5000228 | ACS Med. Chem. Lett. 2014, 5, 576−581