We evaluated the ability of 7 to inhibit the growth of
trophozoites in intraerythrocyte culture by assessing 3H-hypox-
anthine incorporation.26 Hypoxanthine incorporation is
a
measure of parasite growth and its inhibition correlates well with
direct blood smear counts but provides more reliable
a
quantification. Compared with a half-maximal inhibitory concen-
tration (IC50) value .20 mM in the CQ-sensitive HB3 clone with
[Ga-3-Madd]+,14 the incorporation of quinoline into the metal-
loantimalarial 7 improved the IC50 value to 0.6 mM (Fig. 1)
thereby indicating a substantial (.33 fold) enhancement of
its efficacy. In addition, potency of 7 was insignificantly altered
in the CQ-resistant Dd2 clone [IC50: 1.4 mM (7) vs. IC50: 1.8 mM
({Ga-3-Madd}+)] Fig. 2. These results suggest that cytotoxic
targeting properties of this molecule lie in the spatial orientation
of substituents on the peripheral part of the molecule and that
rational drug design of metallotherapeutics may be feasible.
Furthermore, pfcrt, a gene on chromosome 7 encoding a
transmembrane protein PfCRT has been shown to confer
chloroquine resistance on parasites.10,27 The presence of the
quinoline substituents may alter the interaction of the 7 with
the crt transporter. Alternatively, the quinoline moiety itself
may be active on the chloroquine sensitive parasite clone.
Therefore, it will be interesting to evaluate whether different
parasite clones with altered susceptibility to quinolines are also
inhibited by the quinoline-metalloantimalarial 7.
We thank Prof. David Piwnica-Worms for helpful discussions,
and Silvia D. Collins for technical assistance. D.E.G. is a recipient
of the Burroughs Wellcome Fund Scholar Award in Molecular
Parasitology. Financial assistance to this work was provided by
grant from the National Institutes of Health (R01 AI45640).
Joseph A. Ocheskey,a Scott E. Harpstrite,a Anna Oksman,bc
Daniel E. Goldbergbc and Vijay Sharma*a
aMallinckrodt Institute of Radiology, Washington University Medical
School, St. Louis, MO, USA. E-mail: sharmav@mir.wustl.edu;
Fax: 314 362 0152; Tel: 314 362 9358
bHoward Hughes Medical Institute, Washington University Medical
School, St. Louis, MO, USA
cDepartments of Medicine and Molecular Microbiology, Washington
University Medical School, St. Louis, MO, USA
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Fig. 1 Effect of
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Fig. 2 Effect of 7 and [Ga-3-Madd]+ on growth of P. falciparum strains
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This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 1622–1624 | 1623