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E. E. Gordey et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4512–4515
Table 1
IC50 data (
l
M) for CQ, Atovaquone (AQ) and compounds 1–4 tested against P. falciparum strains K1 (CQ resistant) and 3D7 (CQ sensitive)a
Strain
IC50 (lM)
CQ
AQ
1
2
3
4
K1
3D7
NMa
0.0177 ( 0.0002)
0.0177 ( 0.0002)
NMa
0.846 ( 0.156)
0.192 ( 0.012)
0.895 ( 0.134)
0.091 ( 0.015)
0.711 ( 0.127)
0.083 ( 0.026)
>1b
0.308 ( 0.091)
a
NM = not measured.
Value >1 not precisely determined.
b
macrophages without visible pseudopodia, following incubation in
500 M (Table S1: Supplementary data). This concentration depen-
Acknowledgments
l
dent pattern and the general qualitative observations of monocytes
treated with compounds 1 and 2 were very similar to those cells
subjected to CQ solutions. In the two highest concentrations of
compound 3, crystal aggregations in globular- and spike-form were
clearly visible and the cells were considerably more damaged com-
pared to application of all other compounds. A general conclusion
to these observations is that compounds 1–3 have a general toxic-
ity profile similar to CQ and are hence at least relatively non-toxic
to non-target cells.
We are indebted to the assistance of Acadia University, Ryerson
University and the University of Victoria Co-op program (A.L.S.).
This work received the financial support of NSERC Canada (E.E.G.,
R.A.G., T.G.S.), Ryerson (R.A.G.) and Acadia Universities (P.N.Y.,
G.M.J.W., R.A.G., T.G.S.).
Supplementary data
Supplementary data (Qualitative anti-parasitic properties) asso-
ciated with this article can be found, in the online version, at
Mechanisms for drug accumulation in the food vacuole that
include a ‘receptor’ for CQ, an intravacuolar receptor, free heme
molecules acting as a receptor, or a carrier-mediated method,
stress the importance of this 3-D drug structure and subsequent
effectiveness of the compounds themselves.4,5,37,41 Alternatively,
the basicity of a compound affects anti-malarial activity in the
weak base model, which proposes the difference in pH between
the external medium and the food vacuole as the single determi-
nant of CQ accumulation.5 Considering the very similar expected
pKa values between the novel compounds, differences in anti-
malarial activity between the individual novel quinoline com-
pounds and between these compounds and CQ are likely attribut-
able to variation in the side chain structure, supportive of the
receptor mechanism for drug accumulation. The in vitro results
also suggest, based on these concepts, that increasing the overall
basicity of derivatives having the same general structural charac-
teristics of 3 might facilitate greater biological potency. This will
be examined in later compounds by, for example, the replace-
ment of the oxazoline by a more basic oxazole or incorporation
of EDGs or more basic functionalities onto the heterocyclic ring
system.15 These modifications may result in sufficient structural
changes of our materials compated to that of CQ with the objec-
tive of evading the CQ-resistance mechanism(s). It has been noted
that CQ derivatives with shortened and lengthened amine side
chains have been shown to exhibit undiminished activity against
resistant isolates.42
In both the anti-malarial and cytotoxicity analysis, compounds
2 and 3 demonstrated slightly superior activity (in terms of IC50
values at 48 h) and the latter an acceptable toxicity profile. Appli-
cation of compound 1 resulted in the death of all detectable para-
sites (7 d incubation) at the three highest drug concentrations,
proving to be slightly more effective at outright cell death rates
than compounds 2–4 but all with an overall lower potency than
CQ. Furthermore, compound 1 was minimally toxic to monocytes,
compared to the other compounds (2, 3 and CQ).
These data suggest that although the general class of quinoline–
oxazole hybrids appear to have promise as anti-malarial agents
due to their low toxicity and ease of syntheses, considerable
improvements to the general potency, most importantly increasing
activity to the nanomolar level, will be necessary for these com-
pounds to be useful drug candidates. This facet might be facilitated
by the incorporation of electron withdrawing groups or other basic
side chains to the generalized quinoline–oxazole structure, and
such endeavors are currently a focus of our research.
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27. Typical procedure (1): Under an inert atmosphere, 33.5 mg (0.046 mmol) of
[Pd(dppf)Cl2] and 76 mg (0.14 mmol) of dppf16,17 were added to a solution of
0.265 g (0.917 mmol) of 7-chloro-4-iodoquinoline18 and 0.128 g (1.14 mmol)
of t-BuOK suspended in 8 ml of 1,4-dioxane. A sample (0.216 g: 1.14 mmol) of
2-(40-anilinyl)-4,5-dihydro-1,3-oxazole was then added to this mixture. The
contents were then heated to reflux temperature with stirring (3 h) and then
cooled to room temperature; all volatile materials were then removed (rotary
evaporation). The resulting products were subjected to separation by flash
column chromatography (SiO2: 230–400 mesh; EtOAc/Et2O: 3:2 v/v as eluent)
to yield product 1 in the form of a yellow powder (35%). Mp 212–215 °C. Rf