C. C. Musonda et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4733–4736
Table 1. Isolated yields and purities of aminoxazoles 19–28
4735
the unsubstituted or methyl-substituted derivatives. In
the unsubstituted compounds 19–22, the two com-
pounds with the 2- and 3-carbon spacers were the
more active, while this activity was lost in the 4- and
6-carbon-spaced compounds. On the contrary, the
methyl-substituted compound 24 with the 2-carbon
spacer was not as active as the 3-carbon spaced com-
pound 25. The lowest activity was observed with the
piperazinyl derivative 28.
Entry
R
Product
n
%Yield
%Puritya
1
2
H
19
20
21
22
23
24
22
26
27
28
1
70
68
62
39
93
68
51
67
43
87
93
95
97
98
99
96
97
96
95
98
H
2
3
H
3
4
H
5
5
H
—
1
6
CH3
CH3
CH3
CH3
CH3
7
2
8
3
9
10
5
—
The observed improvement in the activities of these no-
vel 4-aminoquinoline 2,4,5-trisubstituted aminoxazoles
may be speculated to result from several factors. The
4-amino-7-chloroquinoline subunit is an antimalarial
pharmacophore that inhibits haem dimerization into
nontoxic haemozoin.12 Therefore, the primary antiplas-
modial activities associated with these compounds may
be arising from inhibition of haem dimerization causing
a build up of the toxic haem, resulting in parasite death.
It is also possible that the increase in basicity caused by
the side chain NH on N and the oxazole N may be
improving the accumulation of the compounds in the
acidic food vacuole of the parasite via pH trapping.13
The presence of the heterocycle in the lateral chain
may also be resulting in secondary interactions with
other targets apart from haem, resulting in the observed
antiplasmodial activities.
a HPLC purity, conditions: flow rate: 1.0 ml/min, UV 220 and 254 nm,
30% CH3CN: 70% 25 mM phosphate buffer.
Table 2. Antiplasmodial activity of 19–28 against CQSa 3D7 and
CQRb K1
Compound
n
R
IC50 (lM)
3D7
K1
CQ
19
20
21
22
23
24
25
26
27
28
—
1
—
H
0.02
0.25c/1.03d
0.0084
0.041
0.079
0.15
0.23c
0.14c
0.099c
0.11d
0.36d
0.25d
0.16d
0.019d
0.037d
0.97d
2
H
3
H
5
H
—
1
H
0.52
0.12
CH3
CH3
CH3
CH3
CH3
2
0.079
0.0038
0.018
0.14
3
In conclusion, we have shown the potential of 4-amino-
quinoline-containing 2,4,5-trisubstituted aminoxazoles
as antiplasmodial agents in vitro and thereby demon-
strated a simple approach to the synthesis of analogues
of existing antimalarial drugs. The efficiency of this ap-
proach is manifested in the preclusion of large-sized li-
braries as the SAR libraries would already be enriched
in antimalarial pharmacophores. Rationally, such a
combination of antimalarial pharmacophores and other
functionalities offers many attractive features for accel-
erating antimalarial drug discovery.
5
—
a CQS, chloroquine-sensitive.
b CQR, chloroquine-resistant.
c Average CQ IC50 was determined to be 0.25 lM.
d In this experiment the average CQ IC50 was determined to be
1.03 lM.
The results also reveal that all compounds were more ac-
tive than chloroquine in the resistant (K1) strain. In the
first experiment, chloroquine had an IC50 of 0.25 lM,
whereas the 2 out of the 3 compounds tested along with
the control drug, namely 20 and 21, were both more po-
tent than chloroquine with respective IC50 values of 0.14
and 0.099 lM. In the second experiment, compounds
22, 23 and 24–27 were several orders of magnitude more
active than chloroquine. In fact, 25, the least active
among the three (IC50 = 0.16 lM), was 6 times more po-
tent than chloroquine (IC50 = 1.03 lM), while 26
(IC50 = 0.019 lM) was 54 times more efficacious than
chloroquine and exhibited the greatest potency.
Acknowledgments
This work was supported by the South African National
Research Foundation under Grant No. 2053362 (K.C.).
The investigation also received support from UNDP/
World Bank/WHO Special Programme for Research
and Training in Tropical Diseases (TDR) (V.Y. and S.L.).
Supplementary data
The results suggest that the introduction of a methyl
=
Experimental details for the synthesis of all compounds
and biological evaluation. Supplementary data associ-
ated with this article can be found, in the online version,
substituent in 20 (IC50 = 0.14 lM) to yield 25 (IC50
0.16 lM) had no effect on the antiplasmodial activity,
whereas a similar change for 21 (IC50 = 0.099 lM)
resulted in significantly improved efficacy for compound
26 (IC50 = 0.019 lM). A similar increase in potency was
seen in the analogous compounds 22 (IC50 = 0.11 lM)
and 27 (IC50 = 0.037 lM).
References and notes
1. World Health Organization Fact Sheet No. 94. Revised
The consequence of altering the length of the carbon
spacer in the lateral side chain was not uniform in either