R. Capela et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3229–3232
3231
Table 1
Effect of hybrid compounds 6, artemisinin (1), artelinic acid (15), dipeptidyl vinyl sulfones 5 and 12d and E64 on the inhibition of falcipain-2, chabaupain-1, and growth of P.
falciparum W2 strain
Compound
R1
R2
R3
IC50
/
lM
IC50/nM
FP-2a
CP-1b
W2 P. falciparuma
Artemisinin
—
—
CH2Ph
CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
—
—
—
H
—
—
ND
ND
ND
ND
12.0 1.97
5.66 0.58
4.09 0.13
2.27 0.73
3.94 0.28
2.08 0.89
4.81 0.12
4.21 0.56
>10,000
15
6a
6b
6c
6d
6e
6f
12d
5
E64
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
—
16.5
22.4
9.22
4.95
21.6
0.35
0.21
0.003c
0.084
56.8
0.40
0.538
2.29
ND
ND
ND
ND
0.009
CH2Ph
CH2Ph
CH2CHMe2
CH2Ph
CH2CHMe2
CH2CHMe2
CH2CHMe2
—
22.0d
1955 121
ND, not determined.
a
Assays of falcipain inhibition and parasite development were determined as described earlier.15
Assay of chabaupain inhibition was performed as described previously.22
Non-recombinant falcipain.16
b
c
d
Itg2 strain.16
Table 2
IC50 values of compounds 6a, 6e and 6f, chloroquine and artemisinin against the W2, FCR3, 3D7, VI/S and D6 P. falciparum strains
Compound
IC50/nM
3D7
W2
FCR3
VI/S
D6
Chloroquine
Artemisinin
6a
6e
6f
78.1 6.91
12.0 1.97
4.09 0.13
4.81 0.12
4.21 0.56
51.1 0.1
11.6 1.1
65.0 4.1
16.9 2.1
14.5 1.2
4.71 0.12
4.75 0.37
4.96 0.66
5.38 0.54
1.75 0.32
2.00 0.02
1.89 0.10
9.71 4.18
3.11 0.72
2.50 1.51
2.48 0.41
4.24 0.54
1.59 0.11
2.25 0.24
1.65 0.11
1). All hybrids 6 displayed activity in the nM range, being more
active than artemisinin and equipotent to artelinic acid, 15. This
result strongly suggests that the endoperoxide pharmacophore
is the major contributor to the antiplasmodial activity exerted
by compounds 6. This hypothesis is further supported by the ab-
sence of swollen food vacuoles in trophozoites incubated with 6.
We have previously shown that this specific abnormality, ob-
served when parasites are incubated with dipeptidyl vinyl sulf-
Acknowledgements
This work was supported by FCT (Portugal) and the National
Institutes of Health; R.C. acknowledges FCT for the PhD grant
SFRH/BD/30418/2006. PJR is a Doris Duke Charitable Foundation
Distinguished Clinical Scientist.
References and notes
ones and E64, is indicative of
a
block in hemoglobin
hydrolysis.23 The lack of a food vacuole abnormality for deriva-
tives 6 can be explained by the relatively poor activity of hybrids
against FP-2 and/or limited access to the food vacuole. Com-
pounds 6a, 6e and 6f were also screened against 4 additional P
falciparum strains with different phenotypes: FCR3 (atovaquone
resistant), 3D7 (chloroquine-sensitive), V1/S (chloroquine and
pyrimethamine resistant) and D6 (chloroquine sensitive, meflo-
quine resistant) (Table 2). The IC50 values show the superior
activity of compounds 6a, 6e and 6f when compared to chloro-
quine and artemisinin against all strains.
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In summary, a new class of hybrid molecules, 6, based on dipep-
tidyl vinyl sulfone and artemisinin cores has been synthesized and
shown to display potent antiplasmodial activity against a panel of
P. falciparum chloroquine-sensitive and multidrug-resistant
strains, with IC50 values ranging from 2 to 5 nM. Despite the fact
that these hybrids incorporate the structural elements required
for falcipain inhibition (e.g., Leu residue at P2), they inhibited FP-
2 only in the
lM range. These results indicate that, although the
artemisinin core or the linker may not be suitable for optimal en-
zyme binding, there is space to improve the bi-functional mole-
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synthesis of novel hybrid molecules incorporating vinyl sulfone
and artemisinin cores is underway.
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