C. Biot et al. / Eur. J. Med. Chem. 35 (2000) 707–714
713
9
.15 Hz, 1H, H-7), 7.29 (d, J = 2.47 Hz, 1H, H-5), 6.12
concentration ranged from 1.4–90.4 nM for HB3 strain
and from 2.8–180.7 nM for Dd2 strain. Concerning each
mefloquine ferrocenyl derivative, they ranged from
16.9–1 084.2 nM for the two P. falciparum strains. The
final concentration of quinine and ferrocenyl analogues
ranged from 52.08–3 333.3 nM for both strains. All these
concentrations contained less than 0.01% dimethyl sul-
phoxide which had no detectable effect on parasite
multiplication [29]. After addition of a suspension of
parasitized erythrocytes in complete culture medium
(
s, 1H, CHOD), 4.11 (m, 1H, 1H Cp), 4.03 (m, 1H, 1H
Cp), 3.94 (d, J = 12.17 Hz, 1H, 1CHN), 3.93 (s, 3H,
CH O), 3.88 (m, 1H, 1H Cp), 3.70 (s, 5H, Cp′), 2.91 (d,
J = 12.85 Hz, 1H, 1CHN), 2.33 (s, 6H, 2CH N). MS
3
3
+
+
+
(
thap): 453 (M+ Na) , 430 M , 386 (M – NMe ) , 385
2
+ +
(M – HNMe ) , 367 (M – (H O + HNMe )) .
2
2
2
5
.1.2.3. [2-(Piperidinomethyl-
ferrocenyl)]-(6-methoxyquinolyl)methanol 6
The preparation is analogous to the preparation of 5
(
200 µL/well, 0.5% initial parasitaemia with a majority of
3
(
58% yield). We were unable to separate the diastereo-
ring stages, 2% haematocrit) and [H ]Hypoxanthine
Amersham, Little Chalfont, Buckinghamshire, UK,
.5 µCu/well), the test plates were incubated at 37 °C in
an atmosphere of 5% O , 5% CO and 90% N for 48 h.
isomers by chromatography column or by HPLC. MS
(
0
+
+
+
(thap): 493 (M+ Na) , 471 MH , 470: M , 386 (M –
+ +
N(CH ) ) , 367: (M – (H O + H N(CH ) )) .
2
5
2
2 5
2
2
2
1
u diastereomer 31% (NMR estimation). H-NMR: δ
.80 (d, J = 4.40 Hz, 1H, H-2), 8.05 (d, J = 9.25 Hz, 1H,
Growth of the parasites was estimated by the incorpora-
3
8
tion of radiolabelled [H ]Hypoxanthine into the parasites
H-8), 7.80 (d, J = 2.82 Hz, 1H, H-5), 7.48 (d, J = 4.45 Hz,
nucleic acids, measured in a liquid scintillation spectrom-
eter (Beckman). Fifty percent inhibitory concentrations
1
1
H, H-3), 7.36 (dd, J = 2.88, 9.25 Hz, 1H, H-7), 6.44 (s,
H, CHOD), 4.15–3.85 (m, 4H, 3H Cp and 1CHN), 4.01
(
IC ) refer to molar concentrations of drug causing 50%
50
3
(
1
1
s, 5H, Cp′), 3.79 (s, 3H, CH O), 3.05 (d, J = 12.80 Hz,
H, 1CHN), 2.53 2 (m, 4H, CH ), 1.63 2 (m, 4H, CH )
2 2
.45 (m, 2H, CH2).
3
reduction in [H ]Hypoxanthine incorporation compared
to drug-free control wells. They were estimated by linear
regression analysis of log dose–response curves.
1
l diastereomer 69% (NMR estimation). H-NMR: δ
,91 (d, J = 4.35 Hz, 1H, H-2), 8.09 (d, J = 9.20 Hz, 1H,
8
Acknowledgements
H-8), 7.78 (d, J = 4.54 Hz, 1H, H-3), 7.40 (dd, J = 2.73,
.22 Hz, 1H, H-7), 7.32 (d, J = 2.71 Hz, 1H, H-5), 6.12
s, 1H, CHOD), 4.15–3.85 (m, 4H, 3H Cp and 1CHN),
9
This research was supported by the ‘Ministère de
l’Enseignement Supérieur et de la Recherche’, the ‘Cen-
tre national de la Recherche Scientifique’, the World
Heath Organisation (contract: ID 980-140) and ‘Pierre
Fabre Medicament’. We thank Sophie Picart-Goetgheluck
for his assistance with the NMR spectra experiments.
(
3
.96 (s, 3H, CH O), 3.63 (s, 5H, Cp′), 2.96 (d, J =
3
1
2.98 Hz, 1H, 1CHN), 2.53 (m, 4H, CH ), 1.63 (m, 4H,
2
CH ), 1.45 CH (m, 2H, CH ).
2
2
2
5
5
.2. Biology protocols
.2.1. Parasite cultures
References
Two culture-adapted strains of P. falciparum were
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.2.2. In vitro activity
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[
[
(
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9
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(
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[
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