1982
J. Leban et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1979–1982
Table 1( continued)
References and notes
Compd
Activity
IC50, nM
Compd structure
1. Campbel, P. Nature Insight 2002, 415, 6872.
2. Session, R. B.; Dewar, V.; Larke, R.; Holbrook, J. J. J.
Protein Engineering 1997, 10, 301.
3. Seifert, H. J.; Wolf, K.; Vitt, D. Biosilico 2003, 1, 143.
4. DeVos, A. J.; Barrowman, P. R.; Coetzer, J. A. W.; Kel-
lermann, T. S.; Onderstepoort J. Vet. Res. 1978, 45, 203.
5. Bell, C. A.; Hall, J. E.; Kyle, D. E.; Grogl, M.; Kwasi,
A. O.; Allen, M. A.; Tidwell, R. R. Antimicrobial Agents
and Chemotherapy 1990, 1381.
27
980
6. Jiang, S.; Prigge, S. T.; Wei, L.; Gao, E.; Hudson, T. H.;
Gerena, L.; Dame, J. B.; Kyle, E. D. Antimicrobial Agents
and Chemotherapy 2001, 2577.
28
90
7. For the determination of the antiplasmodial activity of
the compounds, the multidrug resistant Plasmodium
falciparum clone Dd2 was used. The incorporation of
[8-3H]hypoxanthine into the parasitic nucleic acids was
measured. The plasmodia were incubated at 0.3% para-
sitaemia and an erythrocyte haematocrit of 2.5% in the
presence of different concentrations of the compounds in
a final volume of 200 mL. The medium employed was
RPMI 1640 which contained 10% of heat-treated human
serum and 3 mg/l of gentamycin. In the incubations, the
concentrations of the compounds varied from 0.3 to 100
mM. After 48 h, each batch was treated with 50 mL of
[8-3H]hypoxanthine (1mCi/mL) and incubated for a
further 18 h. The cells were filtered off, washed and
suspended in 20 mL of scintillation fluid. The radio-
active hypoxanthine absorbed by the parasites was then
quantified using a scintillation counter.The results were
presented graphically and the IC50 values were deter-
mined using a fitting function. The value IC50, the
‘inhibition constant’, indicates the value in nMol/l at
which 50% inhibition occurs.
29
>2500
The newly identified class of antimalarial compounds is
more active in a cell based assay against P. falciparum
than chloroquine and almost as active as amicarbalide
(cmpd 1). Since the compounds do not have a bisami-
dine functionality the mechamism of action is not likely
to be due to DNA binding. The compounds are micro-
molar inhibitors of P. falciparum plasmepsin (unpub-
lished observation). This activity does not explain the
potent activity of these compounds against P. falci-
parum. It can be speculated that the compounds are
concentrated in the food vacuole. Such an effect would
amplify the activity against plasmepsin and result in the
nanomolar activity in cell culture assay. However, it has
to be also considered that the compounds may act
against a unknown target.
8. All compounds were characterized by MS and NMR
(300MHz) and exhibited satisfactory properties. Exam-
ples are given for a few compounds. 1H NMR (D6-
DMSO).
13 d=3.99 (d, J=6.3, 2H, CH2), 7.23–7.30 (m, 5H, Ar-
H), 7.36 (d, J=8.3, 1H, Ar-H), 7.40–7.43 (m, 1H, Ar-H),
7.47–7.56 (m, 2H, Ar-H), 7.58–7.61(m, 1H, Ar-H), 7.72–
7.75 (m, 1H, Ar-H), 7.98 (t, J=1.8, 1H, Ar-H), 8.12 (t,
J=1.8, 1H, Ar-H), 8.19 ( t, J=6.3, 1H, N-H), 9.00 (s, 2H,
N-H), 9.35 (s, 2H, N-H), 9.77 (s, 1H, N-H), 9.82 (s, 1H,
N-H).
These novel chemical entities with potent antimalarial
activity will be an addition to the antimalarial chemo-
therapy. Further biological characterization of these
compounds will be presented in future publications.
15 d=3.99 (d, J=6.3, 2H, CH2), 7.24–7.39 (m, 5H, Ar-
H), 7.42 (d, J=7.9, 1H, Ar-H), 7.50 (t, J=7.9, 1H, Ar-H),
7.59 (d, J=7.9, 1H, Ar-H), 7.70 (d, J=8.9, 2H, Ar-H),
7.81(d, J=8.9, 2H, Ar-H), 8.09 (t, J=1.8, 1H, Ar-H),
8.12 (t, J=1.8, 1H, Ar-H), 8.19 ( t, J=6.3, 1H, N-H), 8.83
(s, 2H, N-H), 9.18 (s, 2H, N-H), 9.85 (s, 1H, N-H), 10.02
(s, 1H, N-H).
24 d=4.01(d, J=5.3, 2H, CH2), 7.01–7.07 (m, 1H, Ar-
H), 7.34–7.45 (m, 1H, Ar-H), 7.61 (d, J=8.9, 2H, Ar-H),
7.68 (d, J=7.5, 4H, Ar-H), 7.81(d, J=8.9, 2H, Ar-H),
8.10 (t, J=5.5, 1H, N-H), 8.92 (s, 2H, N-H), 9.20 (s, 2H,
N-H), 10.13 (s, 1H, N-H), 10.23 (s, 1H, N-H).
Acknowledgements
We thank Ines Rystau and Karin Steigleder for techni-
cal assistence, Kristina Wolf for helpful discussions,
Gerhard Keilhauer and Daniel Vitt for support.