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J. Wiesner et al. / Bioorg. Med. Chem. Lett. 12 (2002) 543–545
Scheme 1. (i) R-COCl, toluene/dioxane, 2 h, reflux; (ii) SnCl2Â2H2O, EtOAc, 2 h, reflux; (iii) 4-H7C3–O–C6H4–HC=CH–COCl, toluene/dioxane, 2
h, reflux.
Scheme 2. (i) TFAA, DCM/pyridine, 0 ꢀC, 2 h; (ii) SnCl2Â2H2O, EtOAc, reflux 2 h; (iii) 4-H7C3–O–C6H4–HC=CH–COCl, toluene/dioxane, reflux,
2 h; (iv) K2CO3, dioxane/H2O, reflux, 3 h; (v) 4-F3C–C6H4–CH2–COCl, toluene/dioxane, reflux, 2 h.
Synthesis4 of most of the target compounds 6 was
accomplished starting from commercially available
2-amino-5-nitrobenzophenone 3, which was first acy-
lated at the 2-amino group by appropriate acid chlo-
rides (Scheme 1). Then, the 5-nitro group was reduced
and the resulting amino function was acylated by
4-propoxycinnamic acid chloride which was prepared
from commercially available 4-propoxybenzaldehyde
via Knoevenagel condensation5 and activation using
thionyl chloride.
drugs (chloroquine, cycloguanile and pyrimethamine)
(Table 1).
Throughout the series of compounds, differences in the
activities of particular compounds against the wild type
3D7 strain and the multi-resistant Dd2 strain showed
the same tendency, although, the 3D7 strain proved to
be slightly more sensitive than the Dd2 strain, which is
not an unusual observation also with unrelated com-
pounds. However, these differences were not as pro-
nounced as those seen for some standard drugs as
chloroquine, cycloguanile or pyrimethamine. Since
activity against the multi resistant Dd2 strain is more
relevant, structure–activity relationship will be discussed
with this strain.
Because acylation of 3 by 4-trifluoromethylphenylacetic
acid chloride failed, an alternative route had to be
followed for the preparation of 6j (Scheme 2). First, the
2-amino group of 3 was protected as trifluoroacetamide
(7). After reduction of the 5-nitro group, the resulting
amine 8 was acylated by 4-propoxycinnamic acid
chloride. After removal of the protective group from 9,
the resulting intermediate 10 could by acylated by 4-tri-
fluoromethylphenylacetic acid chloride, yielding com-
pound 6j.
Starting from our novel lead 6e, we first removed the
para-methyl group from the para-tolylacetic acid sub-
structure. The resulting phenylacetic acid derivative 6c
was notably less active than the lead structure 6e dis-
playing an IC50 value of 2500 nM in contrast to the IC50
value of 340nM which has been recorded for 6e.
Removal of the methylene spacer from compound 6c
yielded the benzoic acid derivative 6a (IC50=9000 nM),
which was almost inactive. Replacement of the phenyl
residue in compound 6a by a 1-naphthyl ring (6b) did
not significantly improve activity. Therefore, we
returned to substituted phenylacetic acid derivatives as
acyl substituents at the 2-amino group of the benzo-
phenone core structure. Introduction of a methoxy
Compounds 6a–l were concurrently assayed for their
inhibitory activity against intraerythrocytic forms of
the P. falciparum strains Dd2 and 3D7 using a semi-
automated microdilution assay as described.6,7 The
growth of the parasites was monitored through the
incorporation of tritium-labeled hypoxanthine. In con-
trast to the wild type 3D7 strain, the Dd2 strain is
resistant to several commonly used anti-malarial
Wiesner, Jochen
