Structure-activity relationships of novel anti-malarial agents. Part 3: N-(4-Acylamino-3-benzoylphenyl)-4-propoxycinnamic acid amides

Article abstract of DOI:10.1016/S0960-894X(01)00798-3

We have described 5-(4-propoxycinnamoylamino)-2-(4-tolylacetylamino)benzophenone 6e as a novel lead for anti-malarial agents. Anti-malarial activity of these 5-(4-propoxycinnamoylamino)benzophenones proved to be quite sensitive against variations of the a

Full text of DOI:10.1016/S0960-894X(01)00798-3

Bioorganic & Medicinal Chemistry Letters 12 (2002) 543–545
Structure–Activity Relationships of Novel Anti-Malarial
Agents. Part 3: N-(4-Acylamino-3-benzoylphenyl)-4-
propoxycinnamic Acid Amides
Jochen Wiesner,b,c Katja Kettler,a Hassan Jomaac
and Martin Schlitzera,*
aDepartment fur Pharmazie - Zentrum fur Pharmaforschung, Ludwig-Maximilians-Universitat Munchen,
¨
¨
Butenandtstraße 5-13, D-81377 Munchen, Germany
¨
¨
¨
bBiochemisches Institut der Universitatsklinik Gießen, Friedrichstraße 24, D-35249 Gießen, Germany
¨
cJomaa Pharmaka GmbH, Frankfurter Straße 50, D-35249 Gießen, Germany
Received 16 July 2001; revised 5 November 2001; accepted 26 November 2001
Abstract—We have described 5-(4-propoxycinnamoylamino)-2-(4-tolylacetylamino)benzophenone 6e as a novel lead for anti-
malarial agents. Anti-malarial activity of these 5-(4-propoxycinnamoylamino)benzophenones proved to be quite sensitive against
variations of the acyl substituent at the 2-amino group. Best activity was obtained with phenylacetic acid moieties carrying small
substituents in the para-position. From the para-substituents evaluated, the trifluoromethyl group yielded the most active com-
pound (6j) in this series (IC50=120nM). Deviations from the phenylacetic acid substructure, shifting the substituent into the ortho-
position or bulkier para-substituents resulted in a significant reduction in anti-malarial activity. # 2002 Elsevier Science Ltd. All
rights reserved.
Malaria is one of the most threatening tropical diseases
causing between 1.5 and 2.7 million fatal cases per year,
particularly among children, primarily in Africa.1
Nearly all fatal cases are caused by Plasmodium falci-
parum, the causative agent of Malaria tropica. This is
largely due to the widespread emergence of P. falci-
parum strains resistant to presently available drugs.
Therefore, there is an urgent need for new agents active
against multi-resistant Plasmodium strains.1
different acyl substituents to address the question how
variations in this position would influence the anti-
malarial activity.
By random screen of a small compound library we have
discovered the 2,5-diaminobenzophenone 1 (Fig. 1) as a
novel lead structure of agents active against multi resis-
tant strains of P. falciparum.2 Structural modification of
1 led to compound 6e, in which the phenylpropionyl
substituent at the 5-amino group of 1 has been replaced
by 4-propoxycinnamic acid (Fig. 1). This modification
resulted in a significant improvement in anti-malarial
activity.3 In this study, we replaced the tolylacetyl resi-
due at the 2-amino group of compound 6e by several
*Corresponding author. Tel.: +49-89-2180-7804; e-mail: martin.
schlitzer@cup.uni-muenchen.de
Figure 1. Structures of the lead compounds 1 and 6e.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00798-3

544
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

J. Wiesner et al. / Bioorg. Med. Chem. Lett. 12 (2002) 543–545
Table 1. Anti-malarial activity of compounds 6a–l
545
substituent (6d) in the para-position of the terminal
phenyl resulted in a 4-fold reduction in activity (6d:
IC50=1300 nM) in comparison to the methyl derivative
6e. In contrast, the para-chloro (6g) and the para-bromo
(6h) derivatives were as potent as the para-methyl deri-
vative 6e, displaying IC50 values of 350and 310nM,
respectively. Shifting the methyl and the bromo sub-
stituent from the para- into the ortho-position (6f and
6i) resulted in both cases in a considerable loss in activ-
ity (6f: IC50=2400 nM; 6i: IC50=2800 nM). With com-
pound 6j, we have replaced the para-methyl group of 6e
by a para-trifluoromethyl group resulting in a 3-fold
improvement in anti-malarial activity (IC50=120nM).
Acylation of the 2-amino group of the benzophenone
core by bulky acyl residues resulted in a drastic drop in
activity (6k: IC50=24,000 nM; 6l: IC50=23,000 nM). In
summary, anti-malarial activity of 5-(4-propoxy-
cinnamoylamino)benzophenones proved to be quite
sensitive against variations of the acyl substituent at the
2-amino group. Best activity was recorded with phenyl-
acetic acid moieties carrying small substituents in the
para-position. From the para-substituents evaluated, the
trifluoromethyl group yielded the most active com-
pound is this series. Deviations from the phenylacetic
acid substructure, shifting the substituent into the ortho-
position or bulkier para-substituents resulted in a sig-
nificant reduction in anti-malarial activity. The para-
trifluoromethylphenylacetic acid derivative 6j represents
an important step in the development of a novel poten-
tial anti-malarial agent.
Compd
R
IC50 (nM)
Dd2
9000
3D7
6500
6a
6b
6c
6d
6e
6f
3400
2500
1300
2700
1900
1200
340250
2400
1400
6g
6h
6i
350270
310140
2800
References and Notes
1. Wirth, D. F. Ann. Rep. Med. Chem. 1999, 34, 349.
2. Wiesner, J.; Wißner, P.; Dahse, H.-M.; Jomaa, H.; Schlit-
zer, M. Bioorg. Med. Chem. 2001, 9, 785.
3. Wiesner, J.; Mitsch, A.; Wißner, P.; Jomaa, H.; Schlitzer,
M. Bioorg. Med. Chem. Lett. 2001, 11, 423.
4. Compounds were structurally characterized by IR, 1H
NMR and MS and gave microanalysis within Æ0.4% of the
theoretical values.
2000
6j
0
12010
5. Jones, G. The Knoevenagel Condensation. In Organic
Reactions; Cope, A. C., Ed., John Wiley & Sons: New York,
1967; Vol. 15, p 204.
6k
6l
24,000
19,000
20,000
6. (a) Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chu-
lay, J. D. Antimicrob. Agents Chemother. 1979, 16, 710. (b)
Trager, W.; Jensen, J. B. Science 1976, 193, 673. (c) Ancelin,
M. L.; Calas, M.; Bompart, J.; Cordina, G.; Martin, D.; Bari,
M. B.; Jei, T.; Druilhe, P.; Vial, H. J. Blood 1998, 91, 1.
7. In order to avoid a loss of lipophilic test compounds by
adsorbance to the plastic material used for the assay, complete
culture medium containing erythrocytes was used to dilute the
DMSO stock solutions.
23,000
17020
2200
38096
2500
3029
Chloroquine
Cycloguanile
Quinine
Pyrimethamine
Lumefantrine
7.5
3.0