Structure-activity relationships of novel anti-malarial agents: Part 5. N-(4-acylamino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides

Article abstract of DOI:10.1016/S0960-894X(02)01003-X

We have developed the [5-(4-nitrophenyl)-2-furyl]acrylic acid substituted benzophenone 4g as a novel lead for anti-malarial agents. Here, we demonstrated that the acyl residue at the 2-amino group of the benzophenone core structure has to be a phenylacetic acid substructure substituted in its para-position with methyl or other substituents of similar size. The trifluoromethyl substituted derivative displayed an IC₅₀ of 47 nM against the multi-drug resistant Plasmodium falciparum strain Dd2.

Full text of DOI:10.1016/S0960-894X(02)01003-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 361–363
Structure–Activity Relationships of Novel Anti-Malarial Agents:
Part 5. N-(4-acylamino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-
furyl]acrylic Acid Amides
Jochen Wiesner,b,c Katja Kettler,a Jacek Sakowski,a Regina Ortmann,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, Gießen, Germany
cJomaa Pharmaka GmbH, Frankfurter Straße 50, D-35249 Gießen, Germany
Received 19July 2002; revised 21 October 2002; accepted 13 November 2002
Abstract—We have developed the [5-(4-nitrophenyl)-2-furyl]acrylic acid substituted benzophenone 4g as a novel lead for anti-
malarial agents. Here, we demonstrated that the acyl residue at the 2-amino group of the benzophenone core structure has to be a
phenylacetic acid substructure substituted in its para-position with methyl or other substituents of similar size. The trifluoromethyl
substituted derivative displayed an IC50 of 47 nM against the multi-drug resistant Plasmodium falciparum strain Dd2.
# 2002 Elsevier Science Ltd. All rights reserved.
About 300–500 million clinical cases of malaria every
year and between 1 and 3 million deaths, mostly of
children, represent one of the most serious health and
economic burdens of many developing countries.1 Key
problem is the development of resistance of Plasmodium
falciparum, the causative agent of Malaria tropica, to
many of the presently available drugs. Therefore, new
and affordable anti-malarial medicines capable of over-
coming the widespread resistance, possibly by novel
mechanisms of action, are essential.2
Synthesis of the target compounds 4 is described
elsewhere in detail.8 Briefly, commercially available
2-amino-5-nitrobenzophenone 1, was first acylated at
the 2-amino group by appropriate acid chlorides
(Scheme 1). Then, the 5-nitro group was reduced and
the resulting amino function was acylated by 4-nitro-
phenylfurylacrylic acid chloride.9
Compounds 4a–u were concurrently assayed for their
inhibitory activity against intraerythrocytic forms of the
P. falciparum strains Dd2 using a semi-automated
microdilution assay as described.10,11 The growth of the
parasites was monitored through the incorporation of
tritium-labeled hypoxanthine. The Dd2 strain is resis-
tant to several commonly used anti-malarial drugs such
as chloroquine, cycloguanile, and pyrimethamine but
fully sensitive to lumefantrine (Table 1).
We have initiated the development of a novel class of
anti-malarials derived from farnesyltransferase inhibi-
tors based on the 2,5-diaminobenzophenone scaffold.3
This development led us to the [5-(4-nitrophenyl)-2-fur-
yl]acrylic acid substituted benzophenone 4g as an
important step in this development.4À7 In this study we
replaced the tolylacetyl residue at the 2-amino group of
compound 4g by several different acyl residues to
address the question how variations in this position
would influence anti-malarial activity.
To explore the influence of structural variation of the
acyl residue at the 2-amino function of the benzophe-
none core structure, we first replaced the tolylacetyl
residue of our lead structure 4g7 (IC50=75 nM) by a
benzoyl residue. This resulted in a marked reduction in
anti-malarial activity (4a: IC50=3000 nM). Introduc-
tion of a chlorine into the para-position of the terminal
phenyl of 4a did not improve activity significantly (4b:
*Corresponding author. Tel.: +49-89-2180-7804; fax: +49-89-2180-
79992; e-mail: martin.schlitzer@cup.uni-muenchen.de
0960-894X/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)01003-X

362
J. Wiesner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 361–363
Scheme 1. (I) R-CO-Cl, toluene/dioxane, reflux, 2 h; (II) SnCl2Â2H2O, EtOAc, reflux 2 h; (III) 3-[5-(4-nitrophenyl)-2-furyl]acrylic acid chloride,
toluene/dioxane, reflux, 2 h.
IC50=2500 nM) as did the replacement of the phenyl
residue by a 2-naphthyl ring (4c: IC50=2500 nM). In
Table 1. Anti-malarial activitya (IC50: nM) of compounds 4a–u
contrast, the 1-naphthyl derivative 4d was more active
(IC50=770 nM), but this compound is still 10-fold less
active than our initial lead 4g. So, direct connection of
the aryl residue to the carbonyl proved detrimental to
activity. The unsubstituted phenylacetic acid derivative
4e and the para-methoxy phenylacetic acid compound
Compd
R
IC50
(nM)
Compd
R
IC50
(nM)
4f were considerably more active (4e: IC50=270 nM; 4f:
IC50=320 nM) than the arylcarboxylic acid derivatives
4a–d, but 3–4-fold less active than the para-tolylacetic
acid derivative 4g. Anti-malarial activity of the tolyl-
acetic acid derivative proved sensitive towards the posi-
tion of the methyl substituent at the phenyl ring.
Shifting the methyl from the para- to the meta-position
resulted in a 2-fold reduction of activity (4h: IC50=150
nM). Shifting the methyl group into the ortho-position
resulted in even more pronounced reduction of activity
(4i: IC50=650 nM). Exploration of the influence of
halogens in the para-position of the phenyl residue
revealed that the fluorine which is most similar to
hydrogen produced activity similar to that of the
unsubstituted phenyl derivative (4j: IC50=230 nM vs
4g: IC50=270 nM). In contrast, chlorine (4k) and bro-
mine (4l) in the para-position led to inhibitors which are
equipotent (4k: IC50=64 nM; 4l: IC50=70 nM) to
methyl derivative 4g. This may be attributed to the
similar size of methyl, chlorine and bromine, respec-
tively. As seen with the methyl substituent, shifting of
the bromine from the para- to the ortho-position resul-
ted in a marked drop in anti-malarial activity (4m:
IC50=1000 nM). Replacement of the para-methyl group
by trifluoromethyl yielded the most active compound of
this series (4n: IC50=47 nM). Again, shifting the sub-
stituent from para to ortho resulted in a marked drop in
acitivity (4o: IC50=1000 nM). The polar and strongly
electron withdrawing nitro group yielded a compound
with considerable reduced activity (4p: IC50=1400 nM).
Replacement of the phenyl residue by 1- and 2-naph-
thyl, respectively, resulted in inhibitors almost equipo-
tent (4q: IC50=250 nM; 4r: IC50=210 nM) to the
unsubstituted phenylacetic acid derivative 4e. In con-
trast, the biphenylyl derivative 4s was considerably less
active (IC50=1000 nM). With the last two compounds
of this series the influence of substituents at the a-posi-
tion of the arylacetic acid substructure was determined.
With growing size of the a-substituents increasing
4a
4b
3000
2500
4l
70
4m
1000
4c
4d
4e
4f
2500
770
270
320
75
4n
4o
4p
4q
4r
4s
4t
47
1000
1400
250
4g
4h
4i
210
150
650
230
64
1000
500
4j
4u
5500
4k
Chloroquine
Cycloguanile
170
2200
Pyrimethamine 2500
Lumefantrine 30
aThe accuracy of the in-vitro assay was ensured by concurrent assay of
standard compounds.

J. Wiesner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 361–363
363
reduction of activity was observed (a-methyl derivative
4t: IC50=500 nM; a-phenyl derivative 4u: IC50=5500
nM).
2. Ridley, R. G. Nature 2002, 415, 686.
3. Schlitzer, M. Curr. Pharm. Des. 2002, 8, 1713.
4. Wiesner, J.; Wißner, P.; Dahse, H.-M.; Jomaa, H.; Schlit-
zer, M. Bioorg. Med. Chem. 2001, 9, 785.
5. Wiesner, J.; Mitsch, A.; Wißner, P.; Jomaa, H.; Schlitzer,
M. Bioorg. Med. Chem. Lett. 2001, 11, 423.
6. Wiesner, J.; Kettler, K.; Jomaa, H.; Schlitzer, M. Bioorg.
Med. Chem. Lett. 2002, 12, 543.
7. Wiesner, J.; Mitsch, A.; Wißner, P.; Kramer, O.; Jomaa,
H.; Schlitzer, M. Bioorg. Med. Chem. Lett. 2002, 12, 2681.
8. Kettler, K.; Sakowski, J., Silber, K.; Sattler, I.; Schlitzer,
M. Bioorg. Med. Chem. In press.
9. Compounds were structurally characterized by IR, 1H
NMR and MS and gave microanalysis withinÆ0.4% of the
theoretical values.
10. (a) Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chulay,
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.
11. 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. Precipitation was observed in single
cases at the highest concentration but did not effect the
reproducibility of the IC50 values.
In summary, this study revealed that the acyl residue at
the 2-amino group of the benzophenone core structure
has to be a phenylacetic acid substructure substituted in
its para-position with methyl or other substituents of
similar size. Similar SAR were observed in a series of
related antimalarial compound based on 4-propoxy-
cinnamoic acid substituted benzophenones6 suggesting
that both classes of compounds recognise a common
molecular target. A particular helpful result is that the
methyl group of the initial lead compound can be
replaced by trifluoromethyl yielding not only a com-
pound which is active in a similar range as lumefantrine,
an arylaminoalcohol antimalarial in current clinical use,
but also lacks the metabolic instability which might be
associated with the methyl group.
References and Notes
1. Sachs, J.; Malaney, P. Nature 2002, 415, 680.