Structure-activity relationships of novel anti-malarial agents. Part 6: N-(4-arylpropionylamino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides

Article abstract of DOI:10.1016/S0960-894X(03)00179-3

We have demonstrated that the p-trifluoromethylphenylpropionylamino residue at the 2-position of the core structure leads to an active benzophenone-type anti-malarial agent. The attempt to improve water solubility by introduction of an amino group into th

Full text of DOI:10.1016/S0960-894X(03)00179-3

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1539–1541
Structure–Activity Relationships of Novel Anti-Malarial Agents.
Part 6: N-(4-Arylpropionylamino-3-benzoylphenyl)-[5-(4-nitrophenyl)-
2-furyl]acrylic Acid Amides
Jochen Wiesner,b Katharina Fucik,a Katja Kettler,a Jacek Sakowski,a
Regina Ortmann,a Hassan Jomaab and Martin Schlitzera,*
aDepartment fur Pharmazie -Zentrum fur Pharmaforschung, Ludwig-Maximilians Universitat Munchen,
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¨
Butenandtstraße 5-13, D-81377 Munchen, Germany
¨
¨
¨
bBiochemisches Institut der Universitatsklinik Gießen, Friedrichstraße 24, D-35249 Gießen, Germany
¨
Received 26 November 2002; revised 17 February 2003; accepted 17 February 2003
Abstract—We have demonstrated that the p-trifluoromethylphenylpropionylamino residue at the 2-position of the core structure
leads to an active benzophenone-type anti-malarial agent. The attempt to improve water solubility by introduction of an amino
group into the a-position of the arylpropionyl residue resulted in decreased activity.
# 2003 Elsevier Science Ltd. All rights reserved.
Malaria represents one of the most serious health and
economic burdens of many developing countries.1 This
is mainly due to the continuing development of resis-
tance of Plasmodium falciparum, the causative agent of
Malaria tropica, to many of the presently available
drugs. Therefore, the development of new and afford-
able anti-malarial agents with novel mechanisms of
action is essential.2
the resulting cinnamic acids. Because of the reduction
step involved in the synthesis according to Scheme 1, an
alternative route had to be followed for the preparation
of the nitro compound 4k (Scheme 2). First, the
2-amino group of 1 was protected as trifluoroacetamide
(5). After reduction of the 5-nitro group, the resulting
amine 6 was acylated with 3-[5-(4-nitrophenyl)-2-furyl]-
arylic acid chloride. After removal of the protective
group from 7 the resulting intermediate 8 was acylated
by 4-nitrophenylpropionic acid chloride. The 4-hydroxy
compound 4b was prepared in the same way because of
insufficient yield in the first step (1 ! 2) according to
Scheme 1. The amino acid derivatives 4m, 4o and 4q
were prepared in similar manner from 8 using the
appropriate N-boc protected amino acids, which are
either commercially available or in case of X=CF3 was
prepared from commercially available p-trifluoro-
methylphenylalanine.10 The N-boc protected amino
acids were activated using phosphorous oxychloride in
pyridine.11 The last step in the synthesis of these com-
pounds was the acidic removal of the boc-protective
group from the corresponding intermediates 4l, 4n and
4p (Scheme 3).12
We have initiated the development of a novel class of
anti-malarials derived from farnesyltransferase inhibitors
based on the 2,5-diaminobenzophenone scaffold.3ꢀ8 In
this study we replaced the 2-arylacetylamino residue we
used in former studies by several arylpropionyl residues.
Target compounds were prepared from commercially
available 2-amino-5-nitrobenzophenone (1), which was
first acylated at the 2-amino group by appropriate
3-arylpropionic acid chlorides (Scheme 1). Then, the
5-nitro group was reduced and the resulting amino
function was acylated by 3-[5-(4-nitrophenyl)-2-furyl]-
arylic acid chloride.9 Para-, meta- and ortho-tri-
fluoromethylphenylpropionic acid was obtained from
the corresponding benzaldehydes by Knoevenagel con-
densation and subsequent catalytic hydrogenation of
Compounds 4a–q were assayed for their inhibitory
activity against intraerythrocytic forms of the P. falci-
parum strains Dd2 using a semi-automated microdilu-
tion assay as described.13,14 The growth of the parasites
*Corresponding author. Tel.: +49-89-2180-77804; fax: +49-89-2180-
79992; e-mail: martin.schlitzer@cup.uni-muenchen.de
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00179-3

1540
J. Wiesner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1539–1541
In the series of arylpropionyl substituted inhibitors 4a–
k, a clear dependency of the anti-malarial activity on the
substitution of the terminal phenyl residue is visible. In
comparison to the phenyl-unsubstituted derivative 4a
(IC50=310 nM) most substituents in the para position
of this terminal phenyl result in a decreased activity. This
effect is most pronounced with a hydroxy, methoxy and
nitro group leading to compounds with IC50 values
higher than 1000 nM, while the reduction in activity is
mild with methyl (4d) and fluoro (4h) with IC50 values of
440 nM. In contrast, the chloro (4i) and the bromo deri-
vative (4j) with IC50 values of 130 and 170 nM, respec-
tively, are approximately twice as active as the phenyl
derivative 4a. The para trifluoromethyl derivative 4e is
the most active compound of this series being approxi-
mately 5 times as active as the phenyl derivative 4a with
an IC50 value of 61 nM. The trifluoromethyl substituent
was used to assess the influence of the ring position of the
substituent on the anti-malarial activity. Shifting the tri-
fluoromethyl group into the meta (4f: IC50=630 nM) as
well as into the ortho position (4g: IC50=1100 nM)
resulted in a marked reduction in activity.
Scheme 1. (I) R-CO–Cl, toluene/dioxane, reflux, 2 h; (II)
SnCl2ꢁ2H2O, EtOAc, reflux 2 h; (III) 3-[5-(4-nitrophenyl)-2-furyl]-
acrylic acid chloride, toluene/dioxane, reflux, 2 h.
was monitored through the incorporation of tritium-
labeled hypoxanthine. The Dd2 strain is resistant to
several commonly used anti-malarial drugs such as
chloroquine, cycloguanile, and pyrimethamine but fully
sensitive to lumefantrine and artemisinin (Table 1).
Comparability of different series of measurements is
granted by concurrent assay of standard compounds.
Compounds 4a and 4e were used as basic structures in
an attempt to improve the water solubility of this type
Scheme 2. (I) TFAA, DCM/pyridine, 0 ꢂC, 2 h; (II) SnCl2ꢁ2H2O, EtOAc, reflux 2 h; (III) 3-[5-(4-nitrophenyl)-2-furyl]acrylic acid chloride, toluene/
dioxane, reflux, 2 h; (IV) K2CO3, dioxane/H2O, reflux, 3 h; (V) X–C6H4–(CH2)2–COCl, toluene/dioxane, reflux, 2 h.
Scheme 3. (I) N-Boc amino acid, POCl3, pyridine, 0 ꢂC, 30 min; (II) HCl/dioxane, rt, 2 h.

J. Wiesner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1539–1541
Table 1. Anti-malarial activitya of compounds 4a–q
1541
certain type of farnesyltransferase inhibitors.15 How-
ever, this cannot be the sole explanation for the reduced
activity of the amino acid derivatives since there is a
clear dependence of the activity of the two phenylala-
nines 4m and 4o on the stereochemistry at the a-position
with the R-enantiomer 4o (IC50=580 nM) being con-
siderably more active than the S-enantiomer 4m
(IC50=1200 nM). So there has to be also a disturbance
of the interaction of the inhibitors with the target
structure by the a-amino group to an extent, which
depends on the stereochemistry in this position. In the
case of the para-trifluoromethyl phenylalanine deriva-
tives 4p and 4q, the boc-protected derivative 4p is con-
siderably less active than the unprotected amino acid
derivative 4q, in contrast to the situation observed with
the unsubstituted phenylalanine derivatives. This is most
likely attributable to the poor solubility of the boc-pro-
tected trifluoromethyl phenylalanine derivative 4p.
R
IC50 (nM)
310
R
IC50 (nM)
130
a
b
c
d
e
f
i
j
3300
1300
440
61
170
1400
900
k
l
In conclusion, the p-trifluoromethylphenylpropionyl
residue was identified as a partial structure leading to an
active benzophenone-type anti-malarial agent. How-
ever, the attempt to improve water solubility by intro-
duction of an amino group into the a-position of the
arylpropionyl residue was met with limited success.
m
n
o
p
q
1200
420
630
1100
440
References and Notes
g
h
580
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3200
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Chloroquine
Cycloguanile
170
2200
Pyrimethamine
Lumefantrine
Artemisinin
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30
18
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aValues are estimated to be correct withinꢃ30%.
of compounds. To provide a hydrophilic moiety, we
introduced an amino group into the a-position of the
phenylpropionyl and p-trifluoromethylpropionyl resi-
due, respectively. However, although the resulting phe-
nylalanyl derivatives 4m, 4o and 4q displayed an
enhanced solubility in water their anti-malarial activity
was considerably reduced (4m: IC50=1200 nM; 4o:
IC50=580 nM; 4q: IC50=710 nM) in comparison to the
parent compounds. It is remarkable that the more lipo-
philic boc protected precursors 4l, 4n are slightly more
active than the unprotected phenylalanine derivatives.
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nylalanine derivatives 4m, 4o is in part attributable to a
hindered membrane penetration of the more polar
amino acid derivatives and that the boc derivatives act
as prodrugs liberating the parent amino acid deriva-
tives once they crossed the membrane. Such an intra-
cellular enzymatic removal of carbamate type
protective groups has been shown in cancer cell for a
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NMR and MS and gave microanalysis withinꢃ0.4% of the
theoretical values.
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adsorbance to the plastic material used for the assay, complete
culture medium containing erythrocytes was used to dilute the
DMSO stock solutions.
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