Structure-activity relationships of novel anti-malarial agents. Part 7: N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides with polar moieties

Article abstract of DOI:10.1016/S0960-894X(03)00353-6

In a previous report, we have provided evidence that novel anti-malarial compounds based on 2,5-diaminobenzophenone farnesyltransferase inhibitors might benefit from the presence of a polar moiety at the para position of the terminal phenyl of the arylfur

Full text of DOI:10.1016/S0960-894X(03)00353-6

Bioorganic & Medicinal Chemistry Letters 13(2003) 2159–2161
Structure–Activity Relationships of Novel Anti-Malarial Agents.
Part 7: N-(3-Benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-
furyl)acrylic Acid Amides with Polar Moieties
Jochen Wiesner,c Andreas Mitsch,b Hassan Jomaac and Martin Schlitzera,*
aDepartment fur Pharmazie, Zentrum fur Pharmaforschung, Ludwig-Maximilians-Universitat Munchen,
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Butenandtstraße 5-13, D-81377 Munchen, Germany
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bInstitut fur Pharmazeutische Chemie, Philipps-Universitat Marburg, Marbacher Weg 6, D-35032 Marburg, Germany
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cBiochemisches Institut der Universitat Gießen, Friedrichstraße 24, D-35249 Gießen, Germany
¨
Received 20 December 2002; revised 14 March 2003; accepted 3 April 2003
Abstract—In a previous report, we have provided evidence that novel anti-malarial compounds based on 2,5-diaminobenzophenone
farnesyltransferase inhibitors might benefit from the presence of a polar moiety at the para position of the terminal phenyl of the
arylfurylacryloyl partial structure. Here, we demonstrate that different moieties with hydrogen bond acceptor properties lead to
equipotent or even improved anti-malarial activity in comparison to the nitro group described before.
# 2003Elsevier Science Ltd. All rights reserved.
Malaria is one of the most important infectious dis-
eases. It causes 300–500 million clinical cases every year
1
and 1–3million deaths. Therefore, malaria represents
one of the most serious health burdens in tropical areas,
especially in Africa. This is mainly due to the resistance
of Plasmodium falciparum, the causative agent of
Malaria tropica, to many of the presently available
drugs. The development of novel anti-malarial medi-
cines is therefore mandatory.2
Figure 1. Structure of the lead compound 1.
We have described the development of a novel class of
anti-malarial agents derived from 2,5-diaminobenzo-
phenone-based farnesyltransferase inhibitors3 with pro-
mising activity against multi resistant strains of
P. falciparum.4À8 In a previous paper,7 we have reported
the 4-nitrophenylfurylacryloyl derivative 1 (Fig. 1) as
the most active compound of a series of para-substituted
arylfurylacryloyl derivatives. In contrast to the other
compounds of this series, inhibitor 1 is the only one
which carries a polar group in the para position of the
terminal phenyl residue. This led to the hypothesis that
novel anti-malarial compounds based on 2,5-di-
aminobenzophenone farnesyltransferase inhibitors might
benefit from the presence of a polar moiety with hydrogen
bond acceptor properties at the para position of the term-
inal phenyl of the arylfurylacryloyl partial structure.
Therefore, we prepared a series of derivatives of inhib-
itor 1 in which the terminal nitro group is replaced by
several moieties displaying hydrogen bond acceptor
properties.
Key intermediates for the synthesis of the target com-
pounds 8 were the 5-aryl-2-furfurals 4 which are either
commercially available or were prepared via Suzuki-
coupling (modified from ref 9) from 5-bromofurfural 2
and the appropriate boronic acids 3. Only 5-(4-methoxy-
carbonylphenyl)furfural was prepared in a different
manner using 5-formylfurane-2-boronic acid and
4-bromobenzoic acid methyl ester as coupling partners.
*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 # 2003Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00353-6

2160
J. Wiesner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2159–2161
Scheme 1. (i) (Ph3P)4Pd, K2CO3, toluene/ethanol/water, 5 h, reflux; (ii) malonic acid, pyridine/piperidine, 2 h, reflux; (iii) thionyl chloride, toluene,
2 h, reflux; (iv) toluene/dioxane, 2 h, reflux.
The furfurals 4 were then transformed into the corres-
ponding 3-biarylacrylic acids 5, which were activated as
acid chlorides 6 and reacted with 5-amino-2-tolylacetyl-
aminobenzophenone 710 as described previously11
(Scheme 1).
1). Comparability of different series of measurements is
granted by concurrent assay of standard compounds.
Replacement of the nitro group of lead structure 1 by a
trifluoromethyl residue let to an equipotent compound
(8a) with an IC50 value of 77 nM. Although surprising
at first glance, this result may be explained by some—
albeit weak—hydrogen bond acceptor properties of the
trifluoromethyl residue. The activity of all nitrogen
containing compounds was disappointingly low with
IC50 values ranging between 200 and 560 nM. In the
case of the nitril group, which has only hydrogen bond
acceptor properties, the free electron pair could well
point in the wrong direction, so that no hydrogen bond
can be formed. All other nitrogen containing residues
display hydrogen bond donor in addition to their
acceptor properties. Possibly, in solution hydrogen
bonds are formed to water, which cannot be saturated
when the inhibitor binds to the protein target due to an
apparent lack of appropriate acceptor structures. The
introduction of terminal moieties (inhibitors 8d, i and j)
which display only hydrogen bond acceptor properties
resulted in inhibitors which were at least equipotent to the
lead compound 1. In case of inhibitor 8i the replacement of
the nitro group by a methylsulfonyl moiety resulted in a
2-fold improvement in antimalarial activity (IC50=
37 nM). The lower activity of the corresponding ethyl-
sulfonyl derivative 8j (IC50=60 nM) may be explained by
the increased bulkiness of this moiety since we have shown
in a previous study7 that the increase of the length of linear
substituents over two atomic entities is generally accom-
panied by a reduction of anti-malarial activity.
Compounds 1 and 8a–r were assayed for their inhibi-
tory activity against intraerythrocytic forms of the P.
falciparum strains Dd2 using a semi-automated micro-
dilution assay as described.12,13 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
(chloroquine, cycloguanile and pyrimethamine) (Table
Table 1. Anti-malarial activity of compounds 1 and 8a–k
R
IC50 (nM)
75
R
IC50 (nM)
560
1
8f
8a
8b
8c
8d
8e
77
260
220
67
8g
8h
8i
280
560
37
In conclusion, the trifluoromethyl and the acetyl group
were identified as equipotent replacements of the term-
inal nitro group in this type of anti-malarial agents.
Furthermore, incorporation of a methylsulfonyl moiety
led to an inhibitor twice as active as the lead structure 1.
In addition, this inhibitor lacks the nitro group of lead
structure 1 potentially associated with an unfavorable
toxicological profile.
8j
60
170
8k
200
References and Notes
Chloroquine
Cycloguanile
Quinine
170
2200
380
Pyrimethamine
Lumefantrine
2500
30
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