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

Article abstract of DOI:10.1016/S0960-894X(02)00555-3

In a previous report, we have described novel anti-malarial compounds based on a 2,5-diaminobenzophenone scaffold. Here, we have invesigated acryloyl derivatives carrying a biaryl structure consisting of a terminal aryl residue and a central 2-furyl ring. Several compounds were obtained in the series of para-substituted phenylfurylacryloyl derivatives that displayed improved anti-malarial activity in comparison to earlier described derivatives. From the structure-activity relationships it can be deduced that there has to be a lipophilic moiety in the para-position of the terminal phenyl residue. Furthermore, there are indications that, alternatively, activity may benefit from the presence of a polar moiety with hydrogen bond acceptor properties.

Full text of DOI:10.1016/S0960-894X(02)00555-3

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2681–2683
Structure–Activity Relationships of Novel Anti-Malarial Agents.
Part 4: N-(3-Benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-
furyl)acrylic Acid Amides
Jochen Wiesner,a,b Andreas Mitsch,c Pia Wißner,c Oliver Kramer,c Hassan Jomaab
and Martin Schlitzerd,*
aBiochemisches Institut der Universitatsklinik Gießen, Friedrichstraße 24, D-35249 Gießen, Germany
¨
bJomaa Pharmaka GmbH, Frankfurter Straße 50, D-35249 Gießen, Germany
cInstitut fur Pharmazeutische Chemie, Philipps-Universitat Marburg, Marbacher Weg 6, D-35032 Marburg, Germany
¨
¨
dDepartment fur Pharmazie, Zentrum fur Pharmaforschung, Ludwig-Maximilians-Universitat Munchen,
¨
¨
¨
¨
Butenandtstraße 5-13, D-81377 Munchen, Germany
¨
Received 15April 2002; revised 25June 2002; accepted 12 July 2002
Abstract—In a previous report, we have described novel anti-malarial compounds based on a 2,5-diaminobenzophenone scaffold.
Here, we have invesigated acryloyl derivatives carrying a biaryl structure consisting of a terminal aryl residue and a central 2-furyl
ring. Several compounds were obtained in the series of para-substituted phenylfurylacryloyl derivatives that displayed improved
anti-malarial activity in comparison to earlier described derivatives. From the structure–activity relationships it can be deduced that
there has to be a lipophilic moiety in the para-position of the terminal phenyl residue. Furthermore, there are indications that,
alternatively, activity may benefit from the presence of a polar moiety with hydrogen bond acceptor properties.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
In this study, we have replaced the 4-propoxyphenyl
residue of the cinnamoyl moiety by an biaryl structure
consisting of a terminal aryl residue and a central
2-furyl ring.
Malaria represents one of the most serious health bur-
dens in tropical areas especially in Africa. There are
300–500 million clinical cases every year and between 1
and 3 million deaths, mostly of children.1 Because of the
resistance of Plasmodium falciparum, the causative agent
of Malaria tropica, to many of the presently available
drugs ‘‘continued and sustainable improvements in
antimalarial medicines...are essential...’’.2
We have described the 2,5-diaminobenzophenone 1 (Fig. 1)
as a novel lead structure of agents active against multi
resistant strains of P. falciparum.3 Structural modifi-
cation of 1 led to the 4-propoxycinnamic acid derivative
2 with a more than 10-fold improved anti-malarial
activity 4 (Fig. 1).
*Corresponding author. Tel.: +49-89-2180-7804; fax: +49-89-2180-
79992; e-mail: martin.schlitzer@cup.uni-muenchen.de
Figure 1. Structures of the lead compounds 1 and 2.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00555-3

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J. Wiesner et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2681–2683
Key intermediates for the synthesis of the target com-
pounds 9 were the 5-aryl-2-furfurals 5 which are either
commercially available or were prepared via Suzuki-
coupling5 from 5-bromofurfural 3 and the appropriate
boronic acids 4. These furfurals 5 were then trans-
formed into the corresponding 3-biarylacrylic acids 6,
which were activated as acid chlorides 7 and reacted
with 5-amino-2-tolylacetylaminobenzophenone 86 as
described previously7 (Scheme 1).
Compounds 9a–r were concurrently assayed for their
inhibitory activity against intraerythrocytic forms of the
P. falciparum strains Dd2 using a semi-automated
microdilution assay as described.8,9 The growth of the
Scheme 1. (I) (Ph3P)4Pd, K2CO3, toluene/ethanol/water, 5h, reflux; (II) malonic acid, pyridine/piperidine, 2 h, reflux; (III) thionyl chloride, toluene,
2 h, reflux; (IV) toluene/dioxane, 2 h, reflux.
Table 1. Anti-malarial activitya of compounds 9a–r
9
a
R
IC50 (nM)
415
9
j
R
IC50 (nM)
750
b
c
d
e
f
1000
200
120
88
k
l
210
84
m
n
o
p
q
r
320
145
125
75
85
g
h
i
300
130
300
590
670
Chloroquine
Cycloguanile
Quinine
170
2200
380
Pyrimethamine
Lumefantrine
2500
30
aValues are estimated to be correct within Æ30%.

J. Wiesner et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2681–2683
2683
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 1).
polar moiety. The nitro group was also used to address
the question how repositioning of the residue influences
inhibitory activity. Shifting the nitro group from the
para- to the meta- or ortho-position resulted in a marked
decrease in activity, yielding compounds with IC50
values of 590 and 670 nM, respectively.
The phenylfurylacryloyl derivative 9a inhibited the
growth of the multi-resistant P. falciparum strain Dd2
with an IC50 value of 415nM therefore displaying an
activity comparable to the lead structure 2. Replace-
ment of the terminal phenyl group by a 1-naphthyl
residue resulted in a marked reduction in activity (9b:
IC50=1000 nM). Shifting the connection between the
furyl and the naphthyl moiety from the 1- to the
2-position resulted in improved activity. Inhibitor 9c
(IC50=200 nM) was 5-fold more active than its isomer
9b and twice as active as the unsubstituted phenyl deri-
vative 9a. However, superior activity was observed in
the series of para-substituted phenylfurylacryloyl deri-
vatives. The methyl derivative 9d was even more active
than the 2-naphthyl compound 9c, with an IC50 value of
120 nM. Inhibitory activity was further improved by the
replacement of the terminal methyl group by an ethyl
residue (9e: IC50=88 nM). Introduction of a double
bond into this residue led to an equipotent inhibitor (9f:
IC50=85nM). However, further enlagement of the
alkyl residue as with inhibitor 9g resulted in a decreased
activity (IC50=300 nM). Replacement of the methylene
group in the ethyl residue of inhibitor 9e by an oxygen
also resulted in a reduced activity. The methyl ether
derivative 9h displayed an IC50 value of 120 nM. Activ-
ity even further declined upon elongation of the alkyl
part of the alkoxy residue (ethoxy (9i): IC50=300 nM;
propoxy (9j): IC50=750 nM). This structure–activity
relationship is in marked contrast to that observed with
the alkoxy-substituted cinnamoyl derivatives we descri-
bed before, where activity increases continuously from
methoxy to propoxy.4 The trifluoromethyl ether 9k
turned out to be only nearly half as active as the methyl
ether 9h displaying an IC50 value of 210 nM. One pos-
sible explanation would be that hydrogen bridge accep-
tor properties may be important at this position and
that the already relatively weak acceptor properties of
the aryl ether oxygen are further weakened by the elec-
tron withdrawing effect of the trifluormethyl group. The
methyl thioether 9l displayed activity (IC50=84 nM)
equal to that of the ethyl-substituted inhibitor 9e. This
is not a surprising result, since the thioether sulfur is
generally regarded to be a bioisoster to the methylene
group. In the series of halogene-substituted compounds,
activity improved with increasing size of the halogene
going from an IC50 value of 320 nM of the fluoro com-
pound 9m to an IC50 value of 125nM of the bromo
compound 9o with the chloro compound 9n (IC50=145
nM) being only slightly less active than 9o. Best activity
in the series of compounds described here, was observed
with the para-nitrophenylfurylacryloyl derivative 9p
which displayed an IC50 value of 75nM. In contrast to
the other inhibitors displaying IC50 values around 100
nM or below, this inhibitor carries not a lipophilic but a
Log P values10 for all target compounds 9a–r do not
differ significantly (data not shown) and, therefore, are
of no use for the interpretation of the structure–activity
relationships. This is not an entirely surprising result
since this study dealt with comparably small structural
variations which left the bulk of rather large molecules
unchanged.
In summary, several para-substituted phenylfuryl-
acryloylaminobenzophenonenes with improved anti-
malarial activity in comparison to the earlier described
derivatives3,4 were obtained. This findings will guide
further development of this class of compounds towards
anti-malarials with improved activity.
References and Notes
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