Synthesis, antimalarial and antitubercular activity of acetylenic chalcones

Article abstract of DOI:10.1016/j.bmcl.2009.12.062

A series of acetylenic chalcones were evaluated for antimalarial and antitubercular activity. The antimalarial data for this series suggests that growth inhibition of the W2 strain of Plasmodium falciparum can be imparted by the introduction of a methoxy

Full text of DOI:10.1016/j.bmcl.2009.12.062

Bioorganic & Medicinal Chemistry Letters 20 (2010) 942–944
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antimalarial and antitubercular activity of acetylenic chalcones
Renate H. Hans a, Eric M. Guantai a, Carmen Lategan b, Peter J. Smith b, Baojie Wan c,
Scott G. Franzblau c, Jiri Gut d, Philip J. Rosenthal d, Kelly Chibale a,e,
*
a Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
b Division of Pharmacology, University of Cape Town, Observatory 7925, South Africa
c Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612-723, USA
d Department of Medicine, San Francisco General Hospital, University of California at San Francisco, CA 94143, USA
e Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of acetylenic chalcones were evaluated for antimalarial and antitubercular activity. The antima-
larial data for this series suggests that growth inhibition of the W2 strain of Plasmodium falciparum can be
imparted by the introduction of a methoxy group ortho to the acetylenic group. Most compounds were
more active against non-replicating than replicating cultures of Mycobacterium tuberculosis H37Rv, an
unusual pattern with respect to existing anti-TB agents.
Received 12 November 2009
Revised 14 December 2009
Accepted 15 December 2009
Available online 23 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Chalcones
Falcipain-2
P. falciparum
M. tuberculosis
The greatest concern with infectious diseases, especially malar-
ia and tuberculosis, is the alarming rate at which resistance against
clinically used drugs develops. This imparts a degree of urgency for
the discovery of affordable and effective alternative drugs. The ap-
peal of working with chalcones (1,3-diarylprop-2-en-1-one) stems
from their synthetic accessibility, the various ways the core struc-
ture can be diversified and their ability to confer drug-like proper-
ties to compound libraries modeled on them.1 Consistent with its
privileged status, a wide range of biological activities such as
anti-inflammatory,2 antileishmanial,3 antibacterial,4 antifungal,5
antitumour,6 antimalarial7,8 and anti-TB activity9 have been re-
ported for chalcone derivatives. Regarding the antimalarial activ-
ity, it has been proposed that chalcones exert their mode of
action by the inhibition of cysteine proteases.10 Failure to correlate
the antiplasmodial activity of some chalcones with cysteine prote-
ase inhibition led to the conclusion that other targets and/or path-
ways may be compromised.8d In fact, recent reports suggest that
chalcones also play a role in the inhibition of new permeability
pathways induced by the parasite in the erythrocyte membrane.8g
Moreover, previous SAR studies revealed that the minimum
requirements for antimalarial activity are the presence of the en-
one linker8c and for the double bond in this linker to have a trans
(E)-configuration.8e These basic structural features were retained
in the compounds synthesized in this study. Our drug design effort
was further guided by a study which showed that alkoxylated chal-
cones are more important for antimalarial activity.7a,8g
Interestingly, the number and scope of SAR studies exploring
the antimalarial effects of chalcones is in stark contrast to those
investigating their antitubercular activity. One of the few studies
on TB involved a 47-member chalcone library, which showed that
halogenated chalcones display superior antitubercular activity.9a
Another study explored the inhibitory effect of variously substi-
tuted chalcones on the protein tyrosine phosphatase (PtpA) of
Mycobacterium tuberculosis.9c Incidentally, the latter study repre-
sents one of the few attempts at elucidating the mode of action
of antitubercular chalcones.
In the interest of developing a focused library from which
meaningful SAR can be delineated, the substituent groups chosen
were limited to the methoxy and acetylenic groups. While the for-
mer is based on previous SAR studies,7a,8g the latter not only serves
as a site for further chemical diversification but is also of great
interest in medicinal chemistry and the pharmaceutical industry.
It moreover functions as a key pharmacophoric unit in acetylenic
antibiotics11 and its presence in anticancer12 and antitubercular13
agents is noteworthy. We envisaged that the combination of these
functional groups would contribute towards increasing the lipo-
philicity of the target compounds relative to structurally similar
phenolic compounds, that is, analogues which are devoid of the
acetylenic group. Lipophilicity is an important requirement for
antimalarial, but more so antimycobacterial agents because of
the unusual lipid-rich cell wall of mycobacteria.
* Corresponding author. Tel.: +27 21 650 2553; fax: +27 21 689 7499.
E-mail address: Kelly.Chibale@uct.ac.za (K. Chibale).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.062

R. H. Hans et al. / Bioorg. Med. Chem. Lett. 20 (2010) 942–944
943
1.2 equiv of propargyl bromide in the presence of 1.5 equiv of
K2CO3 in DMF. The intermediate acetylenes 2-3 were obtained in
excellent to quantitative yields. The second step, also known as
the Claisen–Schmidt condensation, provided access to 4 and 5.7a
Using commercially available vanillin and acetovanillone, com-
pounds 8 and 9 were obtained under similar reaction conditions
as shown in Scheme 2.
O
R'
R'
O
O
4
O
O
i
ii
R
R
HO
O
O
R = H, CH3
All synthesized chalcones were characterized with IR, 1H- and
13C NMR, low resolution mass spectroscopy and elemental
analysis.
2
3
R = H
R = CH3
5
R' = 4-methoxy; 2,4-dimethoxy; 2,3,4-trimethoxy
For antiplasmodial evaluation, the chalcones were screened for
activity against chloroquine-sensitive (D10)15 and chloroquine-
resistant (W2)14 strains of Plasmodium falciparum. Evaluation of
in vitro activity against M. tuberculosis H37Rv strain was conducted
using the MABA assay in 7H12 medium.16 The compounds that
were found to be active in the latter were further tested in the
LORA assay17 for activity against slow growing or non-replicating
M. tuberculosis. Results obtained are shown in Table 1.
With regard to the antiplasmodial activity, it is of interest to
note that the introduction of a methoxy group ortho to the acety-
lenic group imparts activity against the W2 strain, as can be con-
cluded when comparing the activities of 4 and 5 with the low
micromolar activities of 8 and 9. Compound 8b is the most active,
Scheme 1. Reagents and conditions: (i) Propargyl bromide, K2CO3, DMF, rt, 16 h for
4 and 24 h for 5; (ii) methoxylated acetophenone or benzaldehyde, 3 w/v % NaOH,
MeOH, rt, 16 h.
O
MeO
O
R'
O
O
8
MeO
O
ii
MeO
HO
i
R
R
O
MeO
O
R = H, CH3
R'
6
7
R = H
R = CH3
with IC50s of 3.4 lM against the D10 and 3.8 lM against the W2
9
strain, respectively. The chalcone series which lacks the ortho
methoxy group showed activity against the chloroquine-sensitive
(D10) strain, but no useful trends regarding the degree of methoxy-
lation, position of attachment of the acetylenic group and the aro-
matic ring preference for substituents could be delineated. None of
the chalcones in this series showed activity against the P. falcipa-
rum cysteine protease falcipain-2.
The limited series 8 and 9, which displayed encouraging anti-
plasmodial activity, showed poor or a lack of antitubercular activ-
ity compared to series 4 and 5. This may be advantageous if the
R' = 4-methoxy; 2,4-dimethoxy; 2,3,4-trimethoxy
Scheme 2. Reagents and conditions: (i) Propargyl bromide, K2CO3, DMF, rt, 12 h;
(ii) methoxylated acetophenone (for 8), methyoxylated benzaldehyde (for 9), 2.5 M
NaOH aq, MeOH, 70 °C, 3 h.
The two-step synthesis of compounds 4 and 5 is outlined in
Scheme 1. As shown, commercially available hydroxyacetophe-
none or benzaldehyde was subjected to O-alkylation with
Table 1
In vitro antimalarial activities against P. falciparum D10 and W2 strains and in vitro antitubercular activities against replicating and non-replicating phenotypes of M. tuberculosis
H37Rv strain
Compd
Substitution
R0
Rec-FP-2a IC50
(l
M)
W2 IC50
(lM)
D10 IC50
(
lM)
MABA MIC (lM)
LORA MIC (
l
M)
C log Pb
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
5h
5i
8a
8b
8c
9a
9b
Ortho
Ortho
Ortho
Meta
Meta
Meta
Para
4-OMe
>100
>100
>100
>100
>100
19.0
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
ND
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
8.4
>100
8.00
50.57
11.60
7.57
>100
>100
54.78
13.34
>100
18.86
>100
>100
>100
33.03
16.52
>100
4.43
9.7
47.5
59.1
61.9
40.0
54.9
54.0
>128
>128
>128
31.1
53.7
98.7
51.2
>128
58.7
>128
31.0
>128
>128
>128
109
50.7
14.9
28.6
31.7
26.1
13.1
ND
4.36
4.45
3.74
4.36
4.45
3.74
4.36
4.45
3.74
4.36
4.45
3.74
4.36
4.45
3.74
4.36
4.45
3.74
4.10
4.13
3.38
4.13
3.38
2,4-diOMe
2,3,4-triOMe
4-OMe
2,4-diOMe
2,3,4-triOMe
4-OMe
2,4-diOMe
2,3,4-triOMe
4-OMe
2,4-diOMe
2,3,4-triOMe
4-OMe
2,4-diOMe
2,3,4-triOMe
4-OMe
2,4-diOMe
2,3,4-triOMe
4-OMe
2,4-diOMe
2,3,4-triOMe
2,4-diOMe
2,3,4-triOMe
Para
Para
ND
ND
Ortho
Ortho
Ortho
Meta
Meta
Meta
Para
56.7
62.8
46.1
>128
ND
29.7
ND
108
ND
ND
ND
ND
ND
Para
Para
ND
ND
ND
ND
3.8
7.0
9.7
6.7
3.4
7.7
>20
4.1
>128
>128
ND
E64
0.047
ND
Chloroquine
Rifampin
Isoniazid
Moxifloxacin
PA824
0.069
0.038
0.05
0.37
0.29
0.16
2.4
>128
31.1
3.3
a
Assay against recombinant falcipain-2 (Rec-FP-2) was performed as previously described.14
Calculated using Chemdraw Ultra 9.0; ND = not determined
b

944
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Acknowledgments
We thank the African American Institute (R.H.H.), the National
Research Foundation (E.G., K.C.), and the South African Research
Chairs Initiative of the Department of Science and Technology
(K.C.) for financial support.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.12.062.
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