3036
R. B. Aher et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3034–3036
Table 2
at the ortho position. Although this initial study involved only a
Drug likeness properties of the active molecules
limited number of symmetrical dibenzylideneacetones, it can be
further extended for detailed SAR of symmetrical as well as
unsymmetrical dibenzylideneacetones. Due to the straightforward
and single step synthesis, these low molecular weight dibenzylide-
neacetones represent a novel antimalarial scaffold, and a potential
starting point for the development of new, safe, effective, cheap
and potent inhibitors/drugs against malaria.
Compd
Mol wt
HA
HD
Mol log P
Mol PSA (Å2)
Mol vol (Å3)
A5
A6
A9
B2
302.03
369.95
354.15
362.16
1
1
5
2
0
0
0
0
5.97
7.4
3.99
6.79
13.24
13.24
45.43
17.19
297.90
332.44
392.32
348.58
HA: Hydrogen acceptor; HD: Hydrogen donor; PSA: Polar surface area.
Acknowledgments
of B1 with fluoro substitution on phenyl rings regained and im-
The authors (R.B.A. and G.W.) acknowledge the financial sup-
port from Ministry of HRD, Govt. of India in the form of fellowships.
We are grateful to Dr. R.C. Pillai, NIMR, New Delhi for providing
chloroquine resistant field isolate (RKL9) of P. falciparum for
screening. We also thank Dr. R.A. Joshi and Dr. R.R. Joshi, National
Chemical Laboratory (NCL), Pune for their technical assistance in
spectral characterization and analysis.
proved the potency (B2, IC50 = 9.10
IC50 >130 M) and methyl (B4, IC50 >141.85
exhibited moderate potency.
l
M) where as methoxy (B3,
l
l
M) substitutions
The derivatives possessing significant antimalarial activity in
3D7 strain were further tested against chloroquine-resistant field
isolate RKL9 of P. falciparum. We found that A5, A6, A9 and B2
were equipotent against RKL9 with resistance indices
RKL9
50
3D7
50
(IC
=IC ) of ꢀ1 (Table 1). Indeed the most active compound,
Supplementary data
A9 with a resistance index of 0.85 is more potent against the chlo-
roquine resistant strain than the sensitive one. Finally the active
Supplementary data associated with this article can be found, in
compounds (A5, A6, A9 and B2) showing IC50 up to 10 lM were
further analyzed for their cytotoxic behavior against HeLa cell lines
by the colorimetric MTT assay.12 Therapeutic indices
HeLa
50
RKL9
50
References and notes
(TC
=IC
) with values ranging between 25 and 150 indicated
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In summary, this study allows us to conclude that desirable
improvement of antimalarial activity in symmetrical dibenzylide-
neacetones requires (a) electron donating group (methoxy) at the
meta and para positions; (b) electron withdrawing (chloro) group