Improved and rapid synthesis of new coumarinyl chalcone derivatives and their antiviral activity

Article abstract of DOI:10.1016/j.tetlet.2007.09.175

Two closely structurally related coumarins, 4-hydroxy-8-isopropyl-5-methylcoumarin and 4-hydroxy-6-chloro-7-methylcoumarin were acylated at C-3 and further converted to the respective chalcones and two series of eighteen new compounds, which were evaluate

Full text of DOI:10.1016/j.tetlet.2007.09.175

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Tetrahedron Letters 48 (2007) 8472–8474
Improved and rapid synthesis of new coumarinyl
chalcone derivatives and their antiviral activity
a
a
b
a
Jalpa C. Trivedi, Jitender B. Bariwal, Kuldip D. Upadhyay, Yogesh T. Naliapara,
c
d
d
a,
*
Sudhir K. Joshi, Christophe C. Pannecouque, Erik De Clercq and Anamik K. Shah
a
Department of Chemistry, Saurashtra University, Rajkot 360 005, India
b
Torrent Research Center, Gandhinagar 382 428, India
H & H. B. Kotak Institute of Science, Rajkot 360 005, India
Rega Institute for Medical Research, Katholieke Universiteit, Leuven B-3000, Belgium
c
d
Received 20 August 2007; revised 14 September 2007; accepted 27 September 2007
Available online 1 October 2007
Abstract—Two closely structurally related coumarins, 4-hydroxy-8-isopropyl-5-methylcoumarin and 4-hydroxy-6-chloro-7-methyl-
coumarin were acylated at C-3 and further converted to the respective chalcones and two series of eighteen new compounds, which
were evaluated for possible antiviral activity.
Ó 2007 Elsevier Ltd. All rights reserved.
The incidence of HIV-1 infection leading to acquired
immunodeficiency syndrome (AIDS) is one of the
world’s greatest threats to human health and there is
All the compounds were synthesized according to
Scheme 1. Substituted coumarins 2 were prepared by
the literature method using an appropriately substituted
phenol and malonic acid, a Lewis acid and as condens-
1
no complete effective remedy for this disease. Couma-
rins and structurally related compounds have been
shown to inhibit replication of HIV and thus exhibit a
therapeutic potential. A large number of structurally
ing agent, phosphorus oxychloride (POCl ). For acetyla-
3
tion of the substituted coumarin, the method of
2
11
Dholakia et al. was employed using glacial acetic acid
novel coumarin derivatives have been reported to show
substantial cytotoxic and anti-HIV activity in vitro and
as acetylating agent in the presence of POCl . In conven-
3
tional methods for chalcone synthesis, the time for com-
pletion of reactions is very long, ranging from 24 to 36 h
3
,4
in vivo. A variety of synthetic coumarins have unique
mechanisms of action referring to the different stages of
1
2,13
at rt.
A small alteration in reaction conditions, using
5
HIV replication. Thus coumarins are important lead
chloroform as solvent with a mild organic base, for
example, piperidine, reduced the reaction time in most
cases, from 1 to 1.5 h (Table 1). Moreover, the isolation
of product 4 or 5 was also easy. Biological assessments
were carried out against HIV-I (III B) and HIV-2
(ROD) and the results are shown in Tables 2 and 3 in
the Supplementary data. The cut-off point for such spe-
cific antiviral activity was P5-fold lower than the cyto-
toxic concentration. However, no specific antiviral
effects were noted for any of the compounds against
any of the viruses evaluated.
compounds for the development of antiviral and/or
6
–8
virucidal drugs against HIV. Some phenyl coumarins
and chalcones have been proposed as suppressors of
LTR-dependent transcription, but the mechanism of
9
action has not been fully characterized. (+)-Calanolide
A, a natural dipyranocoumarin is also currently under-
1
0
going anti-AIDS clinical trials. In our work on
anti-HIV compounds, the 3-acetyl-4-hydroxycoumarin
system was used for the synthesis of potent anti-HIV
compounds using an easy and rapid method, which
improves the yields to a significant level.
Our improved method for the synthesis of coumarinyl
chalcones was effective in terms of time and yields of
the products. Unfortunately, all the compounds were
inactive against HIV.
Keywords: Antiviral; Anti-HIV; Chalcones; 4-Hydroxycoumarins.
*
Corresponding author. Tel.: +91 281 2581013; e-mail:
anamik_shah@hotmail.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.175

J. C. Trivedi et al. / Tetrahedron Letters 48 (2007) 8472–8474
8473
R4
R3
COOH
COOH
OH
H C
2
R2
a
R1
1
R4
R3
R2
O
O
R1
OH
2
b
c
R4
R3
R2
O
O
COCH3
OHC
R
R1
OH
3
R4
R3
R2
O
O
O
R
R1
OH
4a-i and 5a-i
R
=H
=4-OH
=4-OCH3
1
2
4
4
5
a-i, R =CH , R =H R =H, R =CH(CH )
3
,
3
3 2
1
2
3
4
a-i, R =H, R =Cl, R =CH , R =H
3
=
=
=
=
=
=
3-OC H
2-NO2
3-NO2
4-N(CH ), 4-OH
3-OCH , 4-OH
6
5
3
3
3,4-di OCH3
Scheme 1. Synthesis of compounds 4a–i and 5a–i. Reagents and conditions: (a) Anhydrous ZnCl
CHCl , piperidine, 80 °C.
2
3 3
, POCl , 70 °C; (b) glacial acetic acid, POCl ; (c)
3
Table 1. Physical properties of the synthesized coumarinyl chalcone derivatives
R4
R3
R2
O
O
O
R
R1
OH
Compd.
Substitution
Yield (%)
Mol. wt.
Mp (°C)
1
2
3
4
R
R
R
R
R
4
4
4
4
4
4
4
4
a
b
c
d
e
f
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH(CH
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
2
2
2
2
2
2
2
2
H
4-OH
4-OCH
3-OC
2-NO
3-NO
79
75
76
71
73
69
72
71
350
366
378
440
377
377
391
394
170–172
246–248
215–217
96–98
120–124
235–237
245–247
214–216
CH(CH
CH(CH
CH(CH
CH(CH
CH(CH
CH(CH
CH(CH
3
6
H
5
2
2
g
h
4-N(CH
3-OCH3, 4-OH
3
)
2
(continued on next page)

8474
J. C. Trivedi et al. / Tetrahedron Letters 48 (2007) 8472–8474
Table 1 (continued)
Compd.
Substitution
Yield (%)
Mol. wt.
Mp (°C)
1
2
3
4
R
R
R
R
R
4
5
5
5
5
5
5
5
5
5
i
CH
H
H
H
H
H
H
H
H
H
3
H
H
CH(CH
3
)
2
3,4-di-OCH
H
4-OH
3
74
73
68
76
69
67
70
77
79
81
408
195–197
180–182
246–248
220–222
188–190
178–180
230–232
235–237
220–222
258–260
a
b
c
d
e
f
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
H
H
H
H
H
H
H
H
H
340.5
356.5
370.5
432.5
385.5
385.5
383.5
386.5
416.5
4-OCH
3-OC
3
6
H
5
2-NO
3-NO
2
2
g
h
i
4-N(CH
3-OCH
3,4-di-OCH
3
)
2
3
, 4-OH
3
Acknowledgments
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The authors thank CDRI, Lucknow, and RSCI, Punjab
University, Chandigarh, for providing H NMR and
Mass Spectroscopy facilities and Leentje Persoons, Cin-
dy Heens and K. Erven, Rega Institute for Medical Re-
search, Belgium, for excellent technical assistance with
the antiviral assays.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
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