An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

Article abstract of DOI:10.1016/j.tetlet.2011.05.114

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4- one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu ₃.

Full text of DOI:10.1016/j.tetlet.2011.05.114

Tetrahedron Letters 52 (2011) 4375–4377
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient microwave assisted synthesis of novel class of Rhodanine
derivatives as potential HIV-1 and JSP-1 inhibitors
⇑
Sukanta Kamila, Haribabu Ankati, Edward R. Biehl
Department of Chemistry, Southern Methodist University, Dallas, TX 75275, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a–q) derivatives have
been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a–h) with
suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a–d) under microwave condition. The thioxo-
thiazolidine-4-ones were prepared from the corresponding aromatic amines (1a–e) and di-(carboxy-
methyl)-trithiocarbonyl (2). The aldehydes (6a–h) were synthesized from the corresponding acid
chlorides (5a–d) using HSnBu3.
Received 22 April 2011
Accepted 25 May 2011
Available online 12 June 2011
Keywords:
3-Phenyl-2-thioxothiazolidin-4-one
2-(1H-Indol-3-yl)-2-oxoacetaldehyde
Acid chloride
Ó 2011 Elsevier Ltd. All rights reserved.
HSnBu3
MW irradiation
1. Introduction
decarboxylase.7h For the past few years, our group has been prepar-
ing and evaluating biologically important compounds.8 Herein, we
United Nations Program On HIVAIDS (UNAIDS) estimates that
approximately 35.2 million people worldwide are living with HIV
and more than 25 million people have died of AIDS. Thus so far,
28 anti-HIV drugs have been licensed by the United States Food
and Drug Administration (FDA). Most of these drugs belong to two
categories: reverse transcriptase inhibitors (RTI) and protease
inhibitors (PI). Combined application of these antiretroviral drugs
has shown significant synergistic effects.1 However, an increasing
number of patients with HIV infection/AIDS can no longer use such
drugs as a result of drug resistance and serious adverse effects.2
Therefore, it is essential to develop novel anti-HIV drugs targeting
HIV entry. A recent report3 identified 2-aryl-5-(4-oxo-3-phen-
ethyl-2-thioxothiazolidinylidenemethyl)-furans (A, Fig. 1) with
Rhodanine as a core molecule exhibited anti-HIV-1 activity. On
the other hand, Rhodanine4 and its derivatives possessing hydrogen
attached to the nitrogen atom have been patented as fungicides
while the compounds containing nitrogen atom5 were patented as
pesticides, with mention being made of their usefulness as fungi-
cides. 5-Benzylidine-3-pheny-2-thioxo-thiazolidin-4-one core (B,
Fig. 1) was shown to inhibit the Jun NH2-terminal kinase (Jnk) stim-
ulatory phosphatase-1 (JSP-1).6 In addition Rhodanine-based mole-
cules are popular as small molecule inhibitors of numerous targets
such as HCV NS3 protease,7a aldose reductase,7b,c b-lactamase,7d
report the synthesis of a novel class of Rhodanine-based small mol-
ecule with the aim of investigating their inhibitory properties
against JSP-1 and HIV-1 in the low micro molar range.
5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thiox-othiaz-
olidin-4-ones (7a–q) were synthesized by Knoevenagel condensation
of 3-phenyl-2-thioxothiazolidin-4-ones (3a–h) derivatives with suit-
ably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehydes (6a–d) using
MW irradiation and catalytic amount of 2,2,6,6-tetramethyl piperi-
dine (TMP) in ethanol (Scheme 1). Although other bases (Table 1)
can be used as catalyst (e.g., piperidine, pyridine, N-methyl piperidine
(NMP), DBU), TMP works best. The same reaction under conventional
reflux conditionusing ethanolassolvent gavelower yields (11–69%),3
longer time (5 h) and/or compounds required rigorous purification.
However, the MW reaction provides cleaner reaction, 15 min time,
and the products were only required to be washed with cold ethanol.
The yields are good to excellent (Table 3). The optimum temperature
O
O
OH
S
HO
S
R2
R1
N
S
N
S
O
O
O
UDP-N-acetylmuramate/L-alanine UDP-N-acetylmuramate/L-ala-
R1 = H, F, OH, OCH3, Cl
R2 = H, OH, F, Cl
nine ligase,7e antidiabetic agents,7f cathepsin D,7g and histidine
A
B
⇑
Corresponding author. Tel.: +1 2147681280; fax: +1 2147684089.
E-mail addresses: ebiehl@smu.edu, ebiehl@att.net (E.R. Biehl).
Figure 1. Competitive inhibitor of HIV-1 and JSP-1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.114

4376
S. Kamila et al. / Tetrahedron Letters 52 (2011) 4375–4377
NH2
O
HOOCH2CS
HOOCH2CS
R1
R2
Water/Reflux
2h
N
S
R1
S
R1
R2
R2
S
S
2
3a-h
1
N
S
O
O
o
MW/90 C
Ethanol
H
R3
15 mins
O
N
2,2,6,6-Tetramethyl
piperidine
H
7a-q
O
H
Cl
Cl
O
Cl
R3
HSnBu3
O
O
R3
R3
O
o
o
N
H
0
C to RT
N
H
to RT
N
0 C
H
4
5a-d
6a-d
Scheme 1. Schematic representation for the synthesis of 7a–q.
Table 1
Table 2
Screening of solvents, reaction time, and temperature for the synthesis of 7b
Reaction of various aromatic amines with di-(carboxymethyl)-trithiocarbonyl
Base
Conditiona
Temp (°C)
Time (min)
Yieldb (%)
NH2
O
R3
R2
—
—
No solvent
Ethanol
Ethanol
Ethanol
No solvent
Ethanol
Acetonitrile
Acetonitrile
Acetonitrile
DMF
90
90
90
90
90
90
90
130
90
15
15
15
15
15
20
15
15
30
15
30
15
15
15
30
15
15
15
15
Trace
Trace
80
96
Trace
20
76
15
Trace
45
10
Trace
Trace
Trace
Trace
Trace
45
HOOCH2CS
HOOCH2CS
Water
R1
N
S
Piperidene
TMP
TMP
DBU/pyridine
TMP
TMP
DBU
TMP
NMP
DBU
TMP
TMP
—
TMP
TMP
TMP
TMP
S
reflux/ 2 h
R1
R2
S
3a-h
2
1
Entry
R1
H
R2
H
R3
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
H
H
H
H
H
Br
Cl
3.0
2.5
2.5
2.0
4.0
3.0
3.0
3a
3b
3c
3d
3e
3f
75
73
76
75
71
78
76
90
90
CH3
CH3
OCH3
CN
H
CH3
H
DMF
DMF
Water
Water
120–40
90
130
130
90
90
90
90
H
OH
OH
Br
Cl
Water
3g
Toluene
Isopropanol
THF
38
33
N
N
8
H
4.0
3h
75
n-Butanol
S
S
a
All the reaction was carried out in equimolar amounts of each compound in
a
Isolated yield.
2 ml of solvent at 150 psi pressure.
b
Isolated yield.
refluxing equimolar amounts of suitably substituted aromatic
amines (1a–e) and di-(carboxymethyl)-trithiocarbonyl (2). The
aldehydes 6a–d were synthesized by treating corresponding acid
chlorides with HSnBu3.10 The acid chlorides were prepared by acyl-
ation of indole (or substituted indole) with oxalylchloride.11 All
compounds were characterized by 1H NMR, 13C NMR, DEPT-135,
IR and HRMS studies.
In conclusion, we have successfully developed an easy access to
a novel series of (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-phe-
nyl-2-thioxothiazolidin-4-one (7a–q) derivatives. The mild reac-
tion conditions, easy workup, good to excellent yields, and easily
available substrate make this reaction an attractive method for
the preparation of 3-phenyl-2-thioxothiazolidin-4-ones. Efforts to-
ward the synthesis of other important drug molecules with a Rho-
danine moiety by MW irradiation are ongoing in our laboratory.
Also work is in progress to obtain biological activity (antibacterial,
antifungal, anticancer, and neuroprotective kinase inhibitor activ-
ity) of these important compounds. Results in these areas will be
presented in due course.
andconditionforthisMWassistedreactionweredeterminedbyaser-
ies of reactions of 3-phenyl-2-thioxothiazolidin-4-one (3b) and 2-
(1H-indol-3-yl)-2-oxoacetaldehyde (6a). The results are summarized
in Table 1. From this table it is clear that MW irradiation at 90 °C for
15 min in ethanol is the optimum condition for the synthesis of these
molecules. All the compounds 7a–q were isolated as a single (Z) iso-
mer and was confirmed by comparing the vinylic proton shift in 1H
NMR with previously reported3,6 data which appears around d
8.00 ppm. The starting materials 3a–h were synthesized (Table 2)
according to the literature12 procedure.
Compounds 7a–q were obtained in 89–96% yields with high
melting point (>300 °C). They were insoluble in usual organic sol-
vent, water, or hexane. The IR (KBr) spectra of compounds 7a–q ex-
hibit absorption bands due to the stretching vibrations of NH group
of indole cycles (3200 cmÀ1 range). The spectra of compounds 7a–
q display characteristic bands and C@S group (intense bands at
1628–1610 cmÀ1). The 3-phenyl due to stretching vibrations of
two C@O groups (1720 cmÀ1 range -2-thioxothiazolidin-4-ones
(3a–h) derivatives were prepared by the literature9 procedure by

S. Kamila et al. / Tetrahedron Letters 52 (2011) 4375–4377
4377
Table 3
Reaction of various indole based aldehydes with Rhodanine derivatives
R3
R1
R2
S
N
S
H
O
O
O
O
R3
R2
O
MW, ethanol (2 ml)
H
R4
R4
R1
N
S
2,2,6,6-Tetramethyl piperidine
(TMP) (catalytic amount)
N
H
N
S
H
o
90 C, 15 min
3a-h
6a-d
7a-q
Entry
R1
R2
R3
R4
Product
Yielda,b (%)
1
2
3
4
5
6
7
8
9
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
OCH3
OCH3
OCH3
H
7a
7b
7c
7d
7e
7f
7g
7h
7i
95
96
90
93
95
92
94
90
91
89
CH3
CH3
CH3
OCH3
OCH3
H
CN
CN
H
10
H
Cl
7j
N
N
N
N
N
N
11
12
13
H
H
H
H
7k
7l
95
93
91
S
S
S
S
S
S
OCH3
CN
7m
14
15
16
17
OH
OH
OH
OH
Br
Cl
Br
Cl
Br
Cl
Br
Cl
H
H
OCH3
OCH3
7n
7o
7p
7q
90
89
96
90
a
Isolated yield.
b
All the compounds were characterized by 1H NMR, 13C NMR, DEPT-135, IR and HRMS analysis.
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Acknowledgment
The authors are grateful to NIH (1RC2NS064950) for generous
financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.114.
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