Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents

Article abstract of DOI:10.1016/j.bmc.2006.12.003

Compounds having isothiourea or thiourea functional group have shown high anti-HIV-1 activity. Therefore, a series of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones were designed, synthesized, and evaluated for anti-HIV-1 RT activity. The results of in vitro

Full text of DOI:10.1016/j.bmc.2006.12.003

Bioorganic & Medicinal Chemistry 15 (2007) 1725–1731
Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-
thiazolidin-4-ones as anti-HIV agents
Ravindra K. Rawal,a Rajkamal Tripathi,b S. B. Katti,a,* Christophe Pannecouquec
and Erik De Clercqc
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
bMicrobiology Division, Central Drug Research Institute, Lucknow 226 001, India
cRega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium
Received 10 October 2006; revised 25 November 2006; accepted 2 December 2006
Available online 6 December 2006
Abstract—Compounds having isothiourea or thiourea functional group have shown high anti-HIV-1 activity. Therefore, a series of
2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones were designed, synthesized, and evaluated for anti-HIV-1 RT activity. The results of
in vitro tests showed that the compound 9 exhibited EC50 at 0.26 lM with minimal toxicity in MT-4 cells as compared to
0.35 lM for thiazobenzimidazole (TBZ). It may be inferred from the present data that majority of compounds in this series exhibit
higher selectivity index than TBZ.
Ó 2006 Elsevier Ltd. All rights reserved.
imperative to look for new chemical entities having
broad–spectrum activity against a variety of clinically
developed mutant RT enzymes.
1. Introduction
The pathogenesis of HIV-1 is due to uncontrolled viral
replication in CD4+ T cells.1 Several efforts have been
made in the last two decades to understand and control
virus replication. In this direction HIV-1 RT has been
identified as a prime target for designing inhibitors for
treatment of HIV/AIDS.2–4 The introduction of anti-
HIV-1 RT drugs has significantly reduced morbidity
and mortality of HIV/AIDS patients.
In this direction, Barreca et al.6 reported 2,3-diaryl-
substituted-4-thiozolidone scaffold derived from retro-
synthetic opening of the imidazole nucleus of thiazolo-
benzimidazole (TBZ), which selectively inhibits HIV-1
RT. Since then, Barreca and Katti et al. are continuous-
ly trying to achieve enhanced anti-HIV-1 RT activity in
4-thiozolidinones by substituting functional groups at
C-2 and N-3 positions. Detailed QSAR and docking
studies have revealed that the biophoric space around
N-3 can accommodate a variety of heterocyclic moieties
namely, pyridine, pyrimidine, and furfuryl. This
provides compelling rationale for further optimization
at N-3 of thiazolidinone.7–9
Based on function of HIV-1RT there are two types of
inhibitors that can inhibit RT enzyme activity. First,
nucleoside reverse transcriptase inhibitors (NRTIs),
analogs of nucleosides, which bind to the active site of
enzyme and inhibit DNA template elongation. Second,
non-nucleoside reverse transcriptase inhibitors (NNR-
TIs), which bind to the allosteric site of RT and inhibit
enzyme activity. The FDA has approved several NNR-
TIs.5 As it is often observed in anti-viral therapy, the
continuous or discontinuous usage of NNRTIs in
HIV/AIDS patients eventually leads to the development
of resistant virus strains against the drug. Therefore, it is
The rationale behind the present study is a simple
assumption made upon comparison of other NNRTIs
with different skeleton having anti-HIV-RT activity that
there is common thiourea or isothiourea functional
group (Fig. 1). In the present study, the isothiourea or
thiourea was substituted at N-3 position of 4-thiozolid-
inone skeleton. The isothiourea moiety with thiazolidin-
4-one scaffold constitutes the body and remaining part
of the thiazole or benzthiazole moiety and 2,6-
dihalophenyl constitute the wings of the butterfly
Keywords: 4-Thiazolidinones; Anti-HIV activity; HIV-1RT; NNRTIs.
*
Corresponding author. Tel.: +091 522 2212412x4280; fax: +091 522
223405/223938; e-mail: setu_katti@yahoo.com
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.12.003

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R. K. Rawal et al. / Bioorg. Med. Chem. 15 (2007) 1725–1731
analysis of the compounds reported in this study corre-
late with the expected structure.
2.2. Biological evaluation
2.2.1. In vitro HIV-RT kit assay.11 The HIV-RT inhibi-
tion assay was performed by using an RT assay kit
(Roche), and the procedure for assaying RT inhibition
was performed as described in the kit protocol (Roche
Kit). Briefly, the reaction mixture consists of template/
primer complex, dNTPs and reverse transcriptase (RT)
enzyme in the lysis buffer with or without inhibitors.
After 1-h incubation at 37 °C, the reaction mix was
transferred to streptavidine-coated microtitre plate
(MTP). The biotin-labeled dNTPs that are incorporated
in the template due to activity of RT were bound to
streptavidine. The unbound dNTPs were washed using
wash buffer and anti-DIG-POD was added to the
MTP. The DIG-labeled dNTPs incorporated in the tem-
plate were bound to anti-DIG-POD Antibody. The un-
bound anti-DIG-POD was washed and the peroxide
substrate (ABST) was added to the MTP. A colored
reaction product was produced during the cleavage of
the substrate catalyzed by a peroxide enzyme. The
absorbance of the sample was determined at O.D.
405 nm using microtiter plate ELISA reader. The result-
ing color intensity is directly proportional to the actual
RT activity. The percentage inhibitory activity of RT
inhibitors was calculated by comparing to a sample that
does not contain an inhibitor. The percentage inhibition
was calculated by formula as given below
Figure 1. NNRTI lead compounds.
% Inhibition ¼ 100
ꢀ
ꢁ
O:D: 405 nm with inhibitor
conformation of NNRTIs as depicted in Figure 1. The
design, synthesis, and biological activities of these
compounds are presented in this paper.
ꢀ
ꢁ 100 :
O:D: 405 nm without inhibitor
2.2.2. In vitro anti-HIV assay. The methodology of the
anti-HIV assays has been previously described.12 Briefly,
MT-4 or CEM cells were infected with HIV-1IIIB and
HIV-2ROD at 100 times the CCID50 (50% cell culture
infective dose) per milliliter of cell suspension. Then,
100 ll of the infected cell suspension was then trans-
ferred to microtiter plate wells, mixed with 100 ll of
the appropriate dilutions of test compounds, and further
incubated at 37 °C. In CEM cells, after 4 days of incuba-
tion, HIV-1-induced syncytium formation was recorded.
The 50% effective concentration EC50 was defined as the
compound concentration required to inhibit virus-in-
duced syncytium formation by 50%.13 After 5 days of
incubation of MT-4 cells, the number of viable cells
2. Results and discussion
2.1. Chemistry
The synthesis of the new 2,3-diaryl-1,3-thiazolidin-4-
ones (1–15) was carried out according to reported proce-
dure,10 by reacting a suitable (hetero)aromatic amine (1)
with an equimolar amount of 2,6-dihalo-substituted
benzaldehyde (2) in the presence of an excess of mercap-
toacetic acid (3) in toluene reflux (Scheme 1). After com-
pletion of reaction, which takes usually 24 h, the desired
products were obtained in moderate to excellent yields
and purity. The spectral data including the elemental
Scheme 1. General synthetic scheme of 4-thiazolidinones.

Table 1. Anti-HIV-1 activity, cytotoxicity, and selectivity index in MT-4 cells and in CEM cells for selected compounds with HIV-1 RT kit assay for compounds, 1–15
O
N
R1
N
S
X
S
R2
R3
Compound
R1
R2
X
R3
Anti-HIV-1 activity
% HIV-RT inhibition at 100 lg/ml
EC50a(lM)
CC50b(lM)
SIc
20
60
HIV-1IIIBMT-4
HIV-1IIIBCEM
MT-4 cells
CEM cells
MT-4 cells
CEM cells
1
2
H
H
C
C
C
C
C
C
C
C
C
C
N
N
N
Cl
Cl
F
Cl
F
1.51 1.51
0.76 0.35
1.34 0.20
1.51 0.23
1.12 0.46
3.20 1.44
>125.20
0.41 0.06
0.60 0.35
1.17 0.30
1.85 0.64
1.16 0.34
2.72 1.31
NTd
>377.37
44.16 2.00
>419
>377.37
44.16 2.00
>419
>251
58
>893
72
78.56
89.80
94.50
53.30
69.60
81.00
60.08
39.10
81.59
87.88
26.30
18.50
16.70
19.90
45.06
NTd
H
H
3
H
H
F
>313
167
143
>125
<1
>358
135
140
4
Me
Me
Me
Ph
Me
Me
Me
—
H
Cl
Cl
F
Cl
F
249.31 32.99
162.56 144.67
>400.18
249.31 32.99
162.56 144.67
>400.18
NTd
5
H
6
H
F
>147
NTd
>157
138
7
H
Cl
Cl
Cl
F
Cl
Cl
F
126.26
>347.90
8
Me
Me
Me
Et
Et
Et
2.67 2.37
0.26 0.03
0.46 0.15
>53.57
2.23 1.84
0.23 0.06
0.37 0.18
NTd
>347.90
32.73 13.65
>382.98
NTd
131
113
123
<1
9
31.01 15.11
56.37
10
11
12
13
14
15
16
F
>1001
NTd
NTd
NTd
NTd
NTd
P8980
45
Cl
Cl
F
Cl
F
60.59 6.94
18.88 11.84
156.49 78.23
>327.83
—
—
>18.88
>51.01
>327.83
NTd
NTd
<1
<1
F
NTd
NTd
Benzthiazol-2-yl
Benzthiazol-2-yl
Compound 16
TBZ
Cl
Cl
Cl
F
NTd
NTd
<1
12
25.73 19.13
0.030 0.013
0.35 0.14
NTd
213.51 86.75
32.0 0.54
19.20 2.80
NTd
0.030 0.002
1.10 0.32
P269.4
50.0 3.2
1066
54.5
NTd
a EC50 is the 50% effective concentration required to reduce HIV-1 induced cytopathic effect of HIV-1IIIB in MT-4 cells and HIV-1RF in CEM cells.
b The CC50 is the 50% cytotoxic concentration for MT-4 cell and mock-infected CEM cells.
c Selectivity index ratio CC50/EC50
d Not tested. All data represent mean values for at least two separate experiments.
.

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R. K. Rawal et al. / Bioorg. Med. Chem. 15 (2007) 1725–1731
was determined. The 50% effective concentration EC50
was defined as the concentrations of compound required
for reducing the number of cell viability in MT-4 cells.
The cytotoxic concentration CC50 was determined as
the concentrations of compound required to inhibit by
50% the number of viable cells in mock-infected MT-4
and CEM cell cultures.
responding 2,6-dichloro substituted (1, 4, and 8) and
2,6-difluoro substituted (3,6, and 10) compounds. Fur-
ther the favorable effect of 2-chloro-6-fluoro was con-
firmed by the finding that 2,6-difluoro derivative (3, 6,
and 10) possessed intermediate activity between 2,6-
dichloro and 2-chloro-6-fluoro analogues. On the other
hand, the introduction of the 5-ethyl-[1,3,4]-thiadiazol-
2-yl (11–13) at N-3 led to a substantial decrease in the
activity than the thiazol-2yl and benzthiazol-2-yl moie-
ty-containing compounds. Although present series of
compounds are less active than 3-(6-bromopyridin-2-
yl)-2-(2,6-difluorophenyl)-1,3-thiazolidin-4-one (com-
pound 16 in Table 1)6 it may be appropriate to mention
that thiazolidinone scaffold can accommodate heteroaryl
moiety other than pyridine moiety and with further opti-
mization it may be possible to obtain compounds with im-
proved activity.
2.3. Biological activity
All compounds (1–15) were initially analyzed for anti-RT
activity by HIV-RT kit (Roche). The compounds showed
varied inhibition activity against RT in vitro. Further, the
compounds (1–15) and TBZ were evaluated for anti-
HIV-1 activity by determining their ability to inhibit the
HIV-1IIIB or HIV-2ROD reverse transcriptase enzyme in
MT-4 and CEM cells (Table 1). Those compounds show-
ing inhibitory activity against RT in the kit also showed
anti-HIV-1 activity in MT-4 and CEM cells with few
exceptions (Table 1). The results obtained show that our
approach has led to develop a highly potent anti-HIV-1
compound (9), which is active at a concentration of
0.26 lM compared to 0.35 lM of TBZ in MT-4 cells.
The increase in activity of compound 9 than TBZ could
be because it can adoptmore flexible conformation, which
enables an appropriate binding with the non-nucleoside
reverse transcriptase inhibitory binding pocket. Second,
compound 9 is more potent within the series because of
additional lipophilic character at the thiazol-2-yl moiety
in terms of 4,5-dimethyl substitution. Interestingly, other
compounds of the series 1–6 and 8–10 in MT-4 cells were
less active compared to TBZ but were having a high selec-
tive index (Table 1). Similarly, compounds 1, 2, 9, and 10
were active at 0.41, 0.60, 0.23, and 0.37 lM concentration
which were 2.68, 1.80, 4.78, and 2.97 times, respectively,
more active than TBZ in CEM cells. Other compounds
3–8 were less active compared to TBZ but have demon-
strated high selective index (Table 1). The compounds
that were less toxic and having high selective index com-
pared to TBZ clearly suggest that these compounds could
be used at high concentration for conferring high anti-
HIV activity.
3. Conclusions
The introduction of a thiazol-2-yl moiety (with or without
substitution) at the N-3 position of 4-thiazolidinone scaf-
fold has led to an increase in the anti-HIV-1 RT activity
and, in some compounds, activity is higher than for the
lead molecule TBZ. In this series, compound 9 was found
to be the most promising with an EC50 of 0.26 and
0.23 lM, and selectivity index of 113 and 138 in MT-4
cells and CEM cells, respectively. Other compounds in
this series namely, 1, 2, and 10 were more active than
the lead compound TBZ in CEM cells with higher selec-
tivity indices. Taken together these results indicate that
changes at N-3 position of 4-thiazolidinone scaffolds with
different heterocyclic moiety, with an appropriate lipo-
philic character, may provide compounds with improved
activity. It may be noted that substitution at N-3 position
of 4-thiazolidinone skeletons deserves further consider-
ation toward optimizing anti-HIV1 RT activity.
4. Experimental
Melting points (mp) were determined on a Complab
melting point apparatus and are uncorrected. The C,
H, and N analyses were carried out on CARLO-ERBA
EA1108 elemental analyser. Infrared (IR) spectra were
recorded on an FT-IR Perkin-Elmer (model) spectrom-
From the biological activity data reported in Table 1, it
may be inferred that the anti-HIV activity is strongly
dependent on the nature of the substituent at C-2 and
N-3 of the thiazolidinone ring. In particular, a high
activity level was observed for compounds possessing a
2,6-dihalophenyl group at C-2 and a pyridine-2-yl or
pyrimidine-2-yl ring at N-3. As suggested by molecular
modeling studies, the introduction of a lipophilic substi-
tuent in the hetero (aromatic) ring led to a substantial
increase in the antiviral activity. In the present study,
the anti-HIV activity was enhanced by introducing a
substituted and unsubstituted 2-thiazolyl moieties at
the N-3 position by keeping an intact 2,6-dihalo-phenyl
substituent at C-2 of the 4-thiazolidinone ring. In fact,
the compounds with the best combination of high
potency and low toxicity were unsubstituted or 4,5-di-
methyl substituted thiazol-2-yl derivatives, such as 1,
2, 9, and 10. The effect of halogen substituent on the
phenyl ring at C-2, was apparent in compounds 2, 5,
and 9. These compounds were more active than the cor-
1
eter. The H spectra were recorded on a DPX-200 and
DPX-300 Bruker FT-NMR spectrometer. The chemical
shifts are reported as parts per million (d ppm) from
(CH3)4Si (TMS) as an internal standard. The 13C
NMR spectra were recorded on a DPX-300 Bruker
FT-NMR (75 MHz) spectrometer. Mass spectra were
obtained on a JEOL-SX-102 instrument using fast atom
bombardment (FAB positive) technique. Column chro-
matography separations were obtained on silica gel
(230–400 mesh).
4.1. General synthetic procedure for compounds 1–15
The synthesis of compounds 1–15 was performed
according to the previously reported procedure.10,14
The appropriate (hetero)aromatic amine (1.0 mmol)

R. K. Rawal et al. / Bioorg. Med. Chem. 15 (2007) 1725–1731
1729
and 2,6-dihalo-substituted benzaldehyde (1.2 mmol)
were stirred in dry toluene under reflux condition fol-
lowed by addition of mercapto acid (2.0 mmol). The
reaction mixture was refluxed under stirring for an addi-
tional 24–48 h untill the complete consumption of (het-
ero) aromatic amine. The reaction mixture was
concentrated to dryness under reduced pressure and
the residue was taken up in ethyl acetate. The organic
layer was successively washed with 5% aq citric acid,
water, 5% aq sodium hydrogen carbonate, and then
finally with brine. The organic layer was dried over sodi-
um sulfate and solvent was removed under reduced pres-
sure to get a crude product that was purified by column
chromatography on silica gel using hexane–ethyl acetate
as eluent. The structures of all synthesized compounds
347 [M+2]. Anal. Calcd for C12H8ClFN2OS2: C, 45.22;
H, 2.92; N, 8.11. Found: C, 45.11; H, 2.76; N, 8.01.
4.6. 20-(2-Chloro-6-fluoro-phenyl)-4-methyl-[2,30]bithiaz-
olyl-40-one (5)
This compound was obtained as solid in 62% yield, mp
1
130–132 °C IR (KBr): mmax C@O 1694 cmꢀ1; H NMR
(300 MHz, CDCl3): d 2.21 (s, 1H, CH3), 3.83 (dd,
J = 3.33 and 15.96 Hz, 1H, 5-HA), 4.18 (dd, J = 1.38
and 15.96 Hz, 1H, 5-HB), 6.52 (s, 1H, H05-thiazole),
6.89 (m, 1H, H4-Ph), 7.15 (s, 1H, H-2), 7.18–7.24 (m,
2H, H3 and H5-Ph); FAB-MS: m/z 329 [M]+.
4.7. 20-(2,6-Difluoro-phenyl)-4-methyl-[2,30]bithiazolyl-40-
one (6)
1
were characterized by TLC, IR, FAB-MS, H NMR,
and 13C NMR.
This compound was obtained as solid in 54% yield, mp
1
145–148 °C IR (KBr): mmax C@O 1694 cmꢀ1; H NMR
4.2. 20-(2,6-Dichloro-phenyl)-[2,30]bithiazolyl-40-one (1)
(200 MHz, CDCl3): d 2.20 (s, 3H, CH3), 3.80 (dd,
J = 2.00 and 15.98 Hz, 1H, 5-HA), 4.18 (d,
J = 16.02 Hz, 1H, 5-HB), 6.51 (s, 1H, H5-thiazole),
6.81 (t, 1H, H4-Ph), 6.97 (s, 1H, H-2), 7.17–7.22 (m,
2H, H3-Ph and H5-Ph); FAB-MS: m/z 313 [M+1]+.
This compound was obtained as solid in 70% yield, mp
1
183–185 °C IR (KBr): mmax C@O 1693 cmꢀ1; H NMR
(300 MHz, CDCl3) d: 3.93 (d, J = 16.02 Hz, 1H, 5-
HA), 4.16 (dd, J = 1.56 and 16.02 Hz, 1H, 5-HB), 6.97
(d, J = 3.54 Hz, 1H, H-2), 7.10–7.20 (m, 2H, H3 and
H5-Ph), 7.32–7.41 (m, 3H, H4-Ph and H04 and H50 -thia-
zole); 13C NMR (300 MHz, CDCl3): d 169.35, 155.21,
136.50, 134.19, 132.82, 131.38, 129.12, 128.15, 127.52,
112.82, 58.34, 33.32; FAB-MS: m/z 331 [M]+ and 333
[M+2]. Anal. Calcd for C12H8Cl2N2OS2: C, 43.51; H,
2.43; N, 8.46. Found: C, 43.21; H, 2.11; N, 8.08.
4.8. 20-(2,6-Dichloro-phenyl)-4-phenyl-[2,30]bithiazolyl-
40-one (7)
This compound was obtained as solid in 40% yield, IR
(KBr): mmax C@O 1694 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d 3.80 (d, 16.08, 1H, 5-HA), 4.18 (d,
J = 16.02 Hz, 1H, 5-HB), 7.16 (s, 1H, H5-thiazole), 7.18–
7.67 (m, 9H, H-2 and Ar-H);FAB-MS: m/z 313 [M+1]+.
4.3. 20-(2-Chloro-6-fluoro-phenyl)-[2,30]bithiazolyl-40-one
(2)
4.9. 20-(2,6-Dichloro-phenyl)-4,5-dimethyl-[2,30]bithiazol-
yl-40-one (8)
This compound was obtained as solid in 65% yield, mp
1
155–157 °C IR (KBr): mmax C@O 1694 cmꢀ1; H NMR
This compound was obtained as solid in 65% yield, mp
above 210 °C IR (KBr): mmax C@O 1694 cmꢀ1; 1H NMR
(300 MHz, CDCl3): d 2.03 (s, 3H, CH3 at C5-thiazole),
2.23 (s, 3H, CH3 at C4-thiazole), 3.91 (d, J = 15.99 Hz,
1H, 5-HA), 4.10 (dd, J = 2.10 and 15.93 Hz, 1H,
5-HB), 7.10 (m, 2H, H-2 and H4-Ph), 7.33–7.38 (m,
2H, H3-Ph and H5-Ph); 13C NMR (300 MHz, CDCl3):
d 168.85, 150.41, 141.24, 134.59, 132.96, 131.76,
129.04, 127.99, 127.23, 119.50, 57.98, 33.46, 13.08,
9.46; FAB-MS: m/z 359 [M]+ and 361 [M+2]. Anal.
Calcd for C14H12Cl2N2OS2: C, 46.80; H, 3.37; N, 7.80.
Found: C, 46.99; H, 3.20; N, 7.56.
(200 MHz, CDCl3): d 3.81 (dd, J = 3.11 and 16.01 Hz,
1H, 5-HA), 4.15 (d, J = 15.99 Hz, 1H, 5-HB), 6.97 (d,
J = 3.52 Hz, 1H, H-2),7.14–7.37 (m, 5H, Ar-H); FAB-
MS: m/z 315 [M+1]+.
4.4. 20-(2,6-Difluoro-phenyl)-[2,30]bithiazolyl-40-one (3)
This compound was obtained as solid in 58% yield, mp
1
145–148 °C IR (KBr): mmax C@O 1694 cmꢀ1; H NMR
(200 MHz, CDCl3): d 3.83 (d, J = 16.14 Hz, 1H, 5-
HA), 4.21 (d, J = 16.05 Hz, 1H, 5-HB), 6.82 (s, 1H, H-
2), 7.86–7.39 (m, 5H, Ar-H); FAB-MS: m/z 299 [M+1]+.
4.5. 20-(2,6-Dichloro-phenyl)-4-methyl-[2,30]bithiazolyl-
40-one (4)
4.10. 20-(2-Chloro-6-fluoro-phenyl)-4,5-dimethyl-[2,30]-
bithiazolyl-40-one (9)
This compound was obtained as solid in 68% yield, mp
1
This compound was obtained as solid in 60% yield, mp
1
168–170 °C IR (KBr): mmax C@O 1694 cmꢀ1; H NMR
159–161 °C IR (KBr): mmax C@O 1692 cmꢀ1; H NMR
(300 MHz, CDCl3): d 2.15 (s, 1H, CH3), 3.93 (d,
J = 16.02 Hz, 1H, 5-HA), 4.14 (dd, J = 2.04 and
16.02 Hz, 1H, 5-HB), 6.51 (s, 1H, H05-thiazole), 7.09–
7.20 (m, 2H, H-2 and H4-Ph), 7.33–7.40 (m, 2H, H3 and
H5-Ph); 13C NMR (300 MHz, CDCl3): d 169.14, 154.06,
146.25, 134.61, 132.84, 131.73, 129.05, 128.07, 127.27,
107.28, 58.22, 33.45, 15.70; FAB-MS: m/z 345 [M]+ and
(300 MHz, CDCl3): d 2.04 (s, 3H, CH3 at C5-thiazole),
2.24 (s, 3H, CH3 at C4-thiazole), 3.81 (dd, J = 3.36
and 15.93 Hz, 1H, 5-HA), 4.15 (dd, J = 1.50 and
15.93 Hz, 1H, 5-HB), 6.88 (m, 1H, H4-Ph), 7.11 (s, 1H,
H-2), 7.14–7.22 (m, 1H, H3 and H5-Ph); 13C NMR
(300 MHz, CDCl3): d 168.62, 150.64, 141.29, 133.18,
128.35, 125.38, 124.30, 119.44, 114.15, 113.84, 56.44,

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R. K. Rawal et al. / Bioorg. Med. Chem. 15 (2007) 1725–1731
33.47, 13.12, 9.46; FAB-MS: m/z 343[M]+. Anal. Calcd
for C14H12ClFN2OS2: C, 49.05; H, 3.53; N, 8.17. Found:
C, 49.09; H, 3.36; N, 7.94.
1H, 5-HA), 4.19 (dd, J = 1.92 and 16.24 Hz, 1H, 5-
HB), 7.12–7.42 (m, 5H, H3, H4 and H5-Ph and H05 and
H06-benzthiazole), 7.52 (d, J = 1.8 Hz, 1H, H-2), 7.67
(d, J = 8.37 Hz, 1H, H04-benzthiazole), 7.77 (d,
J = 8.38 Hz, 1H, H05-benzthiazole); FAB-MS: m/z 381
[M]+ and 383 [M+2]. Anal. Calcd for C16H10Cl2N2OS2:
C, 50.40; H, 2.64; N, 7.35; S, 16.82. Found: C, 50.03; H,
2.50; N, 7.06; S, 16.88.
4.11. 20-(2,6-Difluoro-phenyl)-4,5-dimethyl-[2,30]bithiaz-
olyl-40-one (10)
This compound was obtained as solid in 52% yield, mp
1
158–160 °C IR (KBr): mmax C@O 1695 cmꢀ1; H NMR
4.16. 3-Bezothiazol-2-yl-2-(2-chloro-6-fluoro-phenyl)-
thiazolidin-4-one (15)
(200 MHz, CDCl3): d 2.07 (s, 3H, CH3 at C5-thiazole),
2.22 (s, 3H, CH3 at C4-thiazole), 3.78 (dd, J = 2.02
and 15.92 Hz, 1H, 5-HA), 4.16 (d, J = 15.90 Hz, 1H, 5-
HB), 6.80 (t, 1H, H4-Ph), 6.93 (d, J = 1.2 Hz, 1H, H-
2), 7.13–7.25 (m, 2H, J = 2.08 Hz, H3-Ph and H5-Ph);
FAB-MS: m/z 327 [M+1]+. Anal. Calcd for
C14H12F2N2OS2: C, 51.52; H, 3.71; N, 8.58. Found: C,
51.50; H, 3.59; N, 8.36.
This compound was obtained as white solid in 41%
yield, mp 160–162 °C; IR (KBr): mmax C@O 1709 cmꢀ1
;
1H NMR (200 MHz, CDCl3) d: 3.93 (dd, J = 2.79 and
16.21 Hz, 1H, 5-HA), 4.20 (d, J = 16.21 Hz HZ, 1H,
5-HB), 7.15–7.33 (m, 5H, H3, H4 and H5-Ph and H50
and H06-benzthiazole), 7.36 (s, 1H, H-2), 7.67 (d,
J = 8.37 Hz, 1H, H04-benzthiazole), 7.67 (d, J =
8.38 Hz, 1H, H05-benzthiazole); FAB-MS: m/z 365
[M+H]+. Anal. Calcd for C16H10ClFN2OS2: C, 52.67;
H, 2.76; N, 7.68; S, 17.58. Found: C, 52.84; H, 2.56;
N, 7.58; S, 17.92.
4.12. 2-(2,6-Dichloro-phenyl)-3-(5-ethyl-[1,3,4]thiadiazol-
2-yl)-thiazolidin-4-one (11)
This compound was obtained as solid in 58% yield, mp
1
162–165 °C IR (KBr): mmax C@O 1693 cmꢀ1; H NMR
(200 MHz, CDCl3): d 1.33 (t, 3H, CH3), 2.94 (q, 2H,
CH2), 3.91 (d, J = 16.29 Hz, 1H, 5-HA), 4.14 (dd,
J = 1.84 and 16.26 Hz, 1H, 5-HB), 7.09 (t, 1H, H4-Ph),
7.33 (d, J = 2.21 Hz, 1H, H-2), 7.37–7.43 (m, 2H, H3-
Ph and H5-Ph); FAB-MS: m/z 360 [M]+ and 362
[M+2]. Anal. Calcd for C12H8ClFN2OS2: C, 43.51; H,
2.43; N, 8.46. Found: C, 43.33; H, 2.40; N, 8.26.
Acknowledgments
The authors thank the Director, CDRI, for the support
and the SAIF for the spectral data. CDRI Communica-
tion No. 7082.
4.13. 2-(2-Chloro-6-fluoro-phenyl)-3-(5-ethyl-[1,3,4]thia-
diazol-2-yl)-thiazolidin-4-one (12)
References and notes
This compound was obtained as solid in 53% yield, IR
1. Turner, B. G.; Summers, M. F. J. Mol. Biol. 1999,
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2. Arnold, E.; Das, K.; Ding, J.; Yadav, P. N. S., et al. Drug
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(KBr): mmax C@O 1693 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d 1.34 (t, 3H, CH3), 2.96 (q, 2H, CH2), 3.84
(d, J = 16.14 Hz, 1H, 5-HA), 4.15 (d, J = 16.01 Hz,
1H, 5-HB), 6.85 (t, 1H, H4-Ph), 7.10 (s, 1H, H-2),
7.17–7.21 (m, 2H, H3-Ph and H5-Ph); FAB-MS: m/z
344 [M]+.
3. Gazzard, B.; Moyle, M. Lancet 1998, 352, 314.
4. De Clercq, E. Trends Pharmacol. Sci. 1990, 11, 198.
5. Ren, J.; Esnouf, R.; Garman, E.; Somers, D.; Ross,
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V. R.; Katti, S. B. Comb. Chem. High Throughput
Screening 2005, 8, 431.
4.14. 2-(2,6-Difluoro-phenyl)-3-(5-ethyl-[1,3,4]thiadiazol-
2-yl)-thiazolidin-4-one (13)
This compound was obtained as solid in 44% yield,
;
1H
mp 110–114 °C IR (KBr): mmax C@O 1705 cmꢀ1
NMR (300 MHz, CDCl3): d 1.38 (t, 3H, CH3), 2.98
(q, 2H, CH2), 3.86 (d, J = 16.23 Hz, 1H, 5-HA), 4.21
(d, J = 16.26 Hz, 1H, 5-HB), 6.85 (t, 2H, H3-Ph and
H5-Ph), 7.01 (s, 1H, H-2), 7.19–7.27 (m, 1H, H4-Ph);
13C NMR (300 MHz, CDCl3): d 168.98, 166.42,
160.92, 157.60, 155.53, 128.88, 115.06, 110.93,
110.60, 52.37, 32.00, 22.20, 12.42; FAB-MS: m/z 328
[M]+.
9. Rawal, R. K.; Prabhakar, Y. S.; Katti, S. B.; De Clercq, E.
Bioorg. Med. Chem. 2005, 13, 6771.
10. Barreca, M. L.; Chimirri, A.; Luca, L. D.; Monforte, A.
M.; Monforte, P.; Rao, A.; Zappala, M.; Balzarini, J.; De
Clercq, E.; Pannecouque, C.; Witvrouw, M. Bioorg. Med.
Chem. Lett. 2001, 11, 1793.
11. Reverse Transcriptase Assay, Colorimetric kit, Roche
Diagnostics GmbH, Roche Applied Science, Sandhofer
Strasses 116, D-68305 Mannheim, Germany.
4.15. 3-Bezothiazol-2-yl-2-(2,6-dichloro-phenyl)-thiazoli-
din-4-one (14)
This compound was obtained as white solid in 49%
;
yield, mp >220 °C; IR (KBr): mmax C@O 1694 cmꢀ1
1H NMR (200 MHz, CDCl3) d: 3.96 (dd, J = 16.22 Hz,

R. K. Rawal et al. / Bioorg. Med. Chem. 15 (2007) 1725–1731
1731
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D.; Herdewijin, P.; Desmyter, J.; De Clercq, E. J. Virol.
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Camarasa, M.-J.; De Clercq, E. Virology 1993, 192,
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14. Holmes, C. P.; Chinn, J. P.; Look, C. G.; Gordon,
E. M.; Gallop, M. A. J. Org. Chem. 1995, 60,
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´
13. Balzarini, J.; Karlsson, A.; Perez-Perez, M.-J.; Vrang, L.;
Walbers, J.; Zhang, H.; Oberg, B.; Vandamme, A.-M.;
´
¨