Novel imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2012.01.052

The increase in the prevalence of multi drug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis case demonstrates the urgent need of discovering new promising compounds with antimycobacterial activity. As part of our research program and with a aim of identifying new antitubercular drug candidates, a new class of 2-(trifluoromethyl)-6- arylimidazo[2,1-b][1,3,4]thiadiazole derivatives has been synthesized by both conventional as well as microwave assisted method and evaluated for their in vitro antitubercular activity against M. tuberculosis H₃₇Rv. Moreover, various drug-likeness properties of new compounds were predicted. Seven compounds from the series exhibited good activity with MIC in range 3.12-1.56 μg/ml. The present study suggests that compounds 6b, 6c, 6d, 6e and 6f may serve as promising lead scaffolds for further generation of new anti-TB agents.

Full text of DOI:10.1016/j.bmcl.2012.01.052

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1917–1921
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic acid
as potential antitubercular agents
⇑
Shankar G. Alegaon , Kallanagouda R. Alagawadi, Pranali V. Sonkusare, Sagar M. Chaudhary,
Dilip H. Dadwe, Amol S. Shah
Department of Pharmaceutical Chemistry, KLE University’s College of Pharmacy, Nehru Nagar, Belgaum 590 010, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The increase in the prevalence of multi drug-resistant and extensively drug-resistant strains of
Mycobacterium tuberculosis case demonstrates the urgent need of discovering new promising compounds
with antimycobacterial activity. As part of our research program and with a aim of identifying new anti-
tubercular drug candidates, a new class of 2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazole
derivatives has been synthesized by both conventional as well as microwave assisted method and
evaluated for their in vitro antitubercular activity against M. tuberculosis H37Rv. Moreover, various
drug-likeness properties of new compounds were predicted. Seven compounds from the series exhibited
Received 29 November 2011
Revised 5 January 2012
Accepted 16 January 2012
Available online 26 January 2012
Keywords:
Imidazo[2,1-b][1,3,4]thiadiazole
Thiazolidine-2,4-diones
Rhodanine acetic acid
Drug-likeness
good activity with MIC in range 3.12–1.56 lg/ml. The present study suggests that compounds6b, 6c, 6d,
6e and 6f may serve as promising lead scaffolds for further generation of new anti-TB agents.
Ó 2012 Elsevier Ltd. All rights reserved.
Antitubercular activity
The prevalence of tuberculosis (TB) has steadily risen in the last
decade. TB is a disease of poverty affecting mostly young adults in
their most productive years. The vast majority of TB deaths are in
the developing countries. The estimated death from TB was 1.7
million in 2009, including 380,000 people with HIV, equal to
4700 deaths a day.1 TB is considered to be a major public health
problem in India. India accounts for one-fifth of the global TB inci-
dent cases. Each year nearly 2 million people in India are infected
by TB, of which around 0.87 million are infectious cases. It is esti-
mated that annually around 330,000 Indians die due to TB.2 Fur-
thermore, the increase in TB cases caused by multi drug-resistant
(MDR) and extensively drug-resistant (XDR) strains of Mycobacte-
rium tuberculosis (Mtb), which are insensitive to one or more of
the first line drugs, has further worsened the situation.3 Moreover,
the association of TB and HIV infections has caused an urgent need
in search of alternative chemotherapeutics for M. tuberculosis
infections.
The diverse biological activities of imidazo[2,1-b][1,3,4]-thiadi-
azole and their derivatives have been known from early 1950s and
since then, the research work on this heterocyclic system has led to
significant developments in their chemistry and biology. Kolavi
et al.4 in 2006 reported some2-(2-furyl)-6-phenylimidazo[2,1-
b][1,3,4]-thiadiazole-5-carbaldehyde and (2-cyclohexyl-6-pheny-
limidazo[2,1-b][1,3,4]-thiadiazol-5-yl)methanol as antitubercular
agents againstM. tuberculosis. Subsequently, a large number of imi-
dazo[2,1-b][1,3,4]-thiadiazole derivatives have been reported to
possess diverse pharmacological activities, viz., antibacterial,5,6
antifungal,7 anticancer,8,9 anticonvulsant and analgesic,10 anthel-
mintic,11 Carbonic anhydrase inhibitors,12 calcium channel block-
er,13 diuretic activity.14
Thiazolidine-2,4-diones, rhodanines and their derivatives have
attracted interest in medicinal chemistry, exhibiting pharmacolog-
ical and therapeutic properties, since the introduction of various
glitazones and epalrestat into clinical use for the treatment of type
II diabetes mellitus and diabetic complications, respectively. Chem-
ical modifications of these heterocycles constantly result in
compounds with a wide spectrum of biological activities. Singh
et al.15 in 2008 reported the antitubercular effects of rhodanines.
Bryk et al.16 in 2008 have reported some of furan derivatives of rho-
danines as irreversible, substrate-dependent and time-dependent
inhibitor of Mtb dihydrolipoamide acylatransferase (DlaT). Tomasic
et al.17 in 2009 have reported some thiazolidine-2,4-diones and
rhodanines are active inhibitors of Mur ligases. Rhodanine-based
molecules have been shown to be small molecule inhibitors of
numerous targets such as hepatitis C virus (HVC) NS3 protease,18
b-lactamase,19 UDP-N-acetylmuramate/ -alanine ligase,20 penicil-
L
lin binding protein (PBP),21 and histidine decarboxylase.22 In addi-
tion, Talele et al.23 in 2010 have reported that rhodanine analogs are
inhibitors of the HCV enzyme NS5B polymerase.
In view of the high degree of bioactivity shown by the above
two heterocyclic system, and continuation of our search for biolog-
ical active heterocyclic compounds, it was envisaged to construct a
⇑
Corresponding author. Tel.: +91 8312471399; fax: +91 8312472387.
E-mail addresses: shankar_alegaon@yahoo.co.in, sgalegaon@gmail.com (S.G.
Alegaon).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.052

1918
S. G. Alegaon et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1917–1921
system, which combines both these systems in a single molecular
frame and to explore the additive effects towards their antituber-
cular activities. Hence we have synthesized and evaluated new ser-
ies of 2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]-thiadiazole
derivatives.
The 21 new 2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]-
thiadiazole derivatives presented in this work were prepared
through the synthetic route illustrated in Scheme 1. The route
adapted for the synthesis of 2-(trifluoromethyl)-6-arylimidazo-
[2,1-b][1,3,4]-thiadiazole compounds using a modified literature
method.24 The starting compounds 2-(trifluoromethyl)-6-arylimi-
dazo[2,1-b][1,3,4]-thiadiazoles (2a–g) were synthesised by
microwave assisted reaction between 5-(trifluoromethyl)-1,3,4-
acid) in the presence of catalytic amount of piperidineacetate to
afford 5-{[2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]-thiadia-
zol-5-yl]methylene}thiazolidine-2,4-dione (4a–g), 5-{[2-(trifluoro-
methyl)-6-arylimidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methylene}-
2-thioxothiazolidin-4-one (5a–g) and 2-[(5Z)-5-{[2-(trifluoro-
methyl)-6-arylimidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methylene}-
4-oxo-2-thioxothiazolidin-3-yl]acetic acid (6a–g) respectively.
Purity of the compounds was checked on TLC plates (silica gel G)
which were visualized by exposing to iodine vapours. All the reac-
tions under microwave irradiation were completed within 10–15
min whereas similar reactions under conventional heating (oil bath)
at reflux gave poor yields after much longer reaction time. The
comparison study data are given in Table 1. The structures of these
compounds were confirmed by IR, NMR, mass spectra and also by
elemental analysis.
thiadiazol-2-amine (1) and various substituted a-haloaryl ketone.
Inthenext step, imidazo[2,1-b][1,3,4]-thiadiazoles (2a–g)weresub-
jected in to Vilsmeier–Haack reaction to afford 2-(trifluoromethyl)-
6-arylimidazo[2,1-b][1,3,4]-thiadiazole-5-carbaldehydes (3a–g).
Then, obtained imidazo[2,1-b][1,3,4]thiadiazoles-5-carbaldehydes
(3a–g) were subjected to Knoevenagel condensation25,26 with
thiazolidine-2,4-dione, 2-thioxothiazolidin-4-one (rhodanine) and
2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid (rhodanine acetic
The formation of 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine
(1) by IR and 1H NMR spectra, which showed the presence of amine
(–NH2) band at 3468 cmÀ1 in the IR spectra and appearance of
amine proton at d 7.96 ppm in the 1H NMR spectra. Structures of
imidazothiadiazole derivatives (2a–g) were established by the ab-
sence of amine (–NH2) band in IR spectra, and the 1H NMR spectra
H
N
NH2
(CF3CO)2O
+
H2N
S
(a)
N
N
F3C
NH2
O
S
(1)
Conven (10 hr)
MW (10-15 min)
Br
(b)
Ar
H
R
N
S
N
F3C
N
(2 a-g)
O
(c)
OH
O
H
N
N
O
O
S
O
S
S
H
H
H
R
R
R
(d)
N
N
N
S
N
S
(f)
N
N
F3C
F3C
F3C
S
N
N
N
Conven (12 hr)
MW (10-12 min)
Conven (12 hr)
MW (10-12 min)
(6 a-g)
(4 a-g)
(3 a-g)
Conven (12 hr)
(e)
MW (10-12 min)
H
N
O
S
S
H
R
N
N
F3C
S
N
(5 a-g)
Scheme 1. Reagents and conditions: (a) À5 to 0 °C, 2 h, 81%; (b) M.W. (600 watts) 10–15 min; 65–71%; (c) Vilsmeiere–Haack reagent, 8 h, 50–66%; (d) thiazolidine-2,4-dione,
M.W. (600 watts) 10 min; 69–72%; (e) rhodanine, M.W. (600 watts) 12 min; 69–75%; (f) rhodanine acetic acid, M.W. (600 watts) 12 min 68–76%.

S. G. Alegaon et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1917–1921
1919
Table 1
Physical constant and antimycobacterial activity of 2-(trifluoromethyl)-6-arylimidazo [2,1-b][1,3,4]-thiadiazole derivatives
HO
O
H
N
H
N
N
O
O
O
O
S
S
S
S
S
H
H
H
R
R
R
N
S
N
S
N
S
N
N
N
F3C
F3C
F3C
N
N
N
(4 a-g)
(5 a-g)
(6 a-g)
Compound
R
Mol. formula
Mol. wt
Mpa (°C)
Conventional method
Microwave method
MIC (lg/ml)
Yield (%)
Period (h)
Yield (%)
Period (min)
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
5f
5g
6a
6b
H
Cl
Br
F
CH3
OCH3
NO2
H
Cl
Br
C
C
C
C
15H7F3N4O2S2
15H6ClF3N4O2S2
15H6BrF3N4O2S2
15H6F4N4O2S2
396
430
475
414
410
426
441
412
446
491
430
426
442
457
470
504
549
488
484
500
515
—
211–212
220–222
150–151
194–195
270–271
270–272
266–267
250–251
210–211
195–197
190–192
270–272
228–230
270–271
246–247
180–182
158–159
210–211
237–238
216–217
255–256
—
57
53
45
52
44
48
50
57
55
52
53
54
56
51
55
51
54
58
56
58
50
—
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
—
69
71
72
71
70
69
72
70
69
71
72
71
75
70
69
69
67
76
73
74
68
—
10
10
10
10
10
10
10
10
10
10
10
10
10
12
10
10
10
10
11
10
13
—
25
3.12
25
25
25
C16H9F3N4O2S2
C16H9F3N4O3S2
C15H6F3N5O4S2
C
C
C
C
C16H9F3N4OS3
C16H9F3N4O2S3
C15H6F3N5O3S3
C
C
C
C
25
50
15H7F3N4OS3
15H6ClF3N4OS3
15H6BrF3N4OS3
15H6F4N4OS3
6.25
50
3.12
6.25
6.25
25
F
CH3
OCH3
NO2
H
Cl
Br
50
17H9F3N4O3S3
17H8ClF3N4O3S3
17H8BrF3N4O3S3
17H8F4N4O3S3
6.25
3.12
3.12
3.12
3.12
1.56
25
6c
6d
6e
6f
F
CH3
OCH3
NO2
—
C18H11F3N4O3S3
C18H11F3N4O4S3
C17H8F3N5O5S3
—
—
6g
Rifampicin
Isoniazid
0.78
1.56
—
—
—
—
—
—
—
a
Melting points are uncorrected.
revealed that singlet at the region of d 7.91–8.12 ppm was assigned
to the imidazole proton (H-5). IR spectra of imidazo[2,1-b][1,3,
4]thiadiazoles-5-carbaldehydes (3a–g) displayed a sharp band for
carbonyl stretching frequency around 1695 cmÀ1 and the signal
for imidazole proton (H-5) in 1H NMR spectrum was absent. A
new signal for aldehyde proton was observed around d 10 ppm
in the 1H NMR spectra, thus substantiating the formation of imi-
dazo[2,1-b][1,3,4]thiadiazole-5-carbaldehydes.
that of standard drug are reported in Table 1 with standard drug
Isoniazid and rifampicin for the comparison.
The data of the antitubercular activity screening reveal that the
compounds (4a–g) having a thiazolidinedione moiety did not show
any considerable activity except compound 4b (MIC at 3.12 lg/ml),
in spite of the changes at position-6 of imidazo[2,1-b][1,3,4]thiadi-
azole system. However, when a rhodanine moiety was introduced
in place of thiazolidinedione (5a–g), it resulted in some molecules
having enhanced antimycobacterial activity. Compounds 5a, 5d,
The formation of title compounds (4a–g), (5a–g) and (6a–g) was
confirmed by the absence of signal for aldehyde proton in 1H NMR
spectra, the appearance of 5-methylidene proton was observed
around d 7.8 ppm. In the 1H NMR spectra of 5-{[2-(trifluoro-
methyl)-6-arylimidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methylene}
thiazolidine-2,4-dione (4a–g) and 5-{[2-(trifluoromethyl)-6-ary-
limidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methylene}-2-thioxothiaz-
olidin-4-one (5a–g) a signal attributable to NH resonance was
diagnostic: in particular 1H NMR spectra showed singlet at d
11.56–12.45 ppm for thiazolidinedione compounds and d 12.65–
12.87 ppm for rhodanine compounds. The structure of rhodanine
acetic acid compounds (6a–g) were also confirmed by means of
their characteristic N–CH2 resonance at d 4.68–4.87 ppm. The ele-
mental analysis results were within 0.4% of the theoretical values.
The antitubercular activities of newly synthesized compounds
(4a–g), (5a–g) and (6a–g) have been assessed against M. tuberculo-
sis H37Rv (ATCC 27294) using the Micro plate Alamar Blue assay
(MABA) method.27 The activity is expressed as minimum inhibitory
concentration (MIC), that is the lowest concentration of compound
which prevented the colour change from blue to pink, the MIC of
the synthesized compounds determined in duplicate along with
and 5e exhibited antitubercular activity at MIC value 6.25
lg/ml,
and 5c at MIC value 3.12 g/ml. Promising antimycobacterial activ-
l
ity profile was also found when rhodanine-3-acetic acid replaced
by rhodanine (6a–g). Among seven compounds in this series, five
compounds ( 6b, 6c, 6d, 6e and 6f) were found to be active with
minimum inhibitory concentration of 1.56–3.12
pound 6f was found to be active against MTB at a MIC 1.56
l
g/ml. The com-
g/
l
ml comparable to that of Isoniazid. Finally, these studies suggests
that imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic
acid as potential antitubercular agents.
The computed molecular properties are shown in Table 2. The
degree of absorption is expressed by the percentage of absorption.
Absorption percent (%ABS) was calculated by using %ABS = 109 À
(0.345 Â TPSA).28,29 Molecular polar surface area (PSA), LogP, num-
berof rotatable bonds, numberof hydrogenbond donorand accepter
atoms of Lipinski’s rule of five30 were calculated using Molinspira-
tion online property calculation toolkit.31 Drug-likeness model score
(a collective property of physic-chemical properties, pharmacoki-
netics and pharmacodynamics of a compound is represented by a
numerical value) was computed by MolSoft32 software.

1920
S. G. Alegaon et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1917–1921
Table 2
Calculated absorption (%ABS), polar surface area (PSA), Lipinski parameters and drug-likeness model score of title compounds (4a–g), (5a–g) and (6a–g)
HO
O
H
N
H
N
N
O
O
O
O
S
S
S
S
S
H
H
H
R
R
R
N
S
N
S
N
S
N
N
N
F3C
F3C
F3C
N
N
N
(4 a-g)
(5 a-g)
(6 a-g)
Compound
R
%ABS
Volume
PSA
80.13
NROTB
HBA
HBD
Logp, calcd
Formula weight
Drug-likeness model score
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
6e
6f
H
Cl
Br
F
CH3
OCH3
NO2
H
Cl
Br
81.35
81.35
81.35
81.35
81.35
78.17
65.54
87.24
87.24
87.24
87.24
87.24
84.05
71.43
78.12
78.12
78.12
78.12
78.12
74.93
62.42
283.58
297.11
301.46
288.51
300.14
309.12
306.91
292.45
305.99
310.34
297.39
309.01
318.00
315.79
336.64
350.17
354.52
341.57
353.20
362.18
359.97
3
3
3
3
3
4
4
3
3
3
3
3
4
4
5
5
5
5
5
6
6
6
6
6
6
6
7
9
5
5
5
5
5
6
8
7
7
7
7
7
8
10
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2.78
3.46
3.59
2.94
3.23
2.83
2.74
3.12
3.80
3.93
3.28
3.57
3.18
3.08
2.43
3.11
3.24
2.60
2.88
2.49
2.39
396
430
475
414
410
426
441
412
446
491
430
426
442
457
470
504
549
488
484
500
515
À0.09
0.01
80.13
80.13
80.13
80.13
89.36
125.95
63.06
63.06
63.06
63.06
63.06
72.29
108.88
89.50
89.50
89.50
89.50
89.50
98.73
135.32
À0.39
À0.32
À0.24
À0.03
À0.64
À0.24
À0.12
À0.50
À0.42
À0.35
À0.11
À0.72
À0.09
0.02
F
CH3
OCH3
NO2
H
Cl
Br
À0.31
À0.24
À0.16
0.15
F
CH3
OCH3
NO2
6g
À0.49
Pharmacokinetic property optimization is a rather complex
undertaking that is likely to require changes in those molecular
determinants that are responsible for binding affinity and specific-
ity like hydrogen bonds. Hydrogen bond acceptor (HBA) and
hydrogen bond donor (HBD) groups in the compound optimize
the drug receptor interaction. Number of hydrogen bond acceptor
(610) and hydrogen bond donor (65) in the proposed compounds
obeys the Lipinski’s rule of five, so it may have some of the com-
pounds good absorption or permeability properties through the
biological membrane. Dissolution is highly interdependent influ-
ences of aqueous solubility, ionizability (pKa) and lipophilicity
(logP). Furthermore, logP is a crucial factor governing passive
membrane partitioning, influencing permeability opposite to its ef-
fect on solubility. The logP values of the synthesized compounds
lie in between 2.39 and 3.93. In addition, molecular weight of
the compound is important in drug action, if the molecular weight
is increased beyond a limit, the bulkiness of the compounds also
increases, which will affect the drug action (affect the drug recep-
tor/DNA interactions). Molecular weight of compounds like 4a–g,
5a–g and 6a, 6d, 6e, and 6f lies between 396 and 500 show that
these compounds follows Lipinski’s rule of five. So the bulkiness
of the compounds is in optimum limit for the action. Molecular po-
lar surface area (PSA) is a sum of surfaces of polar atoms (usually
nitrogen and oxygen attached hydrogen) in a molecule. PSA is a
very useful parameter for the prediction of drug transport prop-
erty. PSA is inversely proportional to %ABS. Compounds like 5a,
5b, 5c, 5d and 5e have maximum absorption as their correspond-
ing polar surface area was least among the series.
down reaction time, increase product purity and yields. The syn-
thesized compounds were evaluated for their in vitro antitubercu-
lar activity against M. tuberculosis H37Rv (ATCC 27294). Based on
SAR studies suggests that compounds 6b, 6c, 6d, 6e and 6f may
serve as promising lead scaffolds for further generation of new
antitubercular agents.
Acknowledgments
Authors are grateful to Dr. A. D. Taranalli, Principal, for provid-
ing necessary facilities. We wish to express our sincere gratitude to
Dr. F. V. Manvi, Dean Faculty of pharmacy and Dr. C. K. Kokate,
Vice-Chancellor for their motivation. Authors are also grateful to
NMR Research center, IISC, Bangalore, India, for providing the spec-
tral data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2012.01.052.
References and notes
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5496.
In conclusion, we have developed a simple, highly efficient, cost
effective, and environmentally friendly method for the synthesis of
2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]-thiadiazole deriv-
atives by using microwave irradiation technique. It has been dem-
onstrated that the use of microwave heating can dramatically cut
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