Microwave-assisted green synthesis of new imidazo[2,1-b]thiazole derivatives and their antimicrobial, antimalarial, and antitubercular activities

Article abstract of DOI:10.1007/s11164-017-2985-5

Abstract: We have synthesized some imidazo[2,1-b]thiazole derivatives by reaction of 1-(2-amino-4-methylthiazol-5-yl)ethanone or ethyl 2-amino-4-methylthiazole-5-carboxylate with α-bromo aralkyl ketones (phenacyl bromides) in presence of polyethylene glycol-400 (PEG-400) as efficient, inexpensive, biodegradable, and green reaction medium and catalyst (dual nature) under Microwave Irradiation (MWI) at 300?W as well as under thermal heating at 90?°C. Moreover, we also synthesized 1-(2-amino-4-methylthiazol-5-yl)ethanone and ethyl 2-amino-4-methylthiazole-5-carboxylate by one-pot reaction of acetyl acetone/ethyl acetoacetate with N-bromosuccinimide (NBS) and thiourea in presence of PEG-400 under microwave irradiation at 180?W. All synthesized compounds were screened for antimicrobial and antimalarial activities. All compounds were found to show good to excellent antibacterial activity, and some analogs exhibited good antimalarial activity.

Full text of DOI:10.1007/s11164-017-2985-5

Res Chem Intermed
DOI 10.1007/s11164-017-2985-5
Microwave-assisted green synthesis of new imidazo
[2,1-b]thiazole derivatives and their antimicrobial,
antimalarial, and antitubercular activities
Rajesh H. Vekariya1 Kinjal D. Patel1
•
•
Mayur K. Vekariya1 Neelam P. Prajapati1
•
•
Dhanji P. Rajani2 Smita D. Rajani2
•
•
Hitesh D. Patel1
Received: 23 March 2017 / Accepted: 9 May 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract We have synthesized some imidazo[2,1-b]thiazole derivatives by reaction of
1-(2-amino-4-methylthiazol-5-yl)ethanone or ethyl 2-amino-4-methylthiazole-5-car-
boxylate with a-bromo aralkyl ketones (phenacyl bromides) in presence of polyethylene
glycol-400 (PEG-400) as efficient, inexpensive, biodegradable, and green reaction
medium and catalyst (dual nature) under Microwave Irradiation (MWI) at 300 W as well
as under thermal heating at 90 °C. Moreover, we also synthesized 1-(2-amino-4-
methylthiazol-5-yl)ethanone and ethyl 2-amino-4-methylthiazole-5-carboxylate by one-
pot reaction of acetyl acetone/ethyl acetoacetate with N-bromosuccinimide (NBS) and
thiourea in presence of PEG-400 under microwave irradiation at 180 W. All synthesized
compounds were screened for antimicrobial and antimalarial activities. All compounds
were found to show good to excellent antibacterial activity, and some analogs exhibited
good antimalarial activity.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2985-5)
contains supplementary material, which is available to authorized users.
&
Hitesh D. Patel
drhiteshpatel1@gmail.com
1
2
Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad, India
Microcare Laboratory and TRC, Surat, Gujarat, India
123

R. H. Vekariya et al.
Graphical Abstract
Keywords Imidazo[2,1-b]thiazoles Á One-pot reaction Á Homogeneous catalysis Á
PEG-400 Á Aqueous-phase synthesis Á Green synthesis Á Antimicrobial activity Á
Antimalarial activity Á Antitubercular activity
Introduction
Green synthesis of bioactive molecules and pharmaceutical intermediates in the
field of bioorganic chemistry can be considered an attractive research opportunity,
associated with advanced features such as waste reduction, energy savings, atom
economy, easy workup processes, and avoidance of use of hazardous chemicals
[1, 2]. Development of green, clean, and ecofriendly protocols for synthesis of
highly potent bioactive molecules is an exciting area of medicinal chemistry with
great potential for further discoveries [3, 4].
Compounds containing the imidazo[2,1-b]thiazole frame have been of interest to
medicinal chemists for many years because of their wide range of therapeutic
applications [5–7]. Imidazo[2,1-b]thiazole derivatives are important heterocyclic
compounds and have drawn much attention because of their various biological and
medicinal activities, including antibacterial [8–13], antiparasitic [14], antifungal
[15–17], antiviral [18], anthelmintic [19, 20], antitumor [21–23], cardiotonic [24],
chemopreventive, antioxidant [25], antiinflammatory [26], and antihypertensive
properties [27]. It has been reported that they possess antitumor properties against a
variety of human cancer cell lines [28–37]. In addition, imidazo[2,1-b]thiazole
derivatives exhibit good antiproliferative activities against a variety of human
cancer cell lines [38–43].
Despite much significant progress in antimicrobial therapy, infectious diseases
caused by bacteria and fungi remain major worldwide health problems due to the
rapid development of resistance to existing antibacterial and antifungal drugs,
making this one of the most important areas of antibacterial research today [44].
Development of new antimicrobial agents is therefore urgently required to address
this situation. It thus seems crucial to investigate novel antimicrobial molecules with
new mechanisms of action, to overcome antimicrobial resistance [45].
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Microwave-assisted green synthesis of new imidazo[2,1-b]…
For this reason, development of imidazo[2,1-b]thiazole derivatives is currently
receiving much attention. Various protocols have been established for synthesis of
imidazo[2,1-b]thiazole derivatives through reaction between 2-aminothiazoles and
various phenacyl bromides under reflux in propan-2-ol [46], methyl ethyl ketone [47],
acetone and hydrochloric acid [48], acetone and hydrobromic acid [49], ethanol [50],
benzene [51], and butanol [52]. However, these reactions are performed in organic
solvents at reflux temperature, giving only moderate yield; such synthetic method-
ologies do not meet the requirements of green chemistry. Also, these methodologies
do not enable synthesis of a wide range of imidazo[2,1-b]thiazole derivatives.
Regulatory pressure is increasingly focusing on the use, manufacture, and disposal
of organic solvents, because their use in an industrial process can cause occupational
health hazards as well as being harmful to the environment. The unique solvent
properties, higher solubilizing power, and cation coordination ability of polyethylene
glycol (PEG) solutions make them useful as green solvents and phase-transfer catalysts
in organic synthesis [53]. PEGs are nonionic, nontoxic, inexpensive, and thermally
stable reaction media that can be recovered by phase-separation methods. In addition,
PEG-400 is nonvolatile, biodegradable, and has low flammability. PEGs have been
found to be stable to acid, base, and high temperature [54, 55]. PEGs exhibit different
solubility in organic solvents, enabling precipitation of PEGs from reaction mixtures in
organic solvents for purification. Therefore, polyethylene glycol (PEG) has been found
to be an exciting reaction medium for many organic syntheses in recent years [56–70].
The importance of green chemistry in organic synthesis has encouraged scientists to
explore use of microwave irradiation. Over recent years, Microwave Irradiation (MWI)
has emerged as a very useful energy source for a wide range of organic transformations
with short reaction time and high yield of products with high purity [71]. Combined use
of MWI with a PEG reaction medium can speed up organic reactions due to selective
absorption of microwave energy by polar molecules.
In continuation of our studies towards development of cheap and environmen-
tally benign methodologies for organic synthesis, we report herein aqueous PEG-
400 as an extremely effective catalytic system for synthesis of imidazo[2,1-
b]thiazole derivatives by reaction of 1-(2-amino-4-methylthiazol-5-yl)ethanone or
ethyl 2-amino-4-methylthiazole-5-carboxylate with a-bromo aralkyl ketones
(phenacyl bromides) at 90 °C or under MWI at 300 W (Scheme 1). Moreover,
we also synthesized 1-(2-amino-4-methylthiazol-5-yl)ethanone/ethyl 2-amino-4-
methylthiazole-5-carboxylate by one-pot reaction of acetyl acetone/ethyl acetoac-
etate with N-bromosuccinimide (NBS) and thiourea in presence of PEG-400 under
microwave irradiation at 180 W (Scheme 1). The reaction proceeded smoothly, and
succinimide was obtained as a byproduct that could be recycled to give NBS [71].
Results and discussion
Initially, it was planned to develop an efficient and green protocol for preparation of
2-aminothiazole derivatives 1a, b. For this purpose, our initial work focused on
optimization of the reaction conditions for synthesis of thiazole derivative 1a using
acetyl acetone, NBS, and thiourea in PEG-400 (2 mL) as model reaction.
123

R. H. Vekariya et al.
Scheme 1 General reaction scheme for preparation of imidazo[2,1-b]thiazole derivatives
Control experiments on the model reaction showed that it did not take place at
room temperature, and unreacted starting materials were observed on Thin Layer
Chromatography (TLC) after 2 h because of the low rate of the a-bromination
process (A) at room temperature. After 4 h, 1a was obtained in good yield (82%)
(Table 1, entry 1). No significant change in the 1a yield was observed after 24 h
(Table 1, entry 2). In general, the reaction rate, solubility of reactants and products,
and selectivity of catalyst are highly dependent on the operating temperature of the
reaction. Thus, in the model reaction, the effect of temperature was investigated,
and the results suggested that temperature had a dramatic effect on the reaction yield
(Fig. 1). Increasing the temperature of the reaction from room temperature to 70 °C
led to a reduction in the reaction time. The highest yield of 1a was obtained at 70 °C
within 4 h (92%) (Table 1, entry 6). From room temperature (r.t.) to 60 °C, product
Table 1 Optimization of
reaction conditions for synthesis
of 1a
Entry
Solvent (2 mL)
Conditions
Time
Yielda (%)
1
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
THF
R.t.
4 h
82
83
83
85
88
94
94
93
91
67
76
69
96
92
2
R.t.
16 h
4 h
3
40 °C
50 °C
60 °C
70 °C
80 °C
90 °C
100 °C
Reflux
Reflux
Reflux
180 W (MWI)
300 W (MWI)
4
4 h
5
4 h
6
4 h
7
4 h
8
4 h
9
4 h
10
11
12
13
14
4 h
Ethanol
4 h
Methanol
PEG-400
PEG-400
4 h
6 min
6 min
a
Isolated yields
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
yield increased significantly (Table 1, entries 3–5), whereas no significant improve-
ment in rate of reaction or product yield was detected at higher temperature from 80
to 100 °C (Table 1, entries 7–9). Various solvents such as Tetrahydrofuran (THF),
ethanol, and methanol were also tested for this one-pot synthesis, but afforded poor
product yield compared with PEG-400 (Table 1, entries 10–12). After that, we
performed this reaction under Microwave Irradiation (MWI) using similar reaction
conditions. Unpredictably, we achieved the greatest yield (96%) of 1a within 6 min
when the reaction was carried out using PEG-400 under 180 W of microwave
irradiation (Table 1, entry 14). In addition, it was also observed that high
microwave irradiation power above 180 W resulted in lower product yield (Table 1,
entry 15). Compared with conventional heating, reaction under microwave irradi-
ation showed higher efficiency in terms of product yield and reaction time. When
considering the heterocyclization step (B) alone, the a-bromination step (A) was
also slightly influenced by the operating temperature of the reaction (Fig. 2).
To optimize the reaction conditions, the reaction was studied by employing
bromination agents such as KBr, KBrO3 and catalytic amount of acetic acid, HBr in
acetic acid, bromine (Br2), and NBS (Table 2, entries 1–4). Among these
bromination reagents, it was observed that, when NBS reagent was used for
bromination of the acetyl acetone under thermal heating at 70 °C in PEG-400, the
bromination completed well followed by heterocyclization with thiourea within 4 h.
The optimal conditions found for synthesis of 1a were successfully applied to the
reactions of ethyl acetoacetate with N-bromosuccinimide (NBS) and thiourea in
presence of PEG-400 under microwave irradiation at 180 W, affording ethyl
2-amino-4-methylthiazole-5-carboxylate in excellent yield (97%) within 6 min.
Based on our present study, we found reaction in PEG-400 at 180 W (MWI) to be
the optimum condition for synthesis of 2-aminothiazoles 1a, b. Furthermore,
products 1a, b were easily purified by recrystallization from ethanol, thus avoiding
extraction steps or chromatographic separation. The purity of the synthesized
compounds was confirmed by TLC and elemental analysis. The structures of the
1
final products were well characterized by Infrared Spectroscopy (IR), mass, and H
and 13C Nuclear Magnetic Resonance Spectroscopy (NMR) spectral analyses.
Effect of temperature on yield of 1a
100
90
80
70
60
50
40
91
93
94
94
88
85
83
75
80
85
Yield of 1a
90
95
Fig. 1 Effect of temperature on yield of 1a
123

R. H. Vekariya et al.
Reusability of PEG-400
94
92
90
88
86
84
82
80
92
91
89
87
4
84
5
1
2
3
Run No.
Fig. 2 Reusability profile of PEG-400
Table 2 Effect of various bromination agents on synthesis of 1a
Entry
Bromination reagent
Solvent and temperature
Time (h)
Yielda (%)
1
2
2
3
a
KBr, KBrO3, AcOH
PEG-400, 70 °C
PEG-400, 70 °C
PEG-400, 70 °C
PEG-400, 70 °C
4
4
4
4
53
60
75
92
HBr in acetic acid
Br2
NBS
Isolated yields
Scheme 2 presents a possible reaction mechanism for the formation of
2-aminothiazoles 1a, b. According to this, initially, terminal –OH group of PEG-
400 forms intermolecular H-bond with carbonyl oxygen of NBS. Simultaneously,
ethereal oxygen of PEG-400 forms intermolecular H-bonding with –OH group of
enol form of acetyl acetone/ethyl acetoacetate. This can activate substrates acetyl
acetone/ethyl acetoacetate and even reagent NBS, for favorable interaction, leading
to a-bromoketones in excellent yield with succinimide as byproduct. After that,
ethereal oxygen of PEG-400 forms hydrogen bond with –SH group of thiourea
(enolic form), which makes S–H bond weaker, enhancing the nucleophilicity of
sulfur for nucleophilic addition to electron-deficient carbon of acetyl acetone/ethyl
acetoacetate. Simultaneously, terminal –OH group of PEG-400 forms hydrogen
bonding with the electron deficiency of carbonyl carbon of a-bromoketones.
Finally, 2-aminothiazoles 1a, b form via intramolecular cyclization and hydrogen
transfer followed by removal of H2O and HBr.
IR spectra of these derivatives showed two characteristic N–H stretching peaks at
3200–3400 cm-1 corresponding to primary NH2 group, C=O stretching peak at
1709 cm-1 corresponding to COCH3 group, and C=O stretching peak at 1674 cm-1
corresponding to COOC2H5 group. The 1H NMR spectra of these derivatives
exhibited a singlet near 7.8 ppm, attributed to primary NH2 group. Furthermore, a
singlet near 2.35 ppm indicated protons of CH3 group of thiazole. In addition, a
singlet near 3.41 ppm indicated protons of COCH3 group of thiazole. Meanwhile,
peaks at 1.23 ppm indicated triplets of CH3 group of ester, and peaks at 4.15 ppm
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
Scheme 2 Proposed reaction mechanism
indicated quartet of CH2 group of ester. The 13C NMR spectrum exhibited a peak at
188.2 ppm, indicating C=O stretching of COCH3 group, while a peak at
170.19 ppm indicated C=O stretching of COOC2H5. In addition, peaks between
13 and 18 ppm indicated CH stretching of CH3 group of thiazole. Electrospray
Ionisation (ESI) Mass Spectrometry (MS) of compounds 1a, b showed correspond-
ing (M ? 1)? peak as well as (M ? 2)? peak. In all spectra, (M ? 2)? peak was
observed due to presence of sulfur atom of thiazole.
After this successful synthesis of 1-(2-amino-4-methylthiazol-5-yl)ethanone and
ethyl 2-amino-4-methylthiazole-5-carboxylate, we planned to develop an efficient and
green protocol for preparation of imidazo[2,1-b]thiazole derivatives 3–20. To
optimize the reaction conditions, the reaction was studied employing several solvents
as well as under solvent-free conditions with the hope of maximizing the product
yield in short reaction time (Table 3). In a model reaction, we used phenacyl bromide
(2 mmol) with 1-(2-amino-4-methylthiazol-5-yl)ethanone (2 mmol) as reactants in
presence of ethanol at 80 °C and found that imidazo[2,1-b]thiazole 3 could be
produced in 54% yield in 16 h (Table 3, entry 1). To improve the yield and optimize
123

R. H. Vekariya et al.
Table 3 Optimization of reaction conditions for synthesis of 3
Entry
Solvent (4 mL)
Conditions
Time
Yielda (%)
1
Ethanol
80 °C
16 h
16 h
16 h
16 h
3 h
54
70
65
42
82
85
86
75
80
92
92
2
Butanol
100 °C
100 °C
90 °C
90 °C
100 °C
90 °C
90 °C
90 °C
300 W (MWI)
3
Propen-2-ol
4
Water
5
PEG-400
6
PEG-400
3 h
7
Water:PEG-400 (1:1)
Water:PEG-400 (9:1)
Water:PEG-400 (7:3)
Water:PEG-400 (1:1)
Water:PEG-400 (1:1)
3 h
8
3 h
9
3 h
10
11
a
7 min
7 min
450 W (MWI)
Isolated yields
the reaction conditions, the same reaction was carried out in presence of solvents such
as butanol and propane-2-ol at 100 °C for 16 h. However, this afforded the product in
moderate yield. We also tested water for this reaction, but it gave poor results
compared with other solvents. After that, the same reaction was performed utilizing
PEG-400 as green and ecofriendly reaction medium. A surprisingly improved result
was observed in terms of yield of 3 after stirring the mixture at 90 °C for 3 h
(Table 3, entry 5). Increasing the temperature of the reaction from 90 to 100 °C led to
no significant change in the reaction time or product yield (Table 3, entry 6). Finally,
the optimized reaction conditions for this cyclocondensation were found to use a 1:1
mixture of water:PEG-400 as solvent system (Table 3, entry 7). We also applied the
water:PEG-400 solvent system at 9:1 and 7:3 for this transformation, but better results
were not afforded compared with the 1:1 solvent system (Table 3, entries 8, 9). After
that, we performed this reaction under Microwave Irradiation (MWI) using similar
reaction conditions. Unpredictably, we achieved the greatest yield (92%) of 3 within
7 min when the reaction was carried out utilizing water:PEG-400 (1:1) under
microwave irradiation of 300 W (Table 3, entry 10). In addition, it was also observed
that high microwave irradiation power up to 450 W did not result in any improvement
(Table 3, entry 11). Compared with conventional heating, reaction under microwave
irradiation showed higher efficiency in terms of product yield and reaction time.
The optimal conditions found for 3 were successfully applied for reaction of
ethyl 2-amino-4-methylthiazole-5-carboxylate with phenacyl bromide in presence
of water:PEG-400 (1:1) under microwave irradiation at 300 W, affording
corresponding imidazo[2,1-b]thiazole derivative 12 in excellent yield (96%) within
7 min. We employed various phenacyl bromides to evaluate the generality of this
protocol. The reaction progressed smoothly and provided excellent yields in all
cases (Table 4). Phenacyl bromides bearing both electron-withdrawing and
electron-donating substituents reacted smoothly with this protocol to afford
products in excellent yields. Furthermore, all synthesized products were easily
purified by recrystallization from ethanol, thus avoiding extraction steps or
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
Table 4 Preparation of imidazo[2,1-b]thiazole derivatives using water:PEG-400 (1:1) as reaction
medium
Compound
R
R1
Thermal heating
(90 °C)
Microwave irradiation
(300 W)
M.p. (°C)
Time (h) Yielda (%) Time (min)
Yielda (%)
3
Me C6H5
3
4
4
3
4
3
4
4
4
4
3
4
4
4
3
3
4
4
3
4
92
90
88
92
89
87
86
89
90
89
93
88
86
91
92
89
87
88
89
88
7
6
7
7
8
8
8
7
6
8
7
7
8
6
7
7
8
7
7
8
93
92
91
95
92
91
90
91
94
92
96
92
88
95
96
90
88
91
93
92
208–210
187–189
236–237
275–277
230–232
223–226
214–216
239–241
196–197
244–246
125–126
226–227
120–122
223–225
242–244
232–234
221–222
200–201
178–180
242–244
4
Me 2-Cl–C6H4
Me 4-Me–C6H4
Me 4-OMe–C6H4
Me 4-Br–C6H4
Me 4-Cl–C6H4
Me 2,4-diCl–C6H3
Me 4-F–C6H4
Me 2-OMe–C6H4
Me 4-NO2–C6H4
OEt C6H5
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
a
OEt 2-Cl–C6H4
OEt 4-Me–C6H4
OEt 4-OMe–C6H4
OEt 4-Br–C6H4
OEt 4-Cl–C6H4
OEt 2,4-diCl-C6H3
OEt 4-F–C6H4
OEt 2-OMe–C6H4
OEt 4-NO2–C6H4
Isolated yields
chromatographic separation. The purity of the synthesized compounds was
confirmed by TLC and elemental analysis. The structures of the final products
1
were well characterized by spectral (IR, mass, and H and 13C NMR) analyses.
IR spectra showed characteristic C=O stretching peak near 1710 cm-1
corresponding to COCH3 group and C=O stretching peak near 1675 cm-1
corresponding to COOC2H5 group. The 1H NMR spectrum exhibited a singlet near
8.45 ppm indicating proton of imidazo nucleus, while peaks between 7.20 and
8.20 ppm were observed for respective aromatic protons. Furthermore, a singlet
near 2.55 ppm indicated protons of CH3 group of thiazole. In addition, a singlet near
2.80 ppm indicated protons of COCH3 group of thiazole. Moreover, peaks between
1.25 to 1.35 ppm indicated triplets of CH3 group of ester, while peaks between
4.20–4.35 indicated quartet of CH2 group of ester. The 13C NMR spectrum
exhibited a peak near 191 ppm indicating C=O stretching of COCH3, while a peak
near 161 ppm indicated C=O stretching of COOC2H5. In addition, peaks near
12–13 ppm indicated CH stretching of CH3 group of thiazole. The ESI–MS spectra
of compounds 3–22 showed corresponding (M ? 1)? peak as well as (M ? 2)?
123

R. H. Vekariya et al.
Scheme 3 Proposed reaction mechanism
peak. In all spectra, (M ? 2)? peak was observed due to presence of sulfur atom in
the imidazo[2,1-b]thiazoles.
To check the ecofriendliness of PEG-400, we recycled PEG-400 and reused it for
five times, revealing slightly decreasing catalytic efficiency (Fig. 2).
Scheme 3 presents a possible reaction mechanism for formation of the
imidazo[2,1-b]thiazole derivatives. According to this, initially, ethereal oxygen of
PEG-400 forms hydrogen bond with –NH– group of 2-aminothiazoles (enolic form),
which makes –N–H– bond weaker, enhancing the nucleophilicity of nitrogen for
nucleophilic addition to electron-deficient carbon of phenacyl bromides. Simulta-
neously, terminal –OH group of PEG-400 forms hydrogen bonding with the electron
deficiency of carbonyl carbon of phenacyl bromides. Finally, imidazo[2,1-b]thia-
zoles (3–22) form via intramolecular cyclization and hydrogen transfer followed by
removal of H2O and HBr.
Pharmacology
Antimicrobial activity
In vitro antibacterial activity
All novel synthesized scaffolds were investigated for their in vitro antibacterial
activity (Table 5). The bioassay results demonstrated that imidazo[2,1-b]thiazole
derivatives 3–22 showed remarkable activity against the tested microorganisms
compared with standard drugs. In general, most of the tested compounds exhibited
better activity against Gram-positive than Gram-negative bacteria. Among the
Gram-positive bacterial strains, Staphylococcus aureus showed relatively higher
sensitivity towards the tested compounds. In this regard, compound 21 bearing
electron-donating –OMe group at 2-position of phenyl ring was found to be the most
active in inhibiting Gram-positive S. aureus bacterial growth with the lowest
minimum inhibitory concentration (MIC) value of 50 lg/mL, compared with the
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
Table 5 In vitro antibacterial activity of compounds 3–22
Compound
E. coli
MTCC 443
MIC (lg/mL)
P. aeruginosa
MTCC 1688
S. aureus
MTCC 96
S. pyogenes
MTCC 442
3
125
200
100
125
500
200
200
125
100
500
250
100
125
100
100
200
100
62.5
62.5
250
100
25
250
200
250
100
250
100
100
250
500
250
250
100
200
62.5
100
100
100
200
250
200
100
25
100
125
100
125
250
250
200
200
100
200
100
62.5
200
100
250
125
100
125
50
200
250
250
200
250
250
125
250
500
125
125
200
250
200
250
100
62.5
100
250
125
100
50
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
100
250
50
Ampicillin
Ciprofloxacin
Chloramphenicol
50
50
50
50
MIC of 250 lg/mL for ampicillin. In addition, compound 14 with chloro group on
phenyl ring exhibited excellent activity with 62.5 lg/mL against S. aureus
bacterium. Furthermore, compounds 3, 5, 11, 13, 16, 19, 22 showed excellent
activity with MIC of 100 lg/mL against S. aureus compared with standard drug
ampicillin, albeit 50% less active than chloramphenicol (MIC 50 lg/mL) or
ciprofloxacin (MIC 50 lg/mL). Meanwhile, compounds 4, 6, 18, 20 exhibited
potent activity with MIC of 125 lg/mL against the same bacterium. Most of the
tested compounds showed excellent activity. However, compounds 7, 8, 17 (MIC
250 lg/mL) showed equipotent activity against S. aureus compared with ampicillin,
whereas analogs 9, 10, 12, 15 (MIC 200 lg/mL) showed good activity compared
with ampicillin. Against S. pyogenes, the best activity was exhibited by compound
19 (MIC 62.5 lg/mL) having two –Cl groups at 2- and 4-position of phenyl ring,
being more potent then ampicillin (MIC 100 lg/mL). In addition, analogs 20, 18
(MIC 100 lg/mL) displayed potency equivalent to ampicillin against the same
species, but 50% less than chloramphenicol (MIC 50 lg/mL) or ciprofloxacin (MIC
50 lg/mL).
123

R. H. Vekariya et al.
Table 6 In vitro antifungal
activity of compounds 3–22
Compound
C. albicans A. niger
MTCC 227 MTCC 282
MIC (lg/mL)
A. clavatus MTCC 1323
3
[1000
250
1000
500
1000
1000
4
5
[1000
1000
1000
1000
500
1000
1000
500
1000
6
1000
7
1000
8
1000
[1000
500
1000
9
[1000
1000
10
250
11
100
1000
[1000
[1000
1000
[1000
1000
500
1000
12
[1000
500
[1000
[1000
[1000
[1000
[1000
500
13
14
500
15
500
16
[1000
[1000
250
17
18
1000
[1000
1000
1000
[1000
100
[1000
500
19
1000
500
20
1000
21
[1000
500
[1000
[1000
100
22
Nystatin
Griseofulvin
100
500
100
100
On the other hand, investigation of the antibacterial activity of all the newly
synthesized analogs against the two tested Gram-negative strains revealed that
analogs 20, 21 (MIC 62.5 lg/mL) displayed excellent activity against E. coli.
Furthermore, analogs 5, 11, 14, 16, 17, 19 (MIC 100 lg/mL) were equipotent to
ampicillin (MIC 100 lg/mL) against E. coli, but 50% less active than chloram-
phenicol (MIC 50 lg/mL). Moreover, compound 8 with electron-donating
substituent of –OMe on phenyl ring inhibited Gram-negative P. aeruginosa
bacterial growth at the lowest minimum inhibitory concentration (MIC) value of
62.5 lg/mL, compared with the MIC of 100 lg/mL for ampicillin. Furthermore,
compounds 6, 8, 9, 14, 17–19 exhibited good activity against Gram-positive
S. pyogenes bacterial growth at minimum inhibitory concentration (MIC) of
100 lg/mL, equivalent to ampicillin.
In vitro antifungal activity
Concerning the antifungal activity of the tested compounds, only one strain, i.e.,
C. albicans, showed certain sensitivity to some of the tested compounds, whereas
the other two fungal strains were insensitive to the same compounds (Table 6). The
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
Table 7 In vitro antimalarial
Compound
Mean IC50 (lg/mL)
activity of compounds 3–22
3
0.79
1.08
0.92
1.14
0.38
0.75
0.20
0.72
1.11
0.95
0.69
1.00
0.69
1.07
1.14
0.52
0.22
0.44
0.90
0.66
0.268
0.02
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Quinine
Chloroquine
antifungal activity data showed that, among analogs 3–22, compounds 4, 10, 18
bearing electron-deactivating halo groups (–Cl and –F) on phenyl ring displayed
excellent activity with MIC of 100 lg/mL against C. albicans, equipotent to
nystatin (MIC 100 lg/mL) but more potent then griseofulvin (MIC 500 lg/mL).
Furthermore, compounds 9, 13–15, 20, 22 showed excellent activity with MIC of
250 lg/mL, better then the MIC of 500 lg/mL for griseofulvin, against C. albicans.
Analogs 6–8, 19 exhibited 50% less efficiency (MIC 1000 lg/mL) against C.
albicans than griseofulvin (MIC 500 lg/mL). Moreover, compounds 3–22 exerted
moderate inhibitory efficiency against A. niger and A. clavatus.
In vitro antimalarial activity
The synthesized compounds were also screened for their in vitro antimalarial
activity against Plasmodium falciparum 3D7 chloroquine-sensitive strain (Micro-
care Laboratory and TRC, Surat, Gujarat, India). All experiments were performed in
duplicate, and the mean 50% Half Maximal Inhibitory Concentration (IC50) values
are presented in Table 7. Compounds 9 (IC50 = 0.2 lg/mL) and 19 (IC50 = 0.22 -
lg/mL) bearing two electron-deactivating groups (–Cl) at 2- and 4-position of
phenyl ring displayed excellent activity against P. falciparum compared with
quinine as standard drug (IC50 = 0.268 lg/mL). This promising antimalarial
123

R. H. Vekariya et al.
Table 8 In vitro antimalarial
activity of compounds 3–22
Compound
MIC (lg/mL)
3
62.5
50
4
5
100
62.5
100
100
50
6
7
8
9
10
100
62.5
62.5
100
100
500
1000
1000
500
500
100
100
500
0.20
0.25
11
12
13
14
15
16
17
18
19
20
21
22
Isoniazid
Rifampicin
activity of compounds 9, 19 may be due to the lowest lipophilicity (lowest Log P)
showing highest antimalarial activity. Other compounds exhibited only moderate
antimalarial activity (IC50 = 0.38–1.14 lg/mL).
In vitro antitubercular activity
Preliminary screening of the title compounds 3–22 for their in vitro antitubercular
activity against Mycobacterium tuberculosis H37Rv strain was carried out. The
observedMICvaluesofthesecompoundsarepresentedinTable 8. Amongthescreened
analogs, 4 and 9 showed the best activity (50 mg/mL), followed by compounds 3, 6, 11,
12 (62.5 mg/mL). Isoniazid and rifampicin were used as standard drugs.
Experimental
Chemicals and reagents
All chemicals were of highest purity available, purchased from commercial sources,
and used as received. Reaction progress was monitored by Thin Layer
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
Chromatography (TLC) analysis on Merck precoated silica gel 60 F254 aluminum
sheets, visualized by ultraviolet (UV) light. Various phenacyl bromides (2a–i) were
synthesized as per protocol previously reported by us [71].
Instrumentation
The reactions were performed using a CEM Discover microwave system as well as
modified Samsung microwave oven. Melting points were measured on an Optimelt
MPA 100 melting point apparatus and are uncorrected. Fourier-transform infrared
(FT-IR) spectra were recorded on a PerkinElmer FT-IR 377 spectrometer using
1
KBr. H NMR spectra were recorded on Bruker AV 400 MHz spectrometer using
dimethyl sulfoxide (DMSO)-d6 as solvent and tetramethylsilane (TMS) as internal
reference. 13C NMR spectra were recorded on a Bruker AV 100 MHz spectrometer
using DMSO as solvent. Mass spectra were recorded at Advion Expression CMS,
USA. Acetone was used as mobile phase, and electron spray ionization (ESI) was
used as ion source. Elemental analysis was performed on a CHNS elemental
analyzer.
Procedure for synthesis of 1-(2-amino-4-methylthiazol-5-yl)ethanone (1a)
To solution of acetyl acetone (2 mmol) in polyethylene glycol PEG-400 (2 mL)
were added N-bromosuccinimide (NBS) (2.2 mmol) and thiourea (2 mmol), and the
mixture was heated under microwave irradiation at 180 W until reaction completion
as indicated by TLC (approximately 5 min). After consumption of starting materials
as indicated by TLC, the reaction mixture was cooled at room temperature, poured
into water, and basified with aqueous ammonia with continuous stirring. The
resulting precipitate was filtered and washed with water, and recrystallized from
ethanol to give pure product.
Off-white solid M.p. = 215–217 °C. IR mmax (KBr) cm-1: 3334, 3268, 3052,
2993, 2379, 1709, 1663, 1511, 1309, 1297, 1102, 972, 761. H NMR (400 MHz,
1
DMSO-d6): dH (ppm) 2.33 (s, 3H, CH3), 2.41 (s, 3H, COCH3), 7.85 (s, 2H, thiazole-
2-NH2). 13C NMR (100 MHz, DMSO): dC (ppm) 188.20, 170.45, 157.66, 121.23,
29.45, 18.27. MS (ESI) m/z for (156.21): 157.1 (M ? 1)?, 258.1 (M ? 2)?.
Elemental analysis: Calculated for C6H8N2OS (156.04): C 46.13%, H 5.16%, N
17.93%, S 20.53%; Found: C 46.11%., H 5.19%, N 17.92%, S 20.51%.
Procedure for synthesis of ethyl 2-amino-4-methylthiazole-5-carboxylate (1b)
To solution of ethyl acetoacetate (2 mmol) in polyethylene glycol-400 (PEG-400)
(2 mL) were added N-bromosuccinimide (NBS) (2.2 mmol) and thiourea (2 mmol),
and the mixture was heated under microwave irradiation at 180 W until reaction
completion as indicated by TLC (approximately 5 min). After consumption of
starting materials as indicated by TLC, the reaction mixture was cooled at room
temperature, poured into water, and basified with aqueous ammonia with continuous
123

R. H. Vekariya et al.
stirring. The resulting precipitate was filtered and washed with water, and
recrystallized from ethanol to give pure product.
White solid M.p. = 177–179 °C. IR mmax (KBr) cm-1: 3372, 3301, 3062, 2960,
1
1674, 1516, 1373, 1279, 1095, 756. H NMR (400 MHz, DMSO-d6): dH (ppm)
1.22-125 (t, 3H, J = 7.2), 2.39 (s, 3H, CH3), 4.13-4.18 (q, 2H, J = 7.1), 7.75 (s, 2H,
thiazole-2-NH2). 13C NMR (100 MHz, DMSO): dC (ppm) 170.19, 161.92, 159.32,
107.29, 59.69, 17.07, 14.27. MS (ESI) m/z for (186.23): 187.1 (M ? 1)?, 188.1
(M ? 2)?. Elemental analysis: Calculated for C7H10N2O2S (186.05): C 45.15%, H
5.41%, N 15.04%, S 17.22%; Found: C 45.13%., H 5.39%, N 15.02%, S 17.20%.
General procedure for synthesis of imidazo[2,1-b]thiazoles 3–20
To stirred solution of polyethylene glycol (PEG-400) (2 mL) in water (2 mL) were
added 1-(2-amino-4-methylthiazol-5-yl)ethanone (2 mmol)/ethyl 2-amino-4-
methylthiazole-5-carboxylate (2 mmol) and a-bromo aralkyl ketones (phenacyl
bromides) (2 mmol), and the mixture was heated at 90 °C or subject to microwave
irradiation at 300 W, until reaction completion as indicated by TLC. After reaction
completion, the reaction mixture was cooled at room temperature, and the solid
product formed was collected by filtration, washed with water, and recrystallized
from ethanol to give pure product. The recovered PEG with water was reused for
five further cycles.
1-(3-Methyl-6-phenylimidazo[2,1-b]thiazol-2-yl)ethanone (3)
Off-white solid IR mmax (KBr) cm-1: 3130.89, 1642.48, 1571.57, 1145.37,
1
1171.78, 1017.64. H NMR (400 MHz, DMSO-d6): dH (ppm) 2.55 (s, 3H, CH3),
2.80 (s, 3H, COCH3), 7.28–7.31 (t, 1H, J = 7.2 Hz, ArH), 7.43–7.40 (t,
J = 7.4 Hz, 2H, ArH), 7.86–7.88 (d, J = 7.2 Hz, 2H, ArH), 8.45 (s, 1H, ArH).
13C NMR (100 MHz, DMSO): dC (ppm) 13.81, 29.36, 108.94, 125.47, 127.59,
128.69, 133.43, 135.60, 146.95, 147.44, 191.18. MS (ESI) m/z for (256.32): 257.2
(M ? 1)?, 258.2 (M ? 2)?. Elemental analysis: Calculated for C11H9NO2
(256.07): C 65.60%, H 4.72%, N 10.93%, S 12.51%; Found: C 65.63%, H
4.70%, N 10.92%, S 12.54%.
1-(6-(2-Chlorophenyl)-3-methylimidazo[2,1-b]thiazol-2-yl)ethanone (4)
Pale-yellow solid IR mmax (KBr) cm-1: 3135.34, 1628.54, 1613.98, 1125.03,
1
1000.97, 745.96, 765.37. H NMR (400 MHz, DMSO-d6): dH (ppm) 2.58 (s, 3H,
CH3), 2.85 (s, 3H, COCH3), 7.42–7.44 (m, 2H, ArH), 7.49–7.51 (d, J = 7.4 Hz, 1H,
ArH), 7.75–7.77 (d, J = 7.4 Hz, 1H, ArH), 8.52 (s, 1H, ArH). 13C NMR (100 MHz,
DMSO): dC (ppm) 13.82, 29.33, 108.95, 122.98, 123.28, 127.69, 130.64, 132.64,
133.57, 134.26, 135.66, 146.93, 147.41, 191.20. MS (ESI) m/z for (290.03): 291.03
(M ? 1)?, 292.03 (M ? 2)?. Elemental analysis: Calculated for C14H11ClN2OS
(290.77): C 57.83%, H 3.81%, N 9.63%, S 11.0%; Found: C 57.82%, H 3.82%, N
9.61%, S 11.02%.
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
1-(3-Methyl-6-(p-tolyl)imidazo[2,1-b]thiazol-2-yl)ethanone (5)
Off-white solid IR mmax (KBr) cm-1: 3210.23, 3036.67, 1690.43, 1092.65, 998.37,
1178.36, 795.98. 1H NMR (400 MHz, DMSO-d6): dH (ppm) 2.55 (s, 3H, CH3), 2.65
(s, 3H, CH3), 2.82 (s, 3H, COCH3), 7.39–7.41 (d, J = 8.2 Hz, 2H, ArH), 7.72–7.74
(d, J = 7.2 Hz, 2H, ArH), 8.52 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC
(ppm) 13.82, 20.78, 29.33, 108.95, 126.76, 127.68, 130.24, 130 58, 131.97, 135.60,
146.93, 147.41, 191.20. MS (ESI) m/z for (270.08): 271.09 (M ? 1)?, 272.08
(M ? 2)?. Elemental analysis: Calculated for C15H14N2OS (270.35): C 66.64%, H
5.22%, N 10.36%, S 11.86%; Found: C 66.62%, H 5.23%, N 10.36%, S 11.02%.
1-(6-(4-Methoxyphenyl)-3-methylimidazo[2,1-b]thiazol-2-yl)ethanone (6)
White solid IR mmax (KBr) cm-1: 3165.64, 1647.72, 1485.37, 1134.60, 1117.90,
1
817.69. H NMR (400 MHz, DMSO-d6): dH (ppm) 2.56 (s, 3H, CH3), 2.84 (s, 3H,
COCH3), 3.66 (s, 3H, OCH3), 7.39–7.41 (d, J = 8.8 Hz, 2H, ArH), 7.87–7.89 (d,
J = 7.6 Hz, 2H, ArH), 8.51 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC (ppm)
13.82, 29.33, 55.20, 108.95, 126.76, 127.68, 130.24, 130 58, 131.97, 135.60,
146.93, 147.41, 191.20. MS (ESI) m/z for (286.08): 287.08 (M ? 1)?, 288.08
(M ? 2)?. Elemental analysis: Calculated for C15H14N2O2S (286.35): C 62.92%, H
4.93%, N 9.78%, S 11.20%; Found: C 62.94%, H 4.92%, N 9.80%, S 11.23%.
1-(6-(4-Bromophenyl)-3-methylimidazo[2,1-b]thiazol-2-yl)ethanone (7)
Yellow solid IR mmax (KBr) cm-1: 3190.39, 1593.99, 1593.74, 1114.48, 1203.18,
798.30, 553.19. 1H NMR (400 MHz, DMSO-d6): dH (ppm) 2.56 (s, 3H, CH3), 2.84
(s, 3H, COCH3), 7.46–7.48 (d, J = 9.4 Hz, 2H, ArH), 7.91–7.93 (d, J = 8.0 Hz,
2H, ArH), 8.52 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC (ppm) 13.79, 20.77,
108.94, 124.67, 126.79, 127.69, 130.23, 130 61, 131.98, 135.62, 146.95, 147.45,
191.22. MS (ESI) m/z for (333.98): 334.98 (M ? 1)?, 335.98 (M ? 2)?. Elemental
analysis: Calculated for C14H11BrN2OS (335.22): C 50.16%, H 3.31%, N 8.36%, S
9.5%; Found: C 50.15%, H 3.29%, N 8.38%, S 9.6%.
1-(6-(4-Chlorophenyl)-3-methylimidazo[2,1-b]thiazol-2-yl)ethanone (8)
Light-yellow solid IR mmax (KBr) cm-1: 3138.16, 1644.97, 1570.75, 1144.11,
1
1048.62, 1008.20, 841.59, 727.66. H NMR (400 MHz, DMSO-d6): dH (ppm) 2.50
(s, 3H, CH3), 2.79 (s, 3H, COCH3), 7.47–7.49 (d, J = 9.6 Hz, 2H, ArH), 7.86–7.88
(d, J = 7.2 Hz, 2H, ArH), 8.49 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC
(ppm) 13.78, 20.74, 108.90, 124.63, 126.78, 127.71, 130.26, 130 65, 131.97, 135.64,
146.98, 147.43, 191.22. MS (ESI) m/z for (290.03): 291.03 (M ? 1)?, 292.03
(M ? 2)?. Elemental analysis: Calculated for C14H11ClN2OS (290.77): C 57.83%,
H 3.81%, N 9.63%, S 11.03; Found: C 57.85%, H 3.80%, N 9.65%, S 11.02%.
123

R. H. Vekariya et al.
1-(6-(2,4-Dichlorophenyl)-3-methylimidazo[2,1-b]thiazol-2-yl)ethanone (9)
Pale-yellow solid IR mmax (KBr) cm-1: 3093.65, 1620.01, 1590.16, 1141.31,
1080.26, 998.87, 800.90, 543.91, 748.27. 1H NMR (400 MHz, DMSO-d6): dH
(ppm) 2.57 (s, 3H, CH3), 2.81 (s, 3H, COCH3), 7.50 (s, 1H, ArH), 7.56–7.58 (d,
J = 8.2 Hz, 1H, ArH), 7.72 (s, 1H, ArH), 8.06–8.08 (d, J = 7.6 Hz, 1H, ArH), 8.52
(s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC (ppm) 13.78, 20.74, 108.90, 124.33,
126.56, 127.88, 127.71, 130.26, 131 98, 133.47, 135.65, 146.96, 147.42, 191.21. MS
(ESI) m/z for (323.99): 325.1 (M ? 1)?, 326.0 (M ? 2)?. Elemental analysis:
Calculated for C14H10Cl2N2OS (325.21): C 51.70%, H 3.10%, N 8.61%, S, 9.86%;
Found: C 51.71%, H 3.11%, N 8.60%, S 9.85%.
1-(6-(4-Fluorophenyl)-3-methylimidazo[2,1-b]thiazol-2-yl)ethanone (10)
White solid IR mmax (KBr) cm-1: 3132.35, 1675.61, 1582.39, 1217.44, 1163.47,
1
1021.38, 1025.98, 775.11. H NMR (400 MHz, DMSO-d6): dH (ppm) 2.52 (s, 3H,
CH3), 2.80 (s, 3H, COCH3), 7.49–7.51 (d, J = 9.6 Hz, 2H, ArH), 7.87–7.89 (d,
J = 7.6 Hz, 2H, ArH), 8.51 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC (ppm)
13.78, 20.80, 108.91, 124.59, 126.82, 127.70, 130.22, 130 61, 131.97, 135.61,
146.94, 147.46, 191.21. MS (ESI) m/z for (274.06): 275.06 (M ? 1)?, 276.06
(M ? 2)?. Elemental analysis: Calculated for C14H11FN2OS (274.31): C 61.30%, H
4.04%, N 10.21%, S 11.69%; Found: C 61.31%, H 4.05%, N 10.22%, S 11.66%.
1-(6-(2-Methoxyphenyl)-3-methylimidazo[2,1-b]thiazol-2-yl)ethanone (11)
Off-white solid IR mmax (KBr) cm-1: 3168.95, 1642.15, 1561.88, 1181.21,
1
1115.51, 750.63. H NMR (400 MHz, DMSO-d6): dH (ppm) 2.58 (s, 3H, CH3),
2.85 (s, 3H, COCH3), 3.65 (s, 3H, OCH3), 7.44–7.46 (m, 2H, ArH), 7.58–7.60 (d,
J = 7.6 Hz, 1H, ArH), 7.79–7.81 (d, J = 7.2 Hz, 1H, ArH), 8.50 (s, 1H, ArH). 13
C
NMR (100 MHz, DMSO): dC (ppm) 13.83, 29.35, 55.23, 108.96, 122.97, 123.31,
127.62, 130.77, 132.32, 133.58, 134.28, 135.67, 146.92, 147.43, 191.21. MS (ESI)
m/z for (286.08): 287.08 (M ? 1)?, 288.08 (M ? 2)?. Elemental analysis:
Calculated for C15H14N2O2S (286.35): C 62.92%, H 4.93%, N 9.78%, S 11.20%;
Found: C 62.93%, H 4.90%, N 9.79%, S 11.21%.
1-(3-Methyl-6-(4-nitrophenyl)imidazo[2,1-b]thiazol-2-yl)ethanone (12)
Dark-yellow solid IR mmax (KBr) cm-1: 3150.95, 1703.47, 1559.65, 1543.36,
1
1367.59, 1098.17, 821.85. H NMR (400 MHz, DMSO-d6): dH (ppm) 2.52 (s, 3H,
CH3), 2.82 (s, 3H, COCH3), 7.40–7.42 (d, J = 8.8 Hz, 2H, ArH), 7.88–7.90 (d,
J = 7.6 Hz, 2H, ArH), 8.49 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC (ppm)
13.76, 20.82, 108.99, 124.19, 126.62, 127.39, 130.12, 130 68, 131.77, 135.62,
146.93, 147.45, 191.20. MS (ESI) m/z for (301.05): 302.05 (M ? 1)?, 303.05
(M ? 2)?. Elemental analysis: Calculated for C14H11N3O3S (301.32): C 55.80%, H
3.68%, N 13.95%, S 10.64%; Found: C 55.83%, H 3.67%, N 13.94%, S 10.63%.
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
Ethyl 3-methyl-6-phenylimidazo[2,1-b]thiazole-2-carboxylate (13)
Off-white solid IR mmax (KBr) cm-1: 3132.58, 1748.13, 1644.84, 1586.15,
1
1231.18, 1141.89, 1178.15, 1017.15. H NMR (400 MHz, DMSO-d6): dH (ppm)
1.28–1.32 (t, J = 7.0 Hz, 3H, CH3), 2.31 (s, 3H, CH3), 4.25–4.31 (q, J = 7.1 Hz,
2H, CH2), 7.29–7.32 (t, 1H, J = 7.4 Hz, ArH), 7.42–7.45 (t, J = 7.6 Hz, 2H, ArH),
7.78–7.80 (d, J = 8.2 Hz, 2H, ArH), 8.31 (s, 1H, ArH). 13C NMR (100 MHz,
DMSO): dC (ppm) 12.81, 20.77, 61.43, 108.11, 112.89, 125.44, 129.25, 130.61,
133.38, 137.17, 146.51, 147.41, 161.48. MS (ESI) m/z for (286.08): 287.08
(M ? 1)?, 288.08 (M ? 2)?. Elemental analysis: Calculated for C15H14N2O2S
(286.35): C 62.92%, H 4.93%, N 9.78%, S 11.20%; Found: C 62.93%, H 4.94%, N
9.79%, S 11.17%.
Ethyl 6-(2-chlorophenyl)-3-methylimidazo[2,1-b]thiazole-2-carboxylate (14)
Pale-yellow solid IR mmax (KBr) cm-1: 3137.90, 1715.25, 1634.25, 1567.98,
1
1231.18, 1113.03, 1005.68, 744.16, 768.48. H NMR (400 MHz, DMSO-d6): dH
(ppm) 1.32–1.36 (t, J = 7.2 Hz, 3H, CH3), 2.33 (s, 3H, CH3), 4.35–4.39 (q,
J = 7.4 Hz, 2H, CH2), 7.30–7.35 (m, 2H, ArH), 7.46–7.48 (d, J = 8.4 Hz, 1H,
ArH), 7.75–7.77 (d, J = 7.6 Hz, 1H, ArH), 8.34 (s, 1H, ArH). 13C NMR (100 MHz,
DMSO): dC (ppm) 12.82, 20.76, 61.44, 108.11, 113.29, 127.24, 128.45, 130.12,
130.88, 132.72, 133.45, 137.18, 146.53, 147.45, 161.49. MS (ESI) m/z for (320.04):
321.04 (M ? 1)?, 322.04 (M ? 2)?. Elemental analysis: Calculated for C15H13-
ClN2O2S (320.79): C 56.16%, H 4.08%, N 8.73%, S 10.00%; Found: C 56.17%, H
4.09%, N 8.70%, S 10.01%.
Ethyl 3-methyl-6-(p-tolyl)imidazo[2,1-b]thiazole-2-carboxylate (15)
Pale-yellow solid IR mmax (KBr) cm-1: 3218.25, 1718.17, 3035.91, 1689.47,
1
1240.54, 1090.23, 1000.15, 1176.34, 791.32. H NMR (400 MHz, DMSO-d6): dH
(ppm) 1.28–1.32 (t, J = 7.0 Hz, 3H, CH3), 2.31 (s, 3H, CH3), 2.73 (s, 3H, CH3),
4.25–4.31 (q, J = 7.1 Hz, 2H, CH2), 7.19–7.21 (d, 1H, J = 8.0 Hz, ArH),
7.73–7.75 (d, J = 7.6 Hz, 2H, ArH), 8.32 (s, 1H, ArH). 13C NMR (100 MHz,
DMSO): dC (ppm) 12.80, 14.01, 20.78, 61.41, 108.09, 112.69, 124.74, 129.15,
130.62, 136.77, 137.17, 146.51, 147.41, 161.48. MS (ESI) m/z for (300.09): 301.09
(M ? 1)?, 302.09 (M ? 2)?. Elemental analysis: Calculated for C16H16N2O2S
(300.38): C 63.98%, H 5.37%, N 9.33%, S 10.67%; Found: C 63.99%, H 5.34%, N
9.34%, S 10.68%.
Ethyl 6-(4-methoxyphenyl)-3-methylimidazo[2,1-b]thiazole-2-carboxylate (16)
White solid IR mmax (KBr) cm-1: 3243.33, 1719.70, 1615.31, 1465.78, 1258.01,
1
1178.54, 1117.90, 807.90. H NMR (400 MHz, DMSO-d6): dH (ppm) 1.30–1.34 (t,
J = 7 Hz, 3H, CH3), 2.76 (s, 3H, CH3), 3.79 (s, 3H, CH3), 4.29–4.34 (q,
J = 7.06 Hz, 2H, CH2), 7.01–7.03 (d, J = 8.4 Hz, 2H, ArH), 7.73–7.75 (d,
J = 6.0 Hz, 2H, ArH), 8.55 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC (ppm)
123

R. H. Vekariya et al.
12.80, 14.01, 20.78, 55.20, 61.41, 108.09, 114.59, 124.18, 134.28, 137.17, 143.51,
145.41, 159.12, 161.48. MS (ESI) m/z for (316.09): 317.09 (M ? 1)?, 318.09
(M ? 2)?. Elemental analysis: Calculated for C16H16N2O3S (316.37): C 60.74%, H
5.10%, N 8.85%, S 10.14%; Found: C 60.77%, H 5.09%, N 8.84%, S 10.13%.
Ethyl 6-(4-bromophenyl)-3-methylimidazo[2,1-b]thiazole-2-carboxylate (17)
White solid IR mmax (KBr) cm-1: 3191.93, 1744.48, 1598.03, 1113.46, 1232.18,
1
1206.27, 1051.81, 1009.31, 799.04, 556.75. H NMR (400 MHz, DMSO-d6): dH
(ppm) 1.30–1.34 (t, J = 7.6 Hz, 3H, CH3), 2.68 (s, 3H, CH3), 4.29–4.35 (q,
J = 7.1 Hz, 2H, CH2), 7.28–7.30 (d, 1H, J = 8.8 Hz, ArH), 7.76–7.78 (d,
J = 8.0 Hz, 2H, ArH), 8.35 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC
(ppm) 12.82, 14.06, 20.76, 61.43, 108.11, 113.89, 126.18, 134.78, 138.09, 144.53,
146.51, 159.14, 161.68. MS (ESI) m/z for (363.99): 364.99 (M ? 1)?, 366.0
(M ? 2)?. Elemental analysis: Calculated for C15H13BrN2O2S (365.24): C 49.33%,
H 3.59%, N, 7.67%, S 8.78%; Found: C 49.32%, H 3.57%, N 7.71%, S 8.77%.
Ethyl 6-(4-chlorophenyl)-3-methylimidazo[2,1-b]thiazole-2-carboxylate (18)
Off-white solid IR mmax (KBr) cm-1: 3164.16, 1715.31, 1637.97, 1573.51,
1243.46, 1149.84, 1044.96, 1007.64, 840.37, 727.38. 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 1.29–1.33 (t, J = 7.8 Hz, 3H, CH3), 2.69 (s, 3H, CH3),
4.28–4.34 (q, J = 7.2 Hz, 2H, CH2), 7.27–7.29 (d, 1H, J = 8.8 Hz, ArH),
7.78–7.80 (d, J = 8.0 Hz, 2H, ArH), 8.38 (s, 1H, ArH). 13C NMR (100 MHz,
DMSO): dC (ppm) 12.81, 14.10, 20.74, 61.48, 108.15, 113.85, 126.17, 134.79,
138.08, 144.51, 146.64, 159.13, 161.67. MS (ESI) m/z for (320.04): 321.04
(M ? 1)?, 322.04 (M ? 2)?. Elemental analysis: Calculated for C15H13ClN2O2S
(320.79): C 56.16%, H 4.08%, N 8.73%, S 10.00%; Found: C 56.19%, H 4.07%, N
8.72%, S 9.99%.
Ethyl 6-(2,4-dichlorophenyl)-3-methylimidazo[2,1-b]thiazole-2-carboxylate (19)
Off-white solid IR mmax (KBr) cm-1: 3098.46, 1717.23, 1619.17, 1593.17,
1240.97, 1144.47, 1050.18, 1009.87, 803.18, 547.29, 746.55. 1H NMR
(400 MHz, DMSO-d6): dH (ppm) 1.32–1.36 (t, J = 7.2 Hz, 3H, CH3), 2.33 (s,
3H, CH3), 4.35–4.39 (q, J = 7.4 Hz, 2H, CH2), 7.36–7.38 (d, J = 8.2 Hz, 1H,
ArH), 7.54 (s, 1H, ArH), 8.76–8.78 (d, J = 7.6 Hz, 1H, ArH), 8.36 (s, 1H, ArH).
13C NMR (100 MHz, DMSO): dC (ppm) 12.81, 20.77, 61.45, 108.12, 113.31,
127.23, 128.42, 130.07, 130.92, 132.61, 134.40, 137.20, 146.51, 147.42, 161.48. MS
(ESI) m/z for (354.00): 355.0 (M ? 1)?, 356.0 (M ? 2)?. Elemental analysis:
Calculated for C15H12Cl2N2O2S (355.24): C 50.72%, H 3.40%, N 7.89%, S 9.03%;
Found: C 50.71%, H 3.43%, N 7.88%, S 9.02%.
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Microwave-assisted green synthesis of new imidazo[2,1-b]…
Ethyl 6-(4-fluorophenyl)-3-methylimidazo[2,1-b]thiazole-2-carboxylate (20)
White solid IR mmax (KBr) cm-1: 3131.39, 1716.56, 1677.84, 1588.51, 1258.35,
1
1215.05, 1160.92, 1020.34, 1027.26, 778.66. H NMR (400 MHz, DMSO-d6): dH
(ppm) 1.28–1.32 (t, J = 7.6 Hz, 3H, CH3), 2.68 (s, 3H, CH3), 4.29–4.33 (q,
J = 7.1 Hz, 2H, CH2), 7.29–7.31 (d, 1H, J = 8.6 Hz, ArH), 7.80–7.82 (d,
J = 8.0 Hz, 2H, ArH), 8.36 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC
(ppm) 12.83, 14.09, 20.73, 61.45, 108.16, 113.88, 126.19, 134.81, 138.10, 144.49,
146.54, 159.12, 161.66. MS (ESI) m/z for (304.07): 305.07 (M ? 1)?, 306.07
(M ? 2)?. Elemental analysis: Calculated for C15H13FN2O2S (304.34): C 59.20%,
H 4.31%, N 9.20%, S, 10.54%; Found: C 59.22%, H 4.30%, N 9.18%%, S 10.55%.
Ethyl 6-(2-methoxyphenyl)-3-methylimidazo[2,1-b]thiazole-2-carboxylate (21)
Off-white solid IR mmax (KBr) cm-1: 3169.25, 1723.25, 1641.75, 1567.95,
1
1245.37, 1186.45, 1118.47, 752.21. H NMR (400 MHz, DMSO-d6): dH (ppm)
1.32–1.36 (t, J = 7.2 Hz, 3H, CH3), 2.34 (s, 3H, CH3), 3.80 (s, 3H, CH3), 4.34–4.38
(q, J = 7.4 Hz, 2H, CH2), 7.28–7.33 (m, 2H, ArH), 7.45–7.47 (d, J = 8.4 Hz, 1H,
ArH), 7.76–7.78 (d, J = 7.6 Hz, 1H, ArH), 8.35 (s, 1H, ArH). 13C NMR (100 MHz,
DMSO): dC (ppm) 12.82, 20.76, 55.22, 61.44, 108.11, 113.29, 127.24, 128.45,
130.12, 130.88, 132.72, 133.45, 137.18, 146.53, 147.45, 161.49. MS (ESI) m/z for
(316.09): 317.09 (M ? 1)?, 318.09 (M ? 2)?. Elemental analysis: Calculated for
C16H16N2O3S (316.37): C 60.74%, H 5.10%, N 8.85%, S 10.14%; Found: C
60.77%, H 5.09%, N 8.84%, S 10.13%.
Ethyl 3-methyl-6-(4-nitrophenyl)imidazo[2,1-b]thiazole-2-carboxylate (22)
Dark-yellow solid IR mmax (KBr) cm-1: 3148.91, 1725.82, 1700.71, 1557.55,
1
1546.15, 1368.86, 1259.25, 1091.08, 828.45. H NMR (400 MHz, DMSO-d6): dH
(ppm) 1.25–1.28 (t, J = 7.4 Hz, 3H, CH3), 2.67 (s, 3H, CH3), 4.27–4.31 (q,
J = 7.2 Hz, 2H, CH2), 7.28–7.30 (d, 1H, J = 8.4 Hz, ArH), 7.82–7.84 (d,
J = 8.0 Hz, 2H, ArH), 8.32 (s, 1H, ArH). 13C NMR (100 MHz, DMSO): dC
(ppm) 12.79, 14.08, 20.75, 61.76, 108.17, 113.89, 125.24, 133.83, 137.99, 144.15,
146.94, 159.12, 161.64. MS (ESI) m/z for (331.06): 332.06 (M ? 1)?, 333.06
(M ? 2)?. Elemental analysis: Calculated for C15H13N3O4S (331.35): C 54.37%, H
3.95%, N 12.68%, S 9.68%; Found: C 54.40, H 3.94%, N 12.67%, S 9.67%.
Microbiology
Antibacterial and antifungal activity
Mueller–Hinton broth and Sabouraud broth were used as nutrient medium to grow
bacteria and fungi, respectively. Inoculum size for the test strain was adjusted to 106
colony-forming units (CFU) per milliliter by comparing turbidity. Serial dilutions
were prepared for primary and secondary screening. Control tube containing no
123

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antibiotic was immediately subcultured (before inoculation) by spreading a loopful
evenly over a quarter plate of medium suitable for growth of the test organism and
incubated at 37 °C for bacteria or 22 °C for fungi overnight. The MIC of the control
organism was read to check the accuracy of the drug concentrations. The lowest
concentration inhibiting growth of the organism was recorded as the MIC. Each test
compound was diluted, obtaining 2000 lg/mL concentration, as stock solution. In
primary screening, 1000, 500, 250, and 125 lg/mL concentrations of the test
compounds were taken. The active synthesized compounds found in this primary
screening were further tested in a second dilution set against all organisms. The
drugs found active in primary screening were similarly diluted to obtain 100, 50,
62.5, 25, 12.5, and 6.25 lg/mL concentrations. The highest dilution showing at least
99% inhibition was taken as the MIC.
All newly synthesized imidazo[2,1-b]thiazole derivatives (3–22) were examined
for antimicrobial activity against two Gram-positive bacterial strains (Staphylococ-
cus aureus MTCC 96, Streptococcus pyogenes MTCC 442), two Gram-negative
bacterial strains (Escherichia coli MTCC 443, Pseudomonas aeruginosa MTCC
1688), as well as three fungal strains (Aspergillus clavatus MTCC 1323, Candida
albicans MTCC 227, and Aspergillus niger MTCC 282) by agar dilution method
[72]. Ampicillin, ciprofloxacin, and chloramphenicol were used as standard control
drugs for antibacterial activity, whereas nystatin and griseofulvin were used as
standard control drugs for antifungal activity.
Antimalarial activity
Stock solution of 5 mg/mL of each test sample as well as standards was prepared in
DMSO, and subsequent dilutions were prepared with culture medium. The diluted
samples in 20 lL volume were added to test wells to obtain final concentrations (at
fivefold dilutions) ranging between 0.4 and 100 lg/mL in duplicate wells containing
parasitized cell preparation. In vitro antimalarial assay was carried out in 96-well
plates according to the microassay protocol of Reickmann and coworkers with
minor modifications [73]. Cultures of P. falciparum strain were maintained in
Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 25 mM
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 1% D-glucose, 0.23%
sodium bicarbonate, and 10% heat-inactivated human serum. Asynchronous
parasites of P. falciparum were synchronized after 5% D-sorbitol treatment to
obtain only ring-stage parasitized cells. To carry out the assay, initial ring-stage
parasitemia of 0.8–1.5% at 3% hematocrit in total volume of 200 lL of RPMI 1640
medium was determined by Jaswant–Singh–Bhattacharya (JSB) staining [74] to
assess percent parasitemia (rings) and uniformly maintained with 50% red blood
cells (RBCs) (O?ve). The culture plates were incubated at 37 °C in a candle jar.
After 36–40 h of incubation, thin blood smears from each well were prepared and
stained with JSB stain. The slides were microscopically observed to record
maturation of the ring-stage parasites into trophozoites and schizonts in presence of
different concentrations of test agents. The test concentration which inhibited
complete maturation into schizonts was recorded as the minimum inhibitory
concentration (MIC). Chloroquine and quinine were used as reference drugs.
123

Microwave-assisted green synthesis of new imidazo[2,1-b]…
Antitubercular activity
The MIC of the test compounds against M. tuberculosis H37Rv was determined by
¨
Lowenstein–Jensen (L–J) agar (MIC) method [75, 76]. Primary 1000, 500, and
250 lg/mL and secondary 200, 100, 50, 25, 12.5, 6.250, and 3.125 lg/mL dilutions
of each test compound were added to liquid L–J medium, which was then sterilized by
inspissation method. Culture of M. tuberculosis H37Rv growing on L–J medium was
harvested in 0.85% saline in bijou bottles. For all test compounds, stock solution of
2000 lg/mL concentration was first prepared in DMSO. These tubes were then
incubated at 37 °C for 24 h, followed by streaking of M. tuberculosis H37Rv
(5 9 104 bacilli per mL). These tubes were then incubated at 37 1 °C. Growth of
bacilli was observed after 12, 22, and finally 28 days of incubation. Tubes containing
compounds were compared with control tubes in which medium alone was incubated
with M. tuberculosis H37Rv. The concentration at which no development of (or fewer
than 20) colonies occurred was taken as the MIC of the test compound. The standard
strain M. tuberculosis H37Rv was tested with known drug rifampicin.
Conclusions
One-pot tandem preparation of 2-aminothiazole derivatives 1a, b was achieved by
reaction of acetyl acetone or ethyl acetoacetate with N-bromosuccinimide (NBS) and
thiourea in presence of green and biodegradable PEG-400 as alternative reaction
medium under microwave irradiation at 180 W. After that, aqueous PEG-400 was
utilized as an extremely effective catalytic system for synthesis of imidazo[2,1-
b]thiazole derivatives 3–22 by reaction of 1a, b with a-bromo aralkyl ketones
(phenacyl bromides) at 90 °C or under MWI at 300 W. The major advantages of the
presented protocol are the use of nonvolatile and biodegradable PEG-400 as substitute
reaction medium, the potential for process scale-up, excellent product yield, short
reaction time, and simple work-up procedure. Moreover, using this methodology,
highly pure products were obtained with no need for column purification. It is therefore
determined that the current protocol is a useful addition to green chemical procedures.
From the bioassays, it is clear that the imidazo[2,1-b]thiazole derivatives showed
greater antimicrobial as well as antimalarial activity. In the present study, compounds
7–9, 18–20 exhibited highly potent activity against most of the tested bacteria.
Acknowledgements The authors are grateful to the Department of Chemistry, Gujarat University,
Ahmedabad, for providing the necessary facilities. UGC-Info net and INFLIBNET Gujarat University are
acknowledged for providing the e-resource facilities, the NFDD Centre for proton NMR and carbon
NMR, and the Synzeal Research Laboratory for mass spectroscopy. R.H.V. is grateful to UGC-BSR [F.7-
74/2007 (BSR)] for financial assistance.
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