Green synthesis and biological evaluation of some novel azoles as antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2010.10.111

A series of novel fluorine-containing triazoles 3, thiadiazoles 4, and oxadiazoles 5 were synthesized from thiosemicarbazides 2. These reactions were carried out by green technique such as ultrasonication and microwave. All products have been characterized by IR, ¹H NMR, and Mass spectral study and screened for their antimicrobial activity.

Full text of DOI:10.1016/j.bmcl.2010.10.111

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7200–7204
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Green synthesis and biological evaluation of some novel azoles
as antimicrobial agents
Sharad Shelke a, , Ganesh Mhaske a, Sunil Gadakh a, Charnsingh Gill b
⇑
a Department of Chemistry, S.S.G.M. College, Kopargaon, Dist-Ahmednagar (MH) 423601, India
b Department of Chemistry, Dr. B.A.M. University, Aurangabad (MH) 423601, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel fluorine-containing triazoles 3, thiadiazoles 4, and oxadiazoles 5 were synthesized from
thiosemicarbazides 2. These reactions were carried out by green technique such as ultrasonication and
microwave. All products have been characterized by IR, 1H NMR, and Mass spectral study and screened
for their antimicrobial activity.
Received 19 August 2010
Revised 21 September 2010
Accepted 22 October 2010
Available online 27 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ultrasound irradiation
Microwave-assisted synthesis
Triazole
Thiadiazole
Antifungal activity
It has known that introduction of fluorine atom in molecule
may lead to significant influence on the biological and physical
properties of compounds due to increase of membrane permeabil-
ity, hydrophobic bonding, stability against metabolic oxidation,
etc.1 Since fluorine-containing compound is of promising pharma-
cological activities which are originated from their unique high
thermal stabilities and lipophilicity.2 Therefore the development
of synthetic methods for fluorine-containing compounds has been
an important field in both organofluorine chemistry syntheses.
Triazoles and their derivatives have enhanced considerable
attention for the past few decades due to their chemotherapeutical
value.3 In particular fluorinated triazoles are of significant interested
because they possess antitubercular4 and anticancer5 activity. Liter-
ature survey indicates that thiosemicarbazide are found to associate
with antibacterial,6 antifungal7 activities. Compounds containing
1,3,4-thiadiazole nucleus has been reported to be a variety of biolog-
ical activities like fungitoxic,8 CNS stimulant,9 anticholinergic,10 and
anticonvulsant.11 Several oxadiazoles and thiadiazoles also exhibit
anti-tubercular,12 antifungal,13 and herbicidal13 properties. Re-
cently literature survey reveals that fluorinated 1,3,4-oxadiazole
derivatives possesses anticancer14 and antibacterial15 activity.
The advantageous use of ultrasound irradiation technique for
activating various reactions is well documented in the literature
such as synthesis of azoles and diazenes,16 Reformatsky reaction,17
oxidation of substrates like hydroquinones,18 Pinacol coupling,19
Suzuki cross-coupling,20 etc.
Commercial microwave-assisted organic reactions occurs more
rapidly, safely and with higher chemicals yields,21–23 render the
microwave method superior to conventional method. The growing
number of publication in microwave-assisted synthesis includes
virtually all types of synthesis like Knoevenagel condensation.24
Triazoles are synthetic compounds with a chemical structure
comprising one or more five-membered azole rings that contain
three nitrogen atoms. They have a higher affinity for fungal than
mammalian target enzymes, which makes them less toxic, for in-
stance, than imidazole compounds like ketoconazole and miconaz-
ole. The currently available systemic triazoles are fluconazole,
itraconazole, voriconazole, and posaconazole. Ravuconazole, albac-
onazole, and isavuconazole are in advanced stages of clinical devel-
opment and will not be discussed in this article. In selecting the
optimal triazole agent for therapy, it is important to consider not
only its spectrum of activity, but also several other pharmacoki-
netic and pharmacodynamic parameters. There are limited data
on pharmacodynamic properties of antifungal agents, but animal
models suggest that killing of fungi with triazoles is optimized
with maximal drug exposure over time (time-dependent kill-
ing).25–27
Biological activities associated with azoles and advantages of
green techniques and in continuation of our work.28,29 We have
prompted us to prepare some fluorinated azoles by conventional
as well as sonochemical and microwave method.
Chemistry: In the present work, we herein report the synthesis
of fluorinated azoles. Scheme for the synthesized compound has
been shown in Scheme 1.
⇑
Corresponding author. Tel.: +91 8888199853.
E-mail address: snshelke@yahoo.co.in (S. Shelke).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.111

S. Shelke et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7200–7204
7201
The aim of the present study was to investigate the antibacterial
activity of synthesized compounds. Thiosemicarbazides 2 have
been prepared from acid hydrazide 1 on treatment with fluori-
nated aryl isothiocyanates. Thiosemicarbazides 2 in 1% NaOH gave
compounds 3, that is, triazoles and in concd H2SO4 gave com-
pounds 4, that is, thiadiazoles. These compounds 2 on treatment
with I2/KI and NaOH gave compounds 5, that is, oxadiazoles. These
compounds were synthesized by conventional method as well as
green technique. Compounds 3 and 4 were obtained 72–88% yield
under green technique. Each experiment was repeated three times
to confirm the consistency of the results. The efficiency of green
technique was evaluated by comparison with the same reaction
in acidic or basic medium. The later method required 90 and
120 min. for synthesis of triazoles and thiadiazoles, respectively.
Yield of conventional method are found to be 65–75% yield.
Antimicrobial activities were determined by agar diffusion as-
say disc method againstStaphylococcus aureus, Escherichia coli, Bacil-
lus subtilis, Pseudomonas aeruginosa bacteria and Aspergillus niger,
Candida albicans fungi. The antibiotic Nystatin (100 U/disc) and
chlorampenicol (10 mcg/disc) was used as control for antibacterial
the filter disc. The plates were further incubated for 18–20 h at
37 °C.
The investigation of antimicrobial screening data revealed that
all the tested compounds 2, 3, 4, and 5 showed moderate to excel-
lent antibacterial and antifungal activities against S. aureus, E. coli,
B. subtilis, P. aeruginosa, and A. niger, C. albicans, respectively. The
2a–2e are active against S. aureus, E. coli, B. subtilis, and P. aerugin-
osa. Among thiosemicarbazides 2c are most active compounds and
are passive for all bacterial species. The 3a–3e are only active
against S. Aureus bacterial and A. niger fungal species. Amoung thi-
adiazoles (4a–4e) 4c and 4e exhibited more active than the chlo-
rampenicol against A. niger and Nystatin against P. aeruginosa,
respectively.
Among oxdiazoles (5a–5e) 5a and 5b exhibited most activity
than the chlorampenicol against A. niger as well as C. albicans
and Nystatin against P. aeruginosa, respectively. The most active
compounds 4e and 5b are passive for P. aeruginosa strains. While
the most active compounds 4c, 5a are passive for both fungal
strains.
All the recorded melting points were determined in open capil-
lary tubes and are uncorrected. IR spectra were recorded on Per-
kin–Elmer FTIR spectrophotometer in KBr disc. The 1H NMR
spectra of some of the compounds of this series were scanned on
300 MHz F spectrophotometer, respectively, using DMSO-d6 as a
solvent and TMS as an internal standard. Peak values are shown
in d ppm.
Mass spectra were obtained by Finnigan mass spectrometer.
Experiment under ultrasound irradiation was carried out in
ultrasonic cleaner model EN-20U-S manufactured by ENERTECH
and antifungal activity, respectively. The samples (100 lg/mL)
were dissolved in dimethyl sulphoxide (DMSO) and used for the
antimicrobial activities. The bacterial cultures of known inoculums
size (1 Â 108 bacteria /mL) of test microorganism were spread on
Muller Hinton agar plates. While the fungial cultures of known
inoculums size (1 Â 106 bacteria/mL) of test microorganism were
spread on potato dextrose ager plates.
The Whatman filter paper discs of 6 mm were placed on the
plate and the sample of appropriate concentration was added to
OCH3
F
F
N
H
N
NH2
O
O
1
R1
R2
R3
N
N
Ethanol
C
C
S
OR
S
Substituted group
OCH3
F
F
N
S
R3
R2
H
N
N
H
NH
O
O
R1
2
2N NaOH
I2/ KI-NaOH
Conc. H2SO4
N
N
O
R1
NH
R3
O
N
N
N
O
R2
OCH3
N
H3CO
R2
R1
NH
F
F
S
N
F
R3
R1
F
H3CO
F
R2
N
F
S
O
N
5
R3
NH
4
3
Scheme 1. Synthesis of fluorinated azoles 2, 3, 4, and 5.

7202
S. Shelke et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7200–7204
ELECTRONICS PVT. LTD, Mumbai, India has maximum power out-
put of 100 W and 33 KHz operating frequency.
All newly synthesized compound were found to be pure
(checked by thin layer chromatography).
2d: IR (KBr) m
/cmÀ1: 3436 (–NH), 1654 (–C@O), 1610 (C@C),
1462 (–C@S), 1245 (–C–O–C), 1199 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.11–1.28 (m, 4H), 2.19 (s, 3H), 2.22–2.38 (m,
1H), 3.27 (s, 3H), 6.93–7.41 (m, 5H), 7.58 (s, 1H), 9.57 (s, 2H),
10.29 (br s, 1H). MS (m/z): 459 (M+1).
All experiments under microwave irradiation were carried out
in unmodified domestic microwave oven model 800T
manufactured by BPL Appliances and Utilities Ltd, Bangalore, In-
dia having maximum power output of 800 W and 2450 MHz
frequency.
The newly synthesized compounds were screened for their anti-
microbial activity against S. aureus, E. coli, B. subtilis, P. aeruginosa
bacteria and A. niger, C. albicans fungi using by agar diffusion assay
disc method. The antimicrobial activity was evaluated by measur-
ing the zone of inhibition in mm and results obtained are shown in
Table 1.
2e: IR (KBr) m
/cmÀ1: 3437 (–NH), 1653 (–C@O), 1608 (C@C),
1463 (–C@S), 1247 (–C–O–C), 1197 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.09–1.29 (m, 4H), 2.20 (s, 3H), 2.26–2.36 (m,
1H), 3.25 (s, 3H), 6.95–7.4 (m, 5H), 7.53 (s, 1H), 9.50 (s, 2H),
10.30 (br s, 1H). MS (m/z): 459 (M+1).
General procedure for synthesis of triazoles (3). By conventional
method: Thiosemicarbazide 2 (0.005 mol) and 10 mL of 2 N so-
dium hydroxide solution were taken in 100 mL RBF and the reac-
tion mixture was heated under mild reflux for 1.5 h. Progress of
the reaction was monitored by TLC. The reaction mixture was
cooled and poured over ice water and acidified with dilute hydro-
chloric acid. Product was separated by filtration and crystallized
with DMF/water to afford the title compounds 3. The formation
of the compounds 3 was confirmed by mp, mixed mp, and spectral
data. Their characterization data is given in Table 2.
By ultrasonic irradiation: Thiosemicarbazide 2 (0.005 mol) and
10 mL of 2 N sodium hydroxide solution was taken in a beaker
(50 mL) and the reaction mixture was subjected to ultrasonic irra-
diated for 30–35 min at room temperature. Progress of the reaction
was monitored by TLC. The reaction mixture was then poured into
ice water and acidified with dilute hydrochloric acid. Product was
separated by filtration and crystallized with DMF/water to afford
the title compounds 3. The formation of the compounds 3 con-
firmed by mp, mixed mp, and spectral data. Their characterization
data is given in Table 2.
By microwave method: Thiosemicarbazide 2 (0.005 mole) was
taken in 50 mL borosilicate glass beaker with 10 mL of 2 N sodium
hydroxide solution. The reaction mixture was irradiated inside a
microwave oven for 1 min to 2.5 min at an output of 300 W power,
with short interruption of 15 s. TLC monitored progress of reaction.
The reaction mixture was cooled and poured into crushed ice.
Product was separated by filtration and crystallized with DMF/
water to afford the titled the compounds. Their characterization
data is given in Table 2.
General procedure for synthesis of thiosemicarbazides (2). Fluori-
nated acid hydrazide (0.01 mol)
1 and aryl isothiocyanates
(0.01 mol) were taken in 100% 15 mL of ethanol and the reaction
mixture was heated under reflux for 60 min. After completions of
the reaction (monitored by TLC) contents were cooled to room
temperature, the white product obtained was separated by filtra-
tion. The formation of the compounds 2 was confirmed by mp,
mixed mp and spectral data. Their characterization data is given
in the Table 2.
2a: IR (KBr) m
/cmÀ1: 3458 (–NH), 1651 (–C@O), 1604 (C@C),
1463 (–C@S), 1240 (–C–O–C), 1178 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.08–1.20 (m, 4H), 2.25–2.31 (m, 1H), 3.31 (s,
3H), 3.33 (s, 3H), 6.88–7.40 (m, 5H), 7.97 (s, 1H), 9.66 (s, 2H),
9.89 (br s, 1H). MS (m/z): 475 (M+1).
2b: IR (KBr) m
/cmÀ1: 3450 (–NH), 1660 (–C@O), 1612 (C@C),
1454 (–C@S), 1247 (–C–O–C), 1186 (–C–F), 1087 (–C–Cl). 1H
NMR (300 MHz, DMSO-d6, d, ppm): 1.05–1.20 (m, 4H), 2.25–2.40
(m, 1H), 3.41 (s, 3H), 7.34–7.55 (m, 5H), 7.58 (s, 1H), 9.88 (s, 2H),
10.12 (br s, 1H). MS (m/z): 479 (M+1), 481.
2c: IR (KBr) m
/cmÀ1: 3447 (–NH), 1661 (–C@O), 1609 (C@C),
1452 (–C@S), 1250 (–C–O–C), 1189 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.03–1.22 (m, 4H), 2.21–2.43 (m, 1H), 3.42 (s,
3H), 6.90–7.51 (m, 5H), 7.55 (s, 1H), 9.79 (s, 2H), 10.14 (br s, 1H).
MS (m/z): 445 (M+1).
Table 1
Antimicrobial activity of synthesized compounds 2, 3, 4 and 5
Compound no.
Substituted group
Zone of inhibition
S. aureus
E. coli
Bacillus subtilis
Pseudomonas aeruginosa
Aspergillus niger
Candida albicans
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
(3-OCH3)
(3-Cl)
(3-H)
(1-CH3)
(2-CH3)
(3-OCH3)
(3-Cl)
14.3
15.9
23.9
17.2
—
23.4
22.2
21.0
21.2
19.8
—
21
17
—
—
28.0
21.06
18.8
—
16.6
15.0
24.1
18.5
—
—
—
—
—
—
—
—
24
—
23.8
—
—
—
—
15.3
15.1
24.1
20.1
—
—
—
—
—
—
—
28
27
—
—
26.7
24.6
25.4
—
22.8
22.6
24.2
20.1
—
—
—
—
—
—
—
—
22
—
—
—
—
18
—
—
14.2
—
—
—
—
—
—
—
—
22
16.3
—
—
25.3
22.5
21.6
21.5
19.9
20.8
21.8
—
—
26.1
—
(3-H)
(1-CH3)
(2-CH3)
(3-OCH3)
(3-Cl)
(3-H)
(1-CH3)
(2-CH3)
(3-OCH3)
(3-Cl)
(3-H)
(1-CH3)
(2-CH3)
27.1
—
28.1
5b
5c
5d
5e
26.1
14.7
—
—
—
—
—
—
—
—
21
Nystatin
Chlorampenicol
NA
32.8
NA
29.14
NA
30.11
NA
24.68
21.12
NA
21.96
NA
*
Abbreviations used: NA = not applicable, — = no zone of inhibition. Diameter in mm calculated by digital vernier Caliper.

S. Shelke et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7200–7204
7203
Table 2
Characterization data of synthesized compounds 2, 3, 4, and 5
Compound
R1
R2
R3
Mp (°C)
Conventional method
Time (min) Yield (%)
Ultrasound method
Time (min) Yield (%)
Microwave METHOD
Time (min) Yield (%)
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
OCH3
Cl
H
H
H
OCH3
Cl
H
H
H
OCH3
Cl
H
H
H
OCH3
Cl
H
H
H
198
204
194
176
196
130
170
178
220
210
246
224
232
190
188
214
220
200
198
212
60
60
60
60
60
90
90
90
90
71
73
75
81
74
75
73
68
65
70
75
72
73
69
65
70
68
72
69
65
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
28
30
30
28
26
35
25
30
35
35
—
83
80
75
72
74
88
83
85
80
87
—
3.0
2.4
2.8
2.6
2.0
2.5
3.2
3.0
2.5
3.0
—
80
76
72
68
71
82
77
79
75
80
—
90
120
120
120
120
120
240
240
240
240
240
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
CH3
Abbreviations used: MP = melting point, min = minute.
3a: IR (KBr)
m
/cmÀ1: 3456 (–NH), 1650 (–C@O), 1694 (–C@N),
By microwave method: Thiosemicarbazide 2 (0.005 mol) was
taken in 50 mL borosilicate glass beaker with 15 mL concd H2SO4.
Reaction mixture was irradiated inside a microwave oven for
1–2.5 min at an output of 300 W power, with short interruption
of 15 s. Progress of the reaction was monitored by TLC. The reaction
mixture was cooled and poured into crushed ice. Product was
separated by filtration and crystallized with DMF/water to afford
the titled the compounds. Their characterization data is given in
Table 2.
1586 (C@C), 1445 (–C@S), 1234 (–C–O–C), 1162 (–C–F). 1H NMR
(300 MHz, DMSO-d6, d, ppm): 1.10–1.38 (m, 4H), 3.34 (s, 3H),
3.72 (s, 3H), 3.89–4.10 (m, 1H), 6.80–7.71 (m, 5H), 8.13 (s, 1H),
11.90 (br s, 1H, exchangeable). MS (m/z): 457 (M+1).
3b: IR (KBr) m
/cmÀ1: 3452 (–NH), 1651 (–C@O), 1693 (–C@N),
1580 (C@C), 1443 (–C@S), 1232 (–C–O–C), 1161 (–C–F), 1086
(–C–Cl). 1H NMR (300 MHz, DMSO-d6, d, ppm): 1.09–1.32 (m,
4H), 3.32 (s, 3H), 3.73–4.10 (m, 1H), 6.81–8.01 (m, 5H), 8.12 (s,
1H), 11.91 (br s, 1H, exchangeable). MS (m/z): 461 (M+1), 463.
4a: IR (KBr) m
/cmÀ1: 3456 (–NH), 1674 (–C@O), 1616 (C@C),
3c: IR (KBr)
m
/cmÀ1: 3454 (–NH), 1652 (–C@O), 1692 (–C@N),
1468 (–C@S), 1327 (–C–O–C), 1145 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.03–1.18 (m, 4H), 2.45–2.83 (m, 1H), 3.57 (s,
3H), 3.69 (s, 3H), 6.09–8.66 (m, 5H), 8.85 (s, 1H), 10.09 (br s, 1H,
exchangeable). MS (m/z): 457 (M+1).
1581 (C@C), 1442 (–C@S), 1233 (–C–O–C), 1164 (–C–F). 1H NMR
(300 MHz, DMSO-d6, d, ppm): 1.08–1.33 (m, 4H), 3.31 (s, 3H),
3.74–4.11 (m, 1H), 6.82–8.09 (m, 5H), 8.14 (s, 1H), 12.01 (br s,
1H, exchangeable). MS (m/z): 427 (M+1).
4b: IR (KBr) m
/cmÀ1: 3445 (–NH), 1680 (–C@O), 1618 (C@C),
3d: IR (KBr)
m
/cmÀ1: 3454 (–NH), 1652 (–C@O), 1695 (–C@N),
1469 (–C@S), 1323 (–C–O–C), 1188 (–C–F), 1097 (–C–Cl). 1H
NMR (300 MHz, DMSO-d6, d, ppm): 1.01–1.16 (m, 4H), 2.26–2.83
(m, 1H), 3.75 (s, 3H), 6.12–8.65 (m, 5H), 8.86 (s, 1H), 10.35 (br s,
1H, exchangeable). MS (m/z): 461 (M+1), 463.
1588 (C@C), 1447 (–C@S), 1237 (–C–O–C), 1164 (–C–F). 1H NMR
(300 MHz, DMSO-d6, d, ppm): 1.08–1.48 (m, 4H), 2.35 (s, 3H),
3.65 (s, 3H), 3.99–4.12 (m, 1H), 6.82–7.7 (m, 5H), 8.12 (s, 1H),
12.0 (br s, 1H, exchangeable). MS (m/z): 441 (M+1).
4c: IR (KBr) m
/cmÀ1: 3455 (–NH), 1679 (–C@O), 1616 (C@C),
3e: IR (KBr)
m
/cmÀ1: 3458 (–NH), 1656 (–C@O), 1698 (–C@N),
1467 (–C@S), 1326 (–C–O–C), 1180 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.06–1.20 (m, 4H), 2.24–2.85 (m, 1H), 3.76 (s,
3H), 6.52–8.64 (m, 6H), 9.01 (s, 1H), 10.29 (br s, 1H, exchangeable).
MS (m/z): 421 (M+1).
1589 (C@C), 1448 (–C@S), 1238 (–C–O–C), 1166 (–C–F). 1H NMR
(300 MHz, DMSO-d6, d, ppm): 1.38–1.49 (m, 4H), 2.34 (s, 3H),
3.99 (s, 3H), 4.20–4.33 (m, 1H), 6.84–7.6 (m, 5H), 8.02 (s, 1H),
12.37 (br s, 1H, exchangeable). MS (m/z): 441 (M+1).
4d: IR (KBr) m
/cmÀ1: 3453 (–NH), 1672 (–C@O), 1618 (C@C),
General procedure for synthesis of thiadiazoles (4). By conven-
tional method: Thiosemicarbazide 2 (0.005 mol) and concentrated
sulphuric acid (5 mL) were taken in a beaker (50 mL) and the reac-
tion mixture was kept at room temperature for 1.5 h. The reaction
mixture was then poured over ice water. Product was separated by
filtration and crystallized with DMF to afford the title compounds
4. The formation of compounds 4 was confirmed by mp, mixed mp,
and spectral data. Their characterization data is given in Table 2.
By ultrasonic irradiation: Thiosemicarbazide 2 (0.005 mol) and
concentrated sulphuric acid (5 mL) were taken in beaker (50 mL)
and the reaction mixture was subjected to ultrasonic irradiated
for 30–35 min at room temperature. Progress of reaction was mon-
itored by TLC. The reaction mixture was then poured over ice
water. Product was separated by filtration and crystallized with
DMF to afford the title compounds 4. The formation of the com-
pounds 4 was confirmed by mp, mixed mp, and spectral data. Their
characterization data is given in Table 2.
1467 (–C@S), 1326 (–C–O–C), 1146 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.09–1.16 (m, 4H), 2.16 (s, 3H), 2.46–2.84 (m,
1H), 3.56 (s, 3H), 6.13–8.69 (m, 5H), 9.0 (s, 1H), 10.12 (br s, 1H,
exchangeable). MS (m/z): 441 (M+1).
4e: IR (KBr) m
/cmÀ1: 3454 (–NH), 1671 (–C@O), 1616 (C@C),
1466 (–C@S), 1325 (–C–O–C), 1150 (–C–F), 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.07–1.19 (m, 4H), 2.15 (s, 3H), 2.49–2.83 (m,
1H), 3.58 (s, 3H), 6.19–8.64 (m, 5H), 8.90 (s, 1H), 10.15 (br s, 1H,
exchangeable). MS (m/z): 441 (M+1).
General procedure for synthesis of oxadiazoles (5). Thiosemicarba-
zide 2 (0.002 mol) was dissolved in 20 mL of ethanol. To this reac-
tion mixture 500 mg of I2 and 640 mg of KI (in 20 mL H2O) was
added with 2 mL of 4 N NaOH and the reaction mixture was heated
under mild reflux for 3 h. Progress of the reaction was monitored
by TLC. Then from reaction mixture around 10 mL of ethanol was
removed by distillation. Then reaction mixture was cooled and
product obtained was separated by filtration and crystallized with

7204
S. Shelke et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7200–7204
ethanol to afford the title compounds 5. The formation of the com-
pounds 5 was confirmed by spectral data. Their characterization
data is given in Table 2.
Acknowledgments
Authors are thankful to the Principal Dr. K.H. Shinde, S.S.G.M.
College, Kopargaon, Ahmednagar for providing necessary facilities
and constant encouragement. One of the authors (S.N.S.) thanks
UGC, New Delhi for funding support (MRP).
5a: IR (KBr) m
/cmÀ1: 3450 (–NH), 1662 (–C@O), 1649 (–C@N),
1618 (C@C), 1246 (–C–O–C), 1176 (–C–F). 1H NMR (400 MHz,
DMSO-d6, d, ppm): 0.9–1.13 (m, 4H), 2.07–2.87 (m, 1H), 3.42 (s,
3H), 3.71 (s, 3H), 6.93–7.89 (m, 5H), 8.48 (s, 1H), 10.36 (br s, 1H,
exchangeable). MS (m/z): 441 (M+1).
References and notes
5b: IR (KBr) m
/cmÀ1: 3454 (–NH), 1662 (–C@O), 1646 (–C@N),
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1617 (C@C), 1248 (–C–O–C), 1167 (–C–F), 1084 (–C–Cl). 1H NMR
(300 MHz, DMSO-d6, d, ppm): 1.05–1.15 (m, 4H), 2.21–2.87 (m,
1H), 3.70 (s, 3H), 6.92–7.95 (m, 5H), 8.52 (s, 1H), 10.30 (br s, 1H,
exchangeable). MS (m/z): 445 (M+1), 447.
5c: IR (KBr) m
/cmÀ1: 3454 (–NH), 1662 (–C@O), 1646 (–C@N),
1617 (C@C), 1248 (–C–O–C), 1167 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.03–1.17 (m, 4H), 2.22–2.86 (m, 1H), 3.71 (s,
3H), 6.63–7.76 (m, 6H), 8.55 (s, 1H), 10.26 (br s, 1H, exchangeable).
MS (m/z): 411 (M+1).
5d: IR (KBr) m
/cmÀ1: 3453 (–NH), 1664 (–C@O), 1645 (–C@N),
1615 (C@C), 1247 (–C–O–C), 1168 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.06–1.16 (m, 4H), 2.14 (s, 3H), 2.21–2.87 (m,
1H), 3.73 (s, 3H), 6.94–7.96 (m, 5H), 8.56 (s, 1H), 10.30 (br s, 1H,
exchangeable). MS (m/z): 425 (M+1).
.
5e: IR (KBr) m
/cmÀ1: 3451 (–NH), 1661 (–C@O), 1647 (–C@N),
1616 (C@C), 1247 (–C–O–C), 1166 (–C–F). 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.9–1.14 (m, 4H), 2.12 (s, 3H), 2.22–2.86 (m,
1H), 3.72 (s, 3H), 6.95–7.91 (m, 5H), 8.50 (s, 1H), 10.34 (br s, 1H,
exchangeable). MS (m/z): 425 (M+1).
This study reports the successful synthesis of the fluorinated
azoles using green technique with 72–88% yield. These green tech-
niques required less time for the completion of the reaction as
compared to conventional method. The newly synthesized hetero-
cycles exhibited moderate to promising antimicrobial activity
against moderate range of bacterial and fungal stains. These results
make them interesting lead molecules for further synthetic and
biological evaluation. It can be concluded that ultrasonicated syn-
thesis is very clean, while microwave method required shorter
time for completion and azoles certainly hold great promise to-
wards the pursuit of discovering novel classes of antimicrobial
agents. Further studies to acquire more information concerning
structure–activity relationships are in progress.