Synthesis, characterization and biological activities of some new benzo[b]thiophene derivatives

Article abstract of DOI:10.1016/j.ejmech.2009.11.015

Benzo[b]thiophene molecules are found to be important tools in synthetic medicinal chemistry. They are of current interest due to their wide spectrum of pharmacological properties. In view of the biological activities of benzo[b]thiophene containing molecules, in this present research work, we propose the synthesis of some new benzo[b]thiophene derivatives such as thiadiazoles, oxadiazoles, pyrazolin & diaryl pyrazoles starting from 3-chlorobenzo[b]thiophene-2-carboxyl chloride. These newly synthesized compounds were characterized by elemental analyses, I.R, NMR and Mass spectral studies. Some of the selected compounds were screened for their antibacterial, antifungal and anti-inflammatory studies. Many of the molecules were found to be potent.

Full text of DOI:10.1016/j.ejmech.2009.11.015

European Journal of Medicinal Chemistry 45 (2010) 825–830
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, characterization and biological activities of some new
benzo[b]thiophene derivatives
,
b
c
Arun M. Isloor a , Balakrishna Kalluraya , K. Sridhar Pai
*
a Department of Chemistry, National Institute of Technology-Karnataka, Surathkal, Mangalore 575 025, India
b Department of Chemistry, Mangalore University, Mangalagangothri, Mangalore 574 199, India
c Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2009
Received in revised form
3 October 2009
Accepted 5 November 2009
Available online 11 November 2009
Benzo[b]thiophene molecules are found to be important tools in synthetic medicinal chemistry. They are
of current interest due to their wide spectrum of pharmacological properties. In view of the biological
activities of benzo[b]thiophene containing molecules, in this present research work, we propose the
synthesis of some new benzo[b]thiophene derivatives such as thiadiazoles, oxadiazoles, pyrazolin &
diaryl pyrazoles starting from 3-chlorobenzo[b]thiophene-2-carboxyl chloride. These newly synthesized
compounds were characterized by elemental analyses, I.R, NMR and Mass spectral studies. Some of the
selected compounds were screened for their antibacterial, antifungal and anti-inflammatory studies.
Many of the molecules were found to be potent.
Keywords:
Benzo[b]thiophene
Anti-inflammatory activity
Antibacterial & antifungal activity
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
2. Chemistry
Sulphur containing heterocycles paved way for the active
research in the pharmaceutical Chemistry. Nowadays benzothio-
phene derivatives in combination with other ring systems have
been used extensively in Pharmaceutical applications such as
antiallergic [1], analgesic [2], anti-inflammatory [3] and Ocular
hypotensive activities [4]. Raloxifene a drug based on benzo[b]-
thiophene has been approved by the U.S Food and Drug Adminis-
tration for the prevention and treatment of osteoporosis associated
with woman postmenopausal [5].
On the other hand compounds bearing 1,2,4-triazole ring are
very well known to exhibit powerful antimicrobial [6], anticonvul-
sant [7], antidepressant [8], analgesic [9] activities. Moreover some
1,2,4-triazolo [3,4-b][1,3,4]thiadiazines are associated with diverse
pharmacological activities [10–14]. Further various oxadiazole
derivatives [15], pyrazolin-5-ones [16], diaryl pyrazole derivatives
[17] also exhibits wide spectrum pharmacological activities.
Continuing our efforts directed [6] towards the synthesis of new
heterocyclic compounds with expected biological activities, we
hereby report the synthesis of some new benzo[b]thiophene
derivatives and their characterization by IR, NMR & Mass spec-
trometry techniques. Newly synthesized compounds were also
screened for their antimicrobial and anti-inflammatory activities.
In the present investigation benzo[b]thiophene moiety is used
as the building block. 3-Chlorobenzo[b]thiophene-2-carboxyl
chloride 2 was prepared from cinnamic acid and thionyl chloride in
chlorobenzene medium using pyridine as the catalyst, following
the procedure of Castle et al. [18]. Acid chloride 2 was converted
into acid 3 by hydrolysis with methanolic potassium hydroxide. It
was reacted with various 3-substituted-4-amino-1,2,4-triazoles to
get the corresponding triazolothiadiazoles 4. In another series, the
acid chloride 2 was converted into the corresponding ester 7 by
treating with methanol, further on reacting with hydrazine hydrate
yielded hydrazide 8. These hydrazides were reacted with ethyl
butyrate derivatives 9 to get substituted pyrazolin-5-one 10 (Fig. 1).
Another series of pyrazoles containing benzo[b]thiophene were
synthesized by reacting its hydrazide 8 and various
a-bromopro-
penones 11. Similarly a series of 2,5-disubstituted oxadiazoles 6
were synthesized by the cyclization of the hydrazide derivative 5
using phosphorous oxychloride. Newly synthesized compounds
were characterized by IR, NMR, Mass spectral and C, H, N analyses.
3. Pharmacology
3.1. Antimicrobial studies
Antibacterial activity studies of newly synthesized compounds
were carried out against four different pathogenic organisms, two
* Corresponding author. Tel.: þ91 824 2474000x3206; fax: þ91 8242474033.
E-mail address: isloor@yahoo.com (A.M. Isloor).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.11.015

826
A.M. Isloor et al. / European Journal of Medicinal Chemistry 45 (2010) 825–830
Fig. 1.
each of Gram negative & Gram positive. They are Staphylococcus
aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa.
Antifungal activity was carried out on the fungus Candida albicans
using the same procedure. Antimicrobial studies were assessed by
Minimum Inhibitory Concentration (MIC) by serial dilution
method [19].
MIC of the new synthetic compounds was determined sepa-
rately for each of the organisms. For antimicrobial, the compound
whose MIC has to be determined is was dissolved in DMF and
serially diluted. A standard drop of the culture prepared for the
assay is added to each of the dilutions, and incubated for 16–18 h at
37 ꢀC. The MIC is the highest dilution of the compound, which
shows clear fluid with no development of turbidity. Furacin was the
standard drug for antibacterial studies, while flucanazol was used
as standard for the antifungal studies.
Institutional animal care and use Committee. The apparatus used
for the measurement of the rat paw volume was that of Buttle et al.
[21] modified by Singh and Ghosh [22].
In our present work, animals were divided into 5 groups of eight
animals each. One group served as control, another served as
a standard (Diclofenac sodium) and the rest of the groups were
used for the test compounds. Rats were dosed orally with at
100 mg/kg body weight test compounds and Diclofenac sodium
was suspended in 4% acacia gum solution.4% Acacia gum mucilage
was used as a vehicle for the control group. Then a three hour
solution of 1% carrageenan was used as an anti-inflammatory agent.
Food was withdrawn overnight with adequate water before the
experiment. The drug was dosed orally with the help of an oral
catcher. After one hour, a subplanter injection of 0.05 ml of 1%
solution of carrageenan was administered. The volume of the
injected paw was measured after 3 h. The average paw swelling in
a group of drug treated rats were compared with that of a group,
treated with the vehicle (control group), and the % inhibition of
edema was calculated using the formula
3.2. Anti-inflammatory studies
For the anti-inflammatory studies, Rat hind paw edema method
was followed using Wrister rats, which is slight modification of
Winter et al. [20] method. All experiments have been approved by
%Inhibition [ ½1LVt=Vcꢁ 3 100:

A.M. Isloor et al. / European Journal of Medicinal Chemistry 45 (2010) 825–830
827
Where Vt ¼ Edema volume in drug treated rats & Vc ¼ Edema
with each other and appeared as multiplets in the region
d
, 7.0–7.96
integrating for eight protons. The mass spectrum of 4b showed the
molecular ion peak at m/z, 412 in agreement with the assigned
molecular formula C19H13N4ClS2O. The chlorine isotope peak was
observed at m/z, 414. Similarly NMR spectra of 10b and 10e were
recorded. Further the mass spectrum of 10b and 10e were recorded
and which is in agreement with the proposed structures. Similarly
the IR, NMR & mass spectrum of pyrazolines 12 were recorded are
presented in Table 3.
volume in control rats
4. Results and discussion
The IR spectrum of 6a showed absorptions at 1617 cmꢂ1
1593 cmꢂ1 due to C]N & C]C bonds. The 1H NMR spectrum of
6a, , 2.29 is due to methyl group. The OCH2 protons came into
resonance as a singlet at , 5.40 integrating for two protons. The
remaining aromatic protons of the benzo[b]thiophene and
phenyl group appeared as multiplets in the region of , 6.96–7.99
&
d
d
d
5. Conclusions
integrating for eight protons. Characterization of the newly
synthesized compounds has been given in Tables 1 and 2.
Similarly NMR spectral details of other compounds have been
given in Table 3.
The mass spectrum of 6b showed molecular ion peak at m/z, 376
consistent with the molecular formula C17H10Cl2N2O2S. The cluster
of isotope peaks due to presence of two chlorine atoms (M þ 2) and
(M þ 4) were observed at m/z 378 & 380. The peak at m/z, 341 is due
to the loss of chlorine radical from the molecular ion.
In the IR spectrum of 4a, the bands corresponding to the NH2
group of the triazole and carboxyl group of the 3-chlor-
obenzo[b]thiophene-2-carboxylic acid were absent in the
condensed product, thereby indicating the involvement of –NH2
and –CO2H group in the condensation reaction. The absorption due
to C]N appeared at around 1617 cmꢂ1. The 1H NMR spectrum of 4a
In the present study we have described synthesis of various
benzo[b]thiophene derivatives. These newly synthesized
compounds were characterized by NMR, mass spectrometry and IR
studies. Few of the selected compounds were screened for their
antimicrobial (MIC – Minimum Inhibitory Concentration) and anti-
inflammatory activities. The antibacterial study reveals that
compounds 12c and 12d having 5-nitro-2-thienyl substitution
exhibited maximum inhibition against S. aureus. Similarly
compound 12d has shown maximum inhibition against fungus C.
albicans. Also compound 12b with phenyl and p-anisyl has shown
maximum inhibition against fungus. All remaining compounds
showed significant activity as compared to the standard drugs.
Antimicrobial screening details has been presented in Table 4.
Benzo[b]thiophene nucleus is one of the active components
present in all molecules.
showed signal due to –OCH2 protons appeared at d, 5.3 as an singlet
integrating for two protons. The signals due to remaining aromatic
protons of the phenyl and benzo[b]thiophene moiety overlapped
Few of the selected compounds were also screened for their
anti-inflammatory activity. It clearly reveals that compound 12a
Table 1
Characterization data of new benzo[b]thiophene derivatives.
Comp. no.
Ar
Yield % & m.pꢀC
Colour & nature
Mol. formula
Analyses % found (Calcd.)
C
H
N
4a
4b
4c
o-Chlorophenyl
p-Tolyl
65
255–57
50
195–96
87
White micro crystals
White micro crystals
White micro crystals
C18H11N4OS2Cl
54.22 (54.18)
2.69 (2.75)
14.02 (14.00)
C
19H13N4OS2Cl
18H10N4OS2Cl2
55.24 (55.25)
49.85 (49.81)
3.14 (3.14)
2.31 (2.30)
13.53 (13.55)
12.90 (12.93)
p-Chlorophenyl
C
216–18
Comp. No
Ar2
Yield % & m.pꢀC
Color & nature
Mol. formula
Analyses % found (Calcd.)
C
H
N
5a
5b
5c
6a
6b
6c
2-methylphenyl
o-Chlorophenyl
2,4-Dichlorophenyl
o-Tolyl
45
152
52
200–01
55
203–04
82
150–51
75
158–60
72
White cotton
C18H15N2O3SCl
C17H12N2O3SCl2
C17H11N2O3SCl3
C18H13N2O2SCl
C17H10N2O2SCl2
C17H9N2O2SCl3
57.64 (57.68)
4.03 (4.00)
7.42 (7.47)
White cotton
51.61 (51.65)
47.50 (47.51)
60.59 (60.56)
54.11 (54.12)
49.59 (49.56)
3.01 (3.03)
2.52 (2.56)
3.65 (3.64)
2.61 (2.65)
2.14 (2.18)
7.02 (7.09)
6.51 (6.52)
7.83 (7.85)
7.38 (7.42)
6.81 (6.79)
White cotton
Colorless micro crystals
Colorless micro crystals
Colorless micro crystals
o-Chlorophenyl–
2,4-Dichlorophenyl–
174–75
Comp. No
10a
R1
Yield % & m.pꢀC
Color & nature
Mol. formula
Analyses % found (Calcd.)
C
H
N
H
60
176–77
62
268–70
55
213–15
68
192–93
65
171–72
57
Yellow micro crystal
Orange micro needles
Yellow cotton
C18H13N4O2SCl
56.20 (56.25)
3.36 (3.38)
14.57 (14.58)
10b
2-Nitro-4-methyl
2,5-Dichloro
4-Chloro-2-methyl
2,5-Dimethyl
4-Nitro
C20H14N5O4SCl
C19H11N4O2SCl3
C20H14N4O2SCl2
C21H17N4O2SCl
C19H12N5O4SCl
52.70 (52.74)
48.90 (48.92)
54.08 (54.05)
59.38 (59.43)
51.61 (51.70)
3.03 (3.07)
2.39 (2.36)
3.18 (3.15)
4.02 (4.00)
2.73 (2.72)
15.35 (15.38)
12.04 (12.01)
12.58 (12.61)
13.17 (13.20)
15.82 (15.87)
10c
10d
Yellow micro crystal
Orange micro crystal
Orange micro crystal
10e
10f
295–96

828
A.M. Isloor et al. / European Journal of Medicinal Chemistry 45 (2010) 825–830
Table 2
Characterization data of new benzo[b]thiophene derivatives.
Comp. no.
R2
Ar1
Yield% & m.pꢀC
Color & nature
Mol. formula
Analyses % found (Calcd.)
C
H
N
12a
12b
12c
12d
12e
p-Chlorophenyl
Phenyl
p-Anisyl
46
128
58
201
36
118
43
Pale yellow micro crystals
Pale yellow micro crystal
Dark brown crystal
C25H16N2O2SCl2
62.61 (62.68)
3.32 (3.34)
5.83 (5.84)
p-Anisyl
C25H17N2O2SCl
C22H12N3O3S2Cl
C22H11N3O3S2Cl2
C25H17N2OSCl
67.49 (67.47)
56.75 (56.70)
52.80 (52.84)
70.03 (70.01)
3.81 (3.82)
2.63 (2.57)
2.23 (2.20)
3.98 (3.97)
6.25 (6.29)
9.00 (9.00)
8.41 (8.40)
6.51 (6.54)
Phenyl
5-Nitro-2-Thienyl
5-Nitro-2-Thienyl
p-Tolyl
p-Chlorophenyl
Phenyl
Golden micro needle
Golden micro needle
163
52
136
Table 3
Spectral characterization of benzo[b]thiophene derivatives.
Comp. no. IR (KBr) (ppm) (CDCl3, 400 MHz)
(cmꢂ1 1H NMR
1617 (C]N), 1556 (C]C), 4.76(s,2H, OCH2) 6.81–7.28 (m, 4H, Ar)
y
)
d
MS m/z
4a
4b
4c
5a
5b
5c
6a
6b
m/z 398 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
230 (due to triazolothiadiazole ring)
3055 (Ar-H), 1028 (C–S str) 7.66–8.06 (m, Ar-H & BT-H) 4H, BT)
1618 (C]N), 1560 (C]C), 2.27(s, 3H, –CH3 tolyl), 4.75 (s, 2H, –OCH2),
3052 (Ar-H), 1015 (C–S str) 6.73–7.00(m, 4H Ar-H), 7.66–8.06 (m, 4H of BT ring)
1619 (C]N), 1550 (C]C), 4.78(s,2H, OCH2) 6.83–7.35(m, 4H, Ar)
3052 (Ar-H), 1032 (C–S str) 7.69–8.10 (m, Ar-H & BT-H) 4H, BT)
1680 (C]O), 1545 (C]C), 4.82 (S, 2H, OCH2), 2.42 (s, 3H, CH3),
1018 (C–S) str, 3048 (Ar-H) 7.52–8.12 (m, Ar-H & BT-H) 4H, BT)
m/z 412 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
246 (due to triazolothiadiazole)
m/z 398 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
230 (due to triazolothiadiazole ring)
m/z 374 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
206 (due to the cleaved hydrazine part)
1675 (C]O), 1542 (C]C),
1025 (C–S) str, 3045 (Ar-H)
1672 (C]O), 1535 (C]C),
1028 (C–S) str, 3042 (Ar-H)
1617 (C]N), 1593 (C]C),
4.75 (S, 2H, OCH2), 7.48–8.10 (m, Ar-H & BT-H) 4H, BT)
m/z 394 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
226 (due to cleaved hydrazine part)
4.78 (S, 2H, OCH2), 7.50–8.28 (m, Ar-H & BT-H) 4H, BT)
4.97(s, 2H, –OCH2), 6.73–7.01(m, 4H Ar-H),
m/z 428 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
226 (due to cleaved hydrazine part)
m/z 356 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
249 (due to oxadiazole)
3060 (Ar-H), 1018 (C–S str) 7.44–7.97(m, 4H of BT ring)
1615 (C]N), 1588 (C]C),
4.98(s 2H –OCH2), 6.92–7.28(m, 4H Ar-H),
m/z 376 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
249 (due to 2-(3-chloro-1-benzothien-2-yl)-
1,3,4-oxadiazole cation)
3055 (Ar-H), 1020 (C–S str) 7.44–7.94(m, 4H of BT ring)
6c
1618 (C]N), 1590 (C]C),
4.97(s, 2H, –OCH2), 6.73–7.01(m, 3H Ar-H),
m/z 410 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
249 (due to 2-(3-chloro-1-benzothien-2-yl)-
1,3,4-oxadiazole cation)
3058 (Ar-H), 1015 (C–S str) 7.44–7.97(m, 4H of BT ring)
10a
10b
10c
1617 (C]N), 1580 (C]C),
1674 (C]O)
2.43 (s, 3H, CH3), 7.41–8.31 (m, 9H, Ar-H & BT-H),
14.0 (s, 1H, NH)
m/z 384 ((Mþ), 168 (due to 3-chloro-1-benzothiophene),
218 (due to (4E)-1-(hydroxymethyl)-1H-pyrazole-4,
5-dione 4-(phenylhydrazone))
1620 (C]N), 1582 (C]C),
1670(C]O)
2.45 (s, 3H, CH3), 2.5 (s, 3H, CH3),
7.35–8.2 (m, 7H, Ar-H & BT-H), 14.2 (s, 1H, NH)
m/z 455 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
277 (due to (4E)-1-(hydroxymethyl)-1H-pyrazole-4,
5-dione 4-[(4-methyl-2-nitrophenyl)hydrazone])
m/z 464 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
287 (due to (4E)-1-(hydroxymethyl)-1H-pyrazole-4,
5-dione 4-[(2,4-dichlorophenyl)hydrazone])
m/z 444 (Mþ), 168 (due to 3-chloro-1-benzothiophene)
1612 (C]N), 1582 (C]C),
1668(C]O)
2.48 (s, 3H, CH3), 7.48–8.40 (m, 7H, Ar-H & BT-H),
13.6 (s, 1H, NH)
10d
10e
16 118 (C]N), 1585 (C]C), 2.32 (s, 3H, CH3), 2.62 (s, 3H, CH3), 7.40–8.51
1665(C]O)
(m, 7H, Ar-H & BT-H), 13.68 (s, 1H, NH)
, 2.37 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.42
(s, 3H, CH3), 6.96–8.01 (m, 7H, Ar-H & BT-H), 13.64 (s, 1H, NH)
1618 (C]N), 1580 (C]C),
1680 (C]O)
d
m/z 424 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
246 (due to (4E)-1-(hydroxymethyl)-1H-pyrazole-4,
5-dione 4-[(2,5-dimethylphenyl)hydrazone])
10f
12a
12b
12c
12d
12e
1618 (C]N), 1582 (C]C),
1668 (C]O)
2.45 (s, 3H, CH3), 7.45–8.38 (m, 8H, Ar-H & BT-H), 13.2 (s, 1H, NH) m/z 433 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
263 (due to (4E)-1-(hydroxymethyl)-1H-pyrazole-4,
5-dione 4-[(4-nitrophenyl)hydrazone])
1645 (C]O), 1590 (C]N),
3065 (Ar-H), 1017 (C–S str) 6.74 (s, pyrazole ring H), 7.44–7.87(m, 4H of BT ring)
4.12(s, 2H, –OCH3), 7.25–8.18 (m, 12H, Ar-H),
m/z, 478 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
312 (due to 5-(4-chlorophenyl)-3-(4-methoxyphenyl)-
1H-pyrazole-1-carbaldehyde)
1650 (C]O), 1594 (C]N),
3068 (Ar-H), 1025 (C–S str) 6.77 (s, pyrazole ring H),7.42–7.88 (m, 4H of BT ring)
4.10 (s, 3H, –OCH3), 7.42–7.65(m, 13H, Ar-H),
m/z, 444 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
312 (due to 5-(4-chlorophenyl)-3-(4-methoxyphenyl)-
1H-pyrazole-1-carbaldehyde)
1645 (C]O), 1598 (C]N),
3065 (Ar-H), 1022 (C–S str) 7.40–7.80 (m, 4H of BT ring)
7.35–8.38 (m, 9H, Ar-H), 6.58 (s, pyrazole ring H),
m/z, 465 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
299 (due to 3-(5-nitrothien-2-yl)-5-phenyl-1H-pyrazole-
1-carbaldehyde)
1648 (C]O), 1590 (C]N),
3060 (Ar-H), 1022 (C–S str) 7.40–7.83 (m, 4H of BT ring)
7.36–8.42 (m, 8H, Ar-H), 6.58 (s, pyrazole ring H),
m/z, 500 (Mþ), 168 (due to 3-chloro-1-benzothiophene),
333 (due to 5-(4-chlorophenyl)-3-(5-nitrothien-2-yl)-
1H-pyrazole-1-carbaldehyde)
1642 (C]O), 1590 (C]N),
2.36 (s, 2H, –CH3), 7.19–7.92 (m, 13H, Ar-H),
m/z, 428 (Mþ),168 (due to 3-chloro-1-benzothiophene),
262 (due to 3-(4-methylphenyl)-5-phenyl-1H-pyrazole-
1-carbaldehyde),77 (due to phenyl ring)
3070 (Ar-H), 1022 (C–S str) 6.76 (s, pyrazole ring H), 7.42–7.88 (m, 4H of BT ring)

A.M. Isloor et al. / European Journal of Medicinal Chemistry 45 (2010) 825–830
829
6.2. General procedure for the preparation of (N1-aroyloxyacetyl)-
Table 4
N2-(3-chlorobenzo[b]thiophene-2carboxyl) hydrazine (5)
Antibacterial and antifungal activity data of newly synthesized benzo [b] thiophene
derivatives.
Comp. no.
Antibacterial activity data in MIC (
m
g/ml)
Antifungal
activity data
The acid chloride 2 (0.001 mol) and suitable aryloxyacethy-
drazide (0.001 mol) were taken in acetone (80 ml), the mixture was
stirred for 4–6 h and allowed to stand for further 2 h. Then the
acetone was removed to one fourth of its volume. The residue was
filtered, washed with cold ethanol and dried. The compounds were
recrystallized from ethanol–dioxan mixture. The physical constants
and characterization data are given in Table 1.
in MIC (mg/ml)
S. aureus B. subtilis E. coli P. aeruginosa C. albicans
4a
4b
6b
6c
10a
10b
10c
10d
12a
12b
12c
12d
6
6
6
6
6
6
12.5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
12.5
–
6
6
6
6
6
6
6
6
6
6
3
6
6
–
6
6
6
6
6
6
6
6
6
6
6
6
12.5
–
6
6
6
6
6
6
6
6
6
3
6
3
6.3. General procedure for the preparation of 2-[3-chloro-
2benzo[b]thiophenyl]-5-aryloxymethyl-1,3,4-oxadiazole (6)
The hydrazide 5 (0.001 mol) was taken in phosphorous oxy-
chloride (20 ml) and heated on a water bath for 6–8 h. The contents
were cooled and poured into crushed ice. The solid obtained was
filtered, washed with water and dried. These newly synthesized
compounds were recrystallized from ethanol–dioxan mixture. The
yield, physical constants and other characterization data are given
in Table 1.
3
3
Furacin (Std) 12.5
DMF (Control)
Flucanazol (Std) 6
–
–
having p-chlorophenyl and p-anisyl substitution has showed the
inhibition almost similar to that of the standard drug. Similarly
compounds 10b and 12b showed significant activities. Remaining
compounds showed moderate anti-inflammatory activity. Anti-
inflammatory results are presented in Table 5.
6.4. General procedure for the preparation of 3-
chlorobenzo[b]thiophene-2-methyl carboxylate (7)
The acid chloride 2 (10 g, 0.043 mol) was refluxed with 250 ml of
methanol for 6 h. The excess of solvent was removed to get the
sweet smelling ester 7. It was recrystallized with ethanol. Yield was
found to be 9 g (81%) and melting point was found to be 67–68 ꢀC
[23].
6. Experimental protocols
Melting points were determined by open capillary method and
were uncorrected. The IR spectra (in KBr pellets) were recorded
using Shimadzu FT-IR 157 spectrophotometer in the range
4000–400 cmꢂ1. 1H NMR spectra were recorded on a Perkin–Elmer
EM 300 MHz spectrometer using TMS as internal standard. The
mass spectra were recorded on a JEOL JMS-D 300 spectrometer
operating at 70 eV. The TLC was performed on alumina silica gel 60
F254 (Merck). All the compounds gave C, H and N analysis within
ꢃ0.5% of the theoretical values.
6.5. General procedure for the preparation of 3-
chlorobenzo[b]thiophene-2-carboxylhydrazine (8)
The ester 7 (4.6 g, 0.02 mol) is dissolved in 25 ml methanol and
hydrazine hydrate (1.5 g, 0.03 mol) was added to it. The solution
was refluxed for 4 h. After confirming the formation of the product
by TLC, excess of solvent was removed under reduced pressure and
the contents were poured into ice-cold water. The solid separated
was filtered, dried and recrystallized from ethanol to yield the
hydrazide 8.Yield was found to be 3.5 g (77%). The melting point is
182 ꢀC [24].
6.1. General procedure for the preparation of 3-(substituted)-6-[3-
chlorobenzo[b]thiophenyl 1,2,4-triazolo [3,4-b] thiadiazoles (4)
3-Substituted-4-amino-5-mercapto-1,2,4-triazole (0.005 mol),
the acid 3 (0.005 mol) and phosphorous oxychloride (15 ml) were
taken in a round bottomed flask and the mixture was heated on
a water bath for 4 h. The contents were cooled and poured into
crushed ice. The solid obtained was filtered, dried and washed with
sodium bicarbonate solution to remove excess of acid. The insol-
uble substance is dried and recrystallized from ethanol–dioxan
mixture. The yield, melting point and other characterization data of
the newly synthesized compounds are given in Table 1.
6.6. General procedure for the preparation of ethyl-2-aryl
hydrazono-3-oxobutyrate (9)
Appropriate amine (0.01 mol) was dissolved in 10 ml dilute
hydrochloric acid and cooled to 0 ꢀC in an ice bath. A cold aqueous
solution of sodium nitrite (0.02 mol) was added. The diazonium salt
solution was filtered into 50 ml cold ethanol containing ethyl-
acetoacetate (0.01 mol) and sodium acetate (0.15 mol). The
resulting yellow solid was filtered, washed with water, dried and
recrystallized from methanol.
Table 5
Anti-inflammatory activity data of newly synthesized benzo [b] thiophene
derivatives.
6.7. General method for the preparation of N1-(3-
chlorobenzo[b]thiophene-2-carbonyl)-3-methyl-4-9 substituted
phenylhydrazono pyrazolin-5-one (10)
Comp. no.
% Inhibition
4a
4b
6a
6b
10a
10b
12a
12b
41.85
43.50
33.74
38.22
48.60
50.25
51.25
50.80
51.88
A mixture of hydrazide 8 (0.01 mol) and ethyl-2-arylhydrazono-
3-oxo butyrate 9 (0.01 mol) in 30 ml ethanol was refluxed for 14 h.
Solid product started separating after few hours. The product was
filtered hot and recrystallized from ethanol–dioxan mixture. The
characterization data are given in Table 1.
Standard (Diclofenac sodium)

830
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Acknowledgements
The authors are thankful to the RSIC, CDRI Lucknow and Director
Punjab University, Chandigarh for providing micro analysis, NMR
and mass spectral data. AMI is thankful to Director NITK Surathkal,
India for providing research facilities and Board of Research in
Nucler Sciences, Government of India for ‘Young Scientsit’ award.
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