Synthesis and biological evaluation of some novel triazol-3-ones as antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2011.08.049

A new series of triazol-3-one derivatives bearing 4-methyl-4H-thieno[30,20: 5,6]thiopyrano [4,3-d][1,3]thiazolyl or 4-(thiophene-3-yl) thiazolyl moiety at 4-position and alkyl substitution at 2-position are synthesized. All the synthesized compounds are c

Full text of DOI:10.1016/j.bmcl.2011.08.049

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6559–6562
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of some novel triazol-3-ones
as antimicrobial agents
⇑
Santosh Pardeshi, Vivek D. Bobade
Department of Chemistry, HPT Arts and RYK Science College, Nashik 422005, India
a r t i c l e i n f o
a b s t r a c t
new series of triazol-3-one derivatives bearing 4-methyl-4H-thieno[30,20: 5,6]thiopyrano
Article history:
Received 26 January 2011
Revised 26 July 2011
Accepted 11 August 2011
Available online 19 August 2011
A
[4,3-d][1,3]thiazolyl or 4-(thiophene-3-yl) thiazolyl moiety at 4-position and alkyl substitution at 2-posi-
tion are synthesized. All the synthesized compounds are characterized by elemental analysis, IR, 1H NMR,
13C NMR, and mass spectral data. The newly synthesized compounds are screened for antifungal and
antibacterial activities.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Thiazole
Thiophene
Thieno thiopyran
Triazol-3-one
Antibacterial activity
Antifungal activity
In the past decades sulfur containing heterocycles have
emerged as an important class of drugs used in various applica-
tions. Thiazole and their derivatives have attracted continuing
interest over the years because of their varied biological activi-
ties.1–8 Thiophene, in particular, has been investigated in great de-
tail. Thiophene nucleus play active role in several biological active
compounds.9–14 Moreover, thienothiopyran derivatives also repre-
sent important building blocks in pharmaceutical chemistry and
have been tested as potential antihypertensive agent, CNS receptor
modulators, and anti glaucoma drugs.15–17 Thienothiopyran-2-sul-
fonamides have shown to be carbonic anhydrase inhibitor.16
1,2,4-triazole and 1,2,4-triazol-3-one are important heterocy-
cles because they have been incorporated into a wide variety of
drugs like Fluconazole, Itraconazole, Voriconazole, Posaconazole,
Letrozole, and Anastrazole used in medical therapy.18–31
The increase in resistance to existing antimicrobial treatment has
resulted in urgent demand for a new class of antimicrobial agent
with a different mode of action and has led medicinal chemist to
explore a wide variety of chemical structures. The current trend in
antimicrobial drug design32 is towards clubbingtwo or three hetero-
cyclic rings having different sites or mode of action. Infact, com-
pounds with two or three heterocyclic rings, for example,
2-substituted 4-(2,5-dichloro thienyl)-1,3-thiazole derivatives have
shown to exhibit good antimicrobial activity.33 Considering the bio-
logical significance of thiazole, thiophene, and thienothiopyran and
in continuation of our work on synthesis of pharmacologically
significant heterocycles,34 two novel series of triazol-3-one bearing
thiophene-3-yl thiazolyl or thieno thiopyrano[4,3-d][1,3]thiazolyl
moiety at C4 position and alkyl substituent at C2 position (Schemes
1 and 2) has been synthesized. The thiazolyl thiophene and thiazolyl
thienothiopyran moeities were incorporated on triazol-3-ones to
evaluate their role and compare their effect, if any, on the antimicro-
bial activity of the triazolo-3-ones. It was also worthwhile to inves-
tigate the effect of N-alkylation of triazol-3-one on biological
activity. The synthesized compounds are novel and evaluated for
in vitro antimicrobial activity.
The synthetic strategies adopted for the synthesis of title
compounds 5, 6, 11, and 12 are depicted in Schemes 1 and 2.
3-(Bromoacetyl) thiophene 1 and 5-bromo-6-methyl-5,6-dihydro-
thieno[2,3-b]thiopyran-4-one 7, the key starting materials were
prepared by bromination of corresponding ketone with NBS in ace-
tonitrile using p-toluensulfonic acid.35 Amino thiazoles 2 and 8
were prepared by reacting corresponding
a-bromoketones 1 and
7 with thiourea in ethanol in good yield.36 The reaction of amino-
thiazoles 2 and 8 with phenychloroformate was accomplished in
acetonitrile using potassium carbonate to obtain carbamates 3
and 9 in excellent yield (80% and 75%, respectively). However,
when reaction was carried out in chloroform using pyridine as
base, yield of carbamates 3 and 9 were 60% and 58%, respectively.30
The semicarbazides 4 and 10 were synthesized by reacting hydra-
zine hydrate with corresponding carbamates 3 and 9 which in turn
cyclized with formamidine acetate in DMF gave 4-substituted tria-
zole-3-ones 5 and 11, respectively.30 N-alkylation of triazol-3-ones
5 and 11 was achieved by reaction with alkyl halide in DMSO using
⇑
Corresponding author. Tel.: +91 253 2572153; fax: +91 253 2574684.
E-mail address: v_bobade31@rediffmail.com (V.D. Bobade).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.049

6560
S. Pardeshi, V. D. Bobade / Bioorg. Med. Chem. Lett. 21 (2011) 6559–6562
O
NH2
S
HN
OPh
O
N
N
Br
S
i
ii
iii
N
S
S
S
v
1
3
2
R
N
H
N
O
O
N
O
N
N
N
HN
S
NHNH2
N
N
iv
S
S
S
S
S
6a-f
4
5
R= CH3; C2H5; CH(CH3)2; CH2CH(CH3)2; CH2CN; (CH2)3OCH3
Scheme 1. Reagents: (i) thiourea, ethanol; (ii) acetonitrile, potassium carbonate, phenyl chloroformate; (iii) dioxane, hydrazine hydrate; (iv) DMF, formamidine acetate; and
(v) DMSO, potassium hydroxide, alkylhalide.
O
HN
OPh
NH2
S
O
N
N
Br
S
ii
iii
i
S
S
S
S
N
S
S
7
8
9
R
N
H
N
O
O
N
O
N
N
HN
NHNH2
N
v
N
N
S
iv
S
S
S
S
S
S
S
S
11
10
R= CH3; C2H5; CH(CH3)2; CH2CH(CH3)2; CH2CN; (CH2)3OCH3
12a-f
Scheme 2. Reagents: (i) thiourea, ethanol; (ii) acetonitrile, potassium carbonate, phenyl chloroformate; (iii) dioxane, hydrazine hydrate; (iv) DMF, formamidine acetate; and
(v) DMSO, potassium hydroxide, alkylhalide.
potassium hydroxide. The yields of target compounds 6a–f and
12a–f were obtained in the range of 60–85%.
show moderate to excellent activity against all tested gram posi-
tive as well as gram negative bacterial and fungal pathogens deter-
All the synthesized compounds were screened for in vitro anti-
bacterial and antifungal activity,37,38 against a panel of gram posi-
tive bacteria (Staphylococcus aureus, Bacillus subtilis), gram negative
bacteria ( Escherichia coli, Klebsiella pneumoniae) and pathogenic
fungus (Fusarium solani, Aspergillus niger, and Candida albicans).
The MIC’s of these compounds were carried out using microdilu-
tion susceptibility method. The antibiotic chloramphenicol and
ketoconazole were used as reference for antibacterial and anti-
fungal activity, respectively.
mined at concentrations (100 and 200 lg/mL). From the
antibacterial activity data, it is observed that compounds 6a, 6e,
and 12b are the most active among the tested compounds against
gram positive bacteria while all other compounds show less anti-
bacterial activity comparable to chloramphenicol. The data indi-
cated that N-alkylation of triazole-3-ones 5 and 11 played a
crucial role in determining the antimicrobial activity. For the series
thiophene thiazolyl 5 and 6a–f, N-CH3 at 2-position (6a) increases
the antibacterial activity while N-CH(CH3)2 (6d) reduces the activ-
ity compared to parent derivative 5 against gram positive bacteria.
In the case of the other series thieno thiopyarano-thiazolyl 11 and
In vitro antibacterial and antifungal activity, assay (Table 1)
indicated that all synthesized compounds (5, 11, 6a–f, and 12a–f)

S. Pardeshi, V. D. Bobade / Bioorg. Med. Chem. Lett. 21 (2011) 6559–6562
6561
Table 1
Antimicrobial activity of synthesized compounds 5, 6a–f, 11 and 12a–f
Compd
R
Conc. (
l
g/ml)
A
B
C
D
E
F
G
5
H
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
25
28
32
35
24
32
25
27
16
20
28
31
24
26
18
21
14
16
25
29
14
16
12
15
13
17
23
28
35
39
—
27
29
34
36
21
27
20
23
16
18
23
26
23
26
20
23
16
19
28
31
13
15
13
16
15
18
31
33
38
41
—
24
26
23
25
23
29
22
24
17
21
26
29
24
28
15
20
18
21
22
27
15
18
12
14
11
13
22
25
40
44
—
22
26
26
28
26
28
26
29
15
18
16
21
25
28
17
20
16
19
24
26
14
16
10
12
11
14
21
24
42
45
—
32
37
40
43
29
32
27
29
26
30
28
34
34
36
22
24
24
26
28
31
17
19
16
20
15
18
39
44
—
34
39
39
42
21
24
30
33
26
27
27
29
26
28
26
29
20
23
23
26
17
22
16
18
16
19
37
41
—
35
38
36
40
23
29
22
24
17
21
28
32
24
28
25
28
22
24
26
29
16
21
17
21
14
18
36
39
—
6a
Methyl
6b
Ethyl
6c
Isopropyl
Isobutyl
6d
6e
Cyanomethyl
3-Methoxy propane
H
6f
11
12a
Methyl
12b
Ethyl
12c
Isopropyl
Isobutyl
12d
12e
Cyanomethyl
3-Methoxy propane
12f
Chloromphenicol
Ketoconazole
—
38
42
—
41
44
36
39
—
—
—
—
(A) Staphylococcus aureus; (B) Bacillus subtilis; (C) Escherichia coli; (D) Klebsiella pneumoniae; (E) Fusarium solaniI; (F) Aspergillus niger; and (G) Candida albicans.
ation. The results also reveal that all the synthesized compounds ex-
hibit better antifungal activity than antibacterial activity, in line
with the fact that sulfur containing compounds are good antifungal
agents.
The antimicrobial activity of all the synthesized compounds
could be attributed to the presence of triazol-3-one ring. This ring
is incorporated into a wide variety of drugs used in medical ther-
apy. Infact, contribution towards biological activity by thiazole
and thiophene or thienothiopyran ring could not be ruled out.
However, based on the observation, it is immature to arrive at
any conclusion on structure activity aspect of these molecules
and further evaluation is needed.
12a–f, N-C2H5 (12b) and N-(CH2)3-OCH3 (12f) at 2 position of tria-
zol-3-one increases the antibacterial activity while N-CH(CH3)2
(12d) reduces the antibacterial activity compared to parent deriv-
ative 11 against gram positive bacteria S. aureus and B. subtills. It
was also observed that for both series, there are subtle difference
in activity of N-substituted derivatives (6a–f) and (12a–f) com-
pared to their parent compound 5 and 11 against gram negative
bacteria E. coli, K. pneumoniae. However, it is worth mentioning
that the synthesized compounds are more active against fungal
pathogens as compared to bacterial strains. Interestingly, it was
found that thiophene thiazolyl derivatives 5 and (6a–f) were more
active than thieno thiopyarano-thiazolyl derivatives 11 and (12a–
f) against both bacterial and fungal pathogens. From the antifungal
activity data it was concluded that compounds 5, 6a, and 12f are
the most active among all the synthesized compounds against
most of the tested organisms comparable with standard drug keto-
conazole. For the thiophene thiazolyl series, N-CH3 (6a) increases
the antifungal activity while other substitution marginally reduces
the activity compared with parent compound 5. Introduction of the
N-(CH2)3-OCH3 (12f) at C2 of triazol-3-one in thieno thiopyarano-
thiazolyl series substantially increases the antifungal activity com-
pared with unsubstituted parent compound 11. Introduction of
isopropyl group (12c), isobutyl group (12d), and cyanomethyl
group (12e) reduce the antifungal activity whereas there is no ef-
fect of ethyl (12b) and methyl (12a) substitution compared with
parent compound 11 against all the tested pathogens.
In summary, we have synthesized two series of novel triazol-3-
one bearing (thiophene-3-yl) thiazolyl and 4-methyl-4H-thie-
no[30,20: 5,6]thiopyrano[4,3-d][1,3]thiazolyl moiety at C4 and alkyl
substitution at C2 for their in vitro antimicrobial evaluation.
Acknowledgments
Authors thanks Department of Chemistry, Pune University, IIT,
Mumbai, for providing spectral analysis and UGC, New Delhi for
financial assistance.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.049.
Based on the activity data for Triazol-3-one derivatives 5 and 11,
it is concluded that triazol-3-one bearing (thiophene-3-yl) thiazolyl
moiety exhibits better antibacterial and antifungal activity than
4-methyl-4H-thieno[30,20: 5,6]thiopyrano[4,3-d][1,3]thiazolyl moi-
ety. Moreover, N-alkylation of triazol-3-one ring seems to have mar-
ginal effect on biological activity. Infact, upon N-alkylation the
biological activity marginally decreases except in case of N-methyl-
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lg/disc) and ketoconazole
(100 g/disc) were used as control for antibacterial and antifungal activity,
l
respectively. The samples were dissolved in DMSO and used for the
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agar plates, while the fungi cultures of known inoculums size
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agar plates. The Whatman filter paper discs of 6 mm were placed and sample of
appropriate concentration was added to the inoculated plate. The plates were
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antifungal activity.
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