Synthesis of Novel 1-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea Derivatives and Evaluation of Their Antimicrobial Activities

Article abstract of DOI:10.1002/jhet.3611

A new series of 1-(5-(benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea derivatives (1a–j) were designed and synthesized. For the first time, (i) a new process was developed for N-methylation of 1,3,4-thiadiazole moiety using dimethyl carbonate an environmentally benign reagent in presence of N,N,N′,N′-tetramethylethylenediamine and (ii) the sulfide was selectively oxidized to sulfoxide in higher yield by using chlorine (g) in aqueous acetic acid media under mild reaction condition. The synthesized compounds (1a–j) were investigated for their antimicrobial activities. The tested compounds (1a–j) were exhibited moderate to excellent antibacterial activities against both Gram-positive and Gram-negative bacterial strains. The same compounds exhibited good antifungal activities against selected fungal strains. Particularly, the compounds 1b, 1d, 1h, and 1i were proved to be promising leads exhibiting both antibacterial and antifungal activities compared with standard drugs, ciprofloxacin, and fluconazole. The presence of 1,3,4-thiadiazole moiety has a significant role in the display of antimicrobial activity. In addition, the presence of both sulfinyl and thiourea or urea functionalities has enhanced the activity as per obtained antimicrobial activity data.

Full text of DOI:10.1002/jhet.3611

Month 2019 Synthesis of Novel 1-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
ylidene)-thiourea/urea Derivatives and Evaluation of Their
Antimicrobial Activities
a,b
b
b
and R. S. Prasad Ka*
Madhava Rao Mannam,
Srimurugan S., Pramod Kumar,
a
Department of Chemistry, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Andhra Pradesh 522 502, India
b
Chemical Research Division, API R&D Centre, Micro Labs Ltd., Bommasandra–Jigani Link Road, Bangalore, Karnataka
60 105, India
5
*
E-mail: krsprasad_fed@kluniversity.in
Received September 27, 2018
DOI 10.1002/jhet.3611
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A new series of 1-(5-(benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea derivatives
1a–j) were designed and synthesized. For the first time, (i) a new process was developed for
(
N-methylation of 1,3,4-thiadiazole moiety using dimethyl carbonate an environmentally benign reagent in
presence of N,N,N′,N′-tetramethylethylenediamine and (ii) the sulfide was selectively oxidized to sulfoxide
in higher yield by using chlorine (g) in aqueous acetic acid media under mild reaction condition. The
synthesized compounds (1a–j) were investigated for their antimicrobial activities. The tested compounds
(
1a–j) were exhibited moderate to excellent antibacterial activities against both Gram-positive and
Gram-negative bacterial strains. The same compounds exhibited good antifungal activities against selected
fungal strains. Particularly, the compounds 1b, 1d, 1h, and 1i were proved to be promising leads exhibiting
both antibacterial and antifungal activities compared with standard drugs, ciprofloxacin, and fluconazole.
The presence of 1,3,4-thiadiazole moiety has a significant role in the display of antimicrobial activity.
In addition, the presence of both sulfinyl and thiourea or urea functionalities has enhanced the activity as
per obtained antimicrobial activity data.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
convulsants [26], antidepressant, anxiolytic [27],
antihypertensive [28], and anticancer [29] activities.
Particularly, the presence of 1,3,4-thiadiazole moiety [30–
38], sulfinyl functionality [39–45], thiourea, and urea [46–
49] groups in newly designed molecules has received
great attention in drug discovery and development
programs as they are present in many biologically active
drugs. The extensive literature search encouraged us to
design a new series of novel molecules with the presence
of aforesaid functionalities. Recently, it was reported that
the molecules with 1,3,4-thiadiazole core structure and
presence of sulfide, urea, and thiourea derivatives
displayed good antibacterial activity [50,51] as shown in
Figure 1.
The feast of infectious diseases is one of the major
troublesome situations in the world because of the
increasing number of multidrug resistant pathogens [1–6].
The reasons behind this include (i) increase of
geriatric population, (ii) increased prevalence of infectious
diseases, and (iii) increase of bacterial and fungal
resistance toward conventional antibiotics because of
genetic mutation and over prescription of antibacterial
and antifungal drugs [7–9]. Hence, there is a great demand
for the development of new antimicrobial drugs and
drug candidates [10]. The extensive literature search
revealed that a huge number of drugs were reported
as antimicrobial agents that are either heterocyclic or
non-heterocyclic molecules. Among them, thiadiazole
moiety possesses numerous biological activities,
for example, antimicrobial [11–14], antituberculosis [15–
It is well known that either sulfur atom or sulfur-related
functionalities (–SO– and –SO –) within heterocyclic
2
moiety or side chain of the heterocyclic core play an
important role in the display of interesting biological
activities [39–45]. Further, the presence of sulfinyl
1
9], antioxidant [20–22], anti-inflammatory [22–25],
©
2019 Wiley Periodicals, Inc.

M. R. Mannam, S. S., P. Kumar, and R. S. P. K
Vol 000
Figure 1. Biologically active urea-based and thiourea-based 1,3,4-thiadiazole derivatives.
functionality in the side chain of heterocyclic moiety leads
to the molecule becoming medicinally more prominent
thiourea/urea derivatives (1a–j) starting from 2-amino-
1,3,4-thiadiazole-5-thiol (2) as shown in Scheme 1.
[39–45].
Many synthetic methods were reported in the literature
for the synthesis of 1,3,4-thiadiazole derivatives, for
example, sulfuration of the corresponding 1,4-dicarbonyl
or acyl precursors using P S and Lawesson’s reagent
RESULTS AND DISCUSSION
2
5
Chemistry. A new series of 1-(5-(benzylsulfinyl-1,3,4-
thiadiazol-2(3H)-ylidene)-thiourea/urea derivatives (1a–j)
were designed and synthesized as depicted in Scheme 1.
At the outset, we chose easily available 5-amino-1,3,4-
thiadiazole-2-thiol (2) as a key starting material. Our
synthesis starts from S-alkylation of 5-amino-1,3,4-
thiadiazole-2-thiol (2) using benzyl chloride in ethanol
under basic conditions that provided the compound 3
in high yield 98% [64]. The resulting S-alkylated
product (3) was converted to sulfoxide derivative (9)
selectively, which further planned to synthesize target
molecule (10). Accordingly, compound 9 was treated with
isothiocyanate/thiocyanate (8) at reflux temperature in
[52] and also prepared from (i) carboxylic acids using
propylphosphonic anhydride [53] in one pot, (ii) from
acid hydrazides under microwave irradiation in a single
step [54], and (iii) N,N-diacylhydrazines in presence of
P S and Lawesson’s reagent [55] and various other
2
5
methods also reported [56–63].
Based on literature data, we have planned to design
and synthesize a series of 1-(5-(benzylsulfinyl)-3-methyl-
1
,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea derivatives
1a–j).
Herein, we report the synthesis of novel 1-(5-
benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-
(
(
Scheme 1. Synthesis of 1-(5-(benzylsulfinyl)-1,3,4-thiadiazol-2-yl/3-methyl-2-(3H)-ylidene)-thioamide/amide derivatives. [Color figure can be viewed at
wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
1-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea
Derivatives and Evaluation of Their Antimicrobial Activities
tetrahydrofuran (THF). Unfortunately, no product (10)
formation was observed even though various parameters
were tried. Next, we changed our strategy to install
N-alkyl functionality in the ring to enhance the reactivity
by destroying the aromaticity of the 1,3,4-thiadiazole
derivative (4). Accordingly, the aromaticity was planned
to destroy by N-alkylation at 3′-position of compound 4
via the acetylation of compound 3 using acetic anhydride
in presence of acetic acid at 25–30°C. The desired
acetylated compound 4 [64] was obtained in high
yield (98%).
Table 3
Optimization of reaction conditions for the synthesis of compound 1a
a
from compound 6 and compound 8a.
b
Yield
(%)
Entry
Solvents
Time (h) Temp(°C) Product
1
2
3
4
5
6
7
Cyclohexane
Toluene
DCM
MeOH
EtOH
24
24
24
24
24
24
24
3
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
RT
Reflux
60–70
60–70
60–70
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
15
25
15
38
44
52
35
75
60
58
55
IPA
THF
The N-alkylation at 3′-position of compound 4 was
carried out by using dimethyl sulfate (DMS) in
methanol/KOH at reflux temperature provided the desired
compound 5 albeit in low yield 43% (entry 1, Table 1).
The major disadvantages associated with DMS include
high reaction temperature, pungent odor, and highly toxic
nature of the by-products [65]. Because of that, N-
methylation has planned to screen using various other
methylating reagents. When CH Br and CH I were used
8
9
DMF
DMSO
DMAc
2
2
1.5
10
DMAc, dimethylacetamide; DMF, dimethylformamide; THF,
tetrahydrofuran.
Reaction conditions: compound 6 (10.0 mmol), compound 8a
a
(
12.0 mmol), and Et
temperature.
Isolated yields.
3
N (15.0 mmol) in solvent (10 vol.) at specified
b
3
3
Table 1
a
Screening of various methylating agents for the synthesis of compound 5 .
b
Entry
Methylating agents
Equivalents
1.2
1.2
1.2
1.2
1.2
1.2
Temp (°C)
Solvents
Base
Product
Yield (%)
c
1
2
3
4
5
6
DMS
Reflux
Reflux
Reflux
90–100
90–100
90–100
MeOH
MeOH
Acetone
DMF
DMSO
DMAc
KOH
KOH
KOH
TMEDA
TMEDA
TMEDA
5
5
5
5
5
5
43
36
40
81
68
62
CH
CH
DMC
3
Br
3
I
d
DMC
DMC
DMAc, dimethylacetamide; DMF, dimethylformamide; TMEDA, tetramethylethylenediamine.
a
Reaction conditions: compound 4 (10.0 mmol) and methylating agent (12.0 mmol) in a solvent (10 vol.) in presence of a base (2.5 equiv.) or catalyst
1.0 mmol) at the specified temperature.
Isolated yield.
(
b
c
DMS: dimethyl sulfate.
d
DMC: dimethyl carbonate.
Table 2
Screening of various oxidizing agents for the synthesis of compound 6 .
a
b
Entry
Oxidants
Mole equiv.
Time (h)
Solvents
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
Sodium hypochlorite
m-CPBA
Oxone
2 2
H O (30%)
Peracetic acid
Magnesium monoperoxyphthalate
1.0
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.5
1.5
1.0
2.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
—
ACN
O–THF (2:1)
ACN
6
6
6
6
6
6
6
6
6
6
6
6
45
55
25
32
45
42
60
82
68
61
—
—
H
2
ACN
H
2
O–ACN (2:1)
O–AcOH (1:9)
O–AcOH (1:5)
O–AcOH (1:2)
O–AcOH (1:1)
AcOH
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
H
2
2
2
2
H
H
H
0
1
2
Water
THF, tetrahydrofuran.
a
Reaction conditions: compound 5 (10.0 mmol) and oxidants in the solvent/mixture of solvents (10 vol.) at 5–15°C.
Isolated yields.
b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. R. Mannam, S. S., P. Kumar, and R. S. P. K
Vol 000
Table 4
a
Synthesis of N-(5-(benzylsulfinyl)-1,3,4-thiadiazol-3-methyl-2(3H)-ylidene)-thiourea/urea derivatives (1a–j) .
Compound 8
b
Entry
1
R
X
S
Time (h)
3
Product
Yield (%)
75
2
S
2
92
3
S
5
78
4
S
2
91
5
6
3
CH CH
2
– 8e
S
3
3
72
75
O
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
1-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea
Derivatives and Evaluation of Their Antimicrobial Activities
Table 4
(
Continued)
Compound 8
b
Entry
7
R
X
O
Time (h)
3
Product
Yield (%)
78
8
O
O
O
5
2
2
85
9
88
10
76
a
Reaction conditions: compound 7 (10.0 mmol), isothiocyanate (8a–e)/isocyanate (8f–j) (12.0 mmol), and Et
Isolated yields.
3
N (15.0 mmol) in THF (10 vol) at 50–60°C.
b
in presence of KOH and obtained the desired product (5)
in low yields, 36%, 40%, respectively (entries 2 and 3).
Even these reagents are also associated with many
drawbacks such as carcinogenic and genotoxic nature.
In this context, we urged to find environmentally
benign and toxic free reagent. The dimethyl carbonate
yield methylating reagent in many literature reports
[66]. Hence, the reaction was carried out using DMC in
presence of tetramethylethylenediamine (TMEDA) in
dimethylformamide (DMF) at 90–100°C and the alkylated
product was obtained in high yield 81% (entry 4, Table 1).
The DMSO and dimethylacetamide were screened in
place of DMF but yields dropped to 68% and 62%,
(DMC) was found to be more promising and high
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. R. Mannam, S. S., P. Kumar, and R. S. P. K
Vol 000
respectively (entries 5 and 6). The study disclosed that DMF
is an optimal solvent for getting higher yield of compound 5
provided sulfoxide (6) in moderate yields 40–55%
(entries 2–6, Table 2). Surprisingly, chlorine in a mixture
of water–acetic acid (1:9 ratio) at 5–15°C afforded
the desired compound in 60% yield (entry 7, Table 2).
This result encouraged us to optimize the conditions to
improve the yield. Further, the various ratio of water and
acetic acid were screened (entries 8–10, Table 2) and
found that in case of water and acetic acid in 1:5 ratio
provided desired product (6) in high yield 82% (entry 8).
The same reaction either in acetic acid or in water alone,
the starting material was intact (entries 11 and 12,
Table 2). As per our knowledge, this is the first report
for mono sulfoxidation using Cl2 in aq. acetic acid
with high yield (82%).
(entry 4).
Number of methods has been reported for the
preparation of sulfones (–SO –), but only few methods
2
were reported for the preparation of sulfoxide (–SO–).
Hence, we have envisioned installing sulfinyl (–SO–)
functional group in compound 5 by testing with various
oxidizing agents. Initially, the sulfide compound (4) was
treated with sodium hypochlorite in neat condition at low
temperature (5–15°C) to yield desired sulfoxide 6 in low
yield 45% (entry 1, Table 2) was obtained. The screening
of other oxidants such as m-CPBA, Oxone, H O (30%),
2
2
peracetic acid, and magnesium monoperoxyphthalate
Table 5
Antimicrobial activities of tested compounds (1a–1j) in terms of the diameter of inhibition zones (mm).
Diameter of inhibition zones in mm
Staphylococcus
aureus
Pseudomonas
aeruginosa
Acinetobactor
baumannii
Escherichia
coli
Klebsiella
pneumonia
5
0
100
50
100
50
100
50
μg mL
100
50
100
À1
À1
À1
À1
À1
Tested compounds
μg mL
μg mL
μg mL
μg mL
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
g
h
i
4
11
0
10
1
5
2
10
9
8
18
0
17
3
7
4
18
17
0
3
10
2
8
0
6
1
9
8
7
17
4
16
0
10
2
16
15
3
5
11
1
8
1
4
0
9
8
9
19
2
17
2
8
0
19
17
6
2
11
3
9
0
6
2
11
10
3
5
18
5
17
0
12
3
18
19
5
3
10
2
8
0
4
3
10
7
0
6
21
3
16
0
10
5
17
15
0
j
0
2
4
Ciprofloxacin
13
21
12
21
13
23
13
22
13
23
Figure 2. Biological activity of synthesized compounds (1a–j) against bacterial strains. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
1-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea
Derivatives and Evaluation of Their Antimicrobial Activities
The deprotection of the acetyl group was performed
as per the literature process [67], that is, deacetylation
using conc. HCl in ethanol afforded desired imine
hydrochloride 7, in high yield. Now, the imine
thiadiazole scaffold (7) was in our hand, and then our
attention turned to prepare a library of new molecules
toluene and Dichloromethane (DCM) provided desired
product 1a in low yields 25% and 15%, respectively
(entries 2 and 3, Table 3). The same reaction in polar
protic solvents such as methanol, ethanol, and IPA
provided desired compound 1a in moderate yields
(entries 4–6). In the case of polar aprotic solvents, the
conversion was improved compared with protic solvents
(entries 7–10). Particularly, in THF, the yield of product
1a was increased to a great extent (75%) (entry 7,
Table 3). The same reaction at room temperature offered
low yield 35% even for prolonged reaction time.
(
(
1a–j) by treating compound 7 with various substrates
8a–j).
At the outset, the imine compound 7 was treated with
substrate 8a in cyclohexane at room temperature and
obtained the desired compound 1a in low yield 5%.
When raising the temperature to reflux for the prolonged
time, there was no considerable yield improvement (15%)
Next, we focused our attention on the scope and utility
of the present developed reaction conditions for the
synthesis of a library of compounds 1b–j as shown in
Table 4. The substrates (8b and 8d) with electron
(entry 1, Table 3). To increase the yield, various polar
and nonpolar solvents were screened, for example,
Table 6
Antifungal activities of tested compounds (1a–1j) in terms of the diameter of inhibition zones (mm).
Diameter of inhibition zones in mm
Candida albicans
Cryptococcus neoformans
5
0
100
50
100
À1
À1
Tested compounds
μg mL
μg mL
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
g
h
i
5
12
4
11
0
4
11
20
7
21
0
7
0
19
18
0
7
14
5
12
0
5
2
15
12
3
13
19
9
18
0
11
3
21
19
5
0
13
10
0
j
Fluconazole
14
22
16
23
Figure 3. Biological activity of synthesized compounds (1a–j) against fungal strains. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. R. Mannam, S. S., P. Kumar, and R. S. P. K
Vol 000
withdrawing groups (–F and –NO ) provided desired
Biological activity studies.
The antibacterial activity
2
products 1b and 1d in high yields 92% and 91%,
respectively (entries 2 and 4, Table 4), but the substrate
screening was carried out using agar disc diffusion
method [68–70]. All the synthesized compounds (1a–1j)
were tested against Gram-positive bacterial strains,
Staphylococcus aureus (ATCC 43300), Gram-negative
bacterial strains, Escherichia coli (ATCC 25922),
Klebsiella pneumoniae (ATCC 700603), non-fermenting
Gram-negative bacterial strains, Pseudomonas aeruginosa
(ATCC 27853), Acinetobacter baumannii (ATCC
19606), and two fungi-like Candida albicans (ATCC
90028) and Cryptococcus neoformans (ATCC 208821).
The zones of inhibition were measured and compared
with the standard antibiotics, ciprofloxacin against
bacterial strains and fluconazole against fungi. The
preliminary results of antibacterial testing of compounds
(1a–j) are shown in Table 5 and Figure 2 and the results
of antifungal activities are shown in Table 6 and
Figure 3. The minimum inhibitory concentration (MIC)
of lead compounds 1b, 1d, 1h, and 1i were assessed
8c with –Cl group provided the desired product 1c in
moderate yield 78% (entry 3). It may be because of
moderate inductive effect of chloro substituent. In the
case of substrates 8e–g with alkyl groups provided
moderate yields of products 1e–g (72–78%). The similar
trend was observed in case of other substrates 8h–j and
also, for example, the yield range of products 1h–j was
76–85%, (entries 8–10).
Interestingly, it was observed that thiourea-based
derivatives of 1,3,4-thiadiazoles (1a–c and 1e) displayed
1
tautomerism except for compound 1d as confirmed by H
1
NMR. To confirm the same, H NMR of compound
1b was performed at higher temperature (50°C). The
N-methyl group at room temperature (Figure S29a)
appeared as doublet while at 50°C appeared as singlet
(Figure S29b).
Table 7
Minimum inhibitory concentration of newly synthesized active compounds.
À1
Minimum inhibitory concentration in μg mL
Bacterial strains
Fungal strains
Tested
compounds
Staphylococcus
aureus
Pseudomonas
aeruginosa
Acinetobacter
baumannii
Escherichia
coli
Klebsiella
pneumonia
Candida
albicans
Cryptococcus
neoformans
1
1
1
b
d
h
3
4
5
4
2
4
6
4
3
2
4
4
5
6
2
5
7
5
8
3
5
6
4
6
2
6
4
5
4
5
6
4
7
1
i
Ciprofl-
oxacin
—
Fluconazole
—
3
3
Figure 4. Minimum inhibitory concentration (MIC) of lead compounds (1b, 1d, 1h, and 1i) against bacterial strains and fungal strains. [Color figure can
be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
1-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea
Derivatives and Evaluation of Their Antimicrobial Activities
using twofold serial dilution technique [71] and the
obtained results were presented in Table 7 and Figure 4.
As depicted in Table 5 and Figure 2, a few of the
tested compounds, for example, compounds 1b, 1d, 1h,
and 1i, showed potent antibacterial activity against
all the bacterial strains. Most of the compounds
exhibited promising activity against S. aureus,
P. aeruginosa, K. pneumonia, A. baumannii, and E. coli.
It was observed that the newly synthesized urea-based/
thiourea-based 1,3,4-thiadiazole derivatives with (i) 4-
fluorophenyl substitution (1b and 1i), (ii) 4-nitro phenyl
substitution (1d), and (iii) 3-trifluoro-4-chlorophenyl
substitution (1h) were exhibited potential bacterial growth
of inhibition against all the tested bacteria, almost
comparable activity was observed with standard
ciprofloxacin as shown in Table 5 and Figure 2 and their
MIC values were reported in Table 7 and Figure 4. The
compounds 1a and 1f displayed low to moderate activity
toward Gram-positive bacteria and moderate activity
toward Gram-negative bacterial strains. The compounds
thiourea/urea derivatives (1a–j) starting from easily
available substrates (2 and 8a–j). The notable advantages
of the present work include (i) use of DMC, an
environmentally benign and toxic free reagent, for N-
methylation of compound 4 in presence of TMEDA in
DMF; (ii) avoided the use of toxic and carcinogenic
methylating agents, for example, DMS, MeBr, and
MeI; and (iii) selective mono oxidation of sulfide (5) by
using chlorine (g) in aqueous acetic acid system (1:5
ratio) with excellent isolated yields (81%). For the first
time, we have identified, synthesized, and characterized a
new intermediate, N-(5-(benzylsulfinyl)-3-methyl-1,3,4-
thiadiazol-2(3H)-ylidene)acetamide (6). In addition, the
synthesized compounds (1b, 1d, 1h, and 1i) showed
excellent antibacterial activity against Gram-positive and
Gram-negative bacterial strains and also good activity
against fungal strains. The screening of antituberculosis
activities of the present molecules is under progress. We
hope that the present work is highly useful for new drug
discovery and development programs.
1c, 1e, 1g, and 1j exhibited the least activity against both
bacterial strains. The overall study revealed that thiourea-
based 1,3,4-thiadiazole derivatives (1b and 1d) showed
good antibacterial activity compared with urea-based
EXPERIMENTAL
1
,3,4-thiadiazole derivatives (1h and 1i).
In the case of antifungal activity studies revealed that
Reagents and instruments. The solvents and reagents
were obtained from commercial sources and were used
without any purification. Nuclear magnetic resonance
the same compounds (1b, 1d, 1h, and 1i) exhibited
good growth of inhibition against C. neoformans
and C. albicans. The thiourea-based 1,3,4-thiadiazole
derivatives (1b and 1d) and urea-based 1,3,4-thiadiazole
derivatives (1h and 1i) displayed promising activity
against both fungal strains, C. neoformans and C. albicans
as shown in Table 6 and Figure 3 and their MIC values
were reported in Table 7 and Figure 4. The other
compounds (1a, 1c, 1e–g, and 1j) showed inferior activity.
The structure–activity relationship studies of the
synthesized compounds revealed that the presence of
(NMR) spectra of the synthesized compounds were
recorded on Ascend Bruker 400 (Bruker, Fallanden,
1
Switzerland) instrument and operating at 400 MHz for H
13
NMR and 100 MHz for C NMR using DMSO-d solvent
6
and tetramethylsilane as an internal standard. Spin multi-
plicities are given as s (singlet), d (doublet), dd (doublet
of doublet), qd (quartet of doublet), t (triplet), and m (mul-
1
tiplet) as well as brs (broad singlet). The H chemical shift
values were reported on δ scale in ppm, relative to
13
tetramethylsilane (δ = 0.00 ppm) and the C chemical shift
electron withdrawing groups (–NO2, –F, and –CF ) on
values were reported relative to DMSO-d (δ = 39.5 ppm).
3
6
the phenyl ring of urea-based/thiourea-based 1,3,4-
thiadiazole derivatives (1d, 1h, and 1i) displayed good
antibacterial and antifungal activities. The compounds
having electron donating groups (–Cl) on phenyl ring
The ESI/MS experiments were performed on a Velos Pro
Ion Trap mass spectrometer from Thermo Scientific
(San Jose, CA, USA).
2-Amino-5-benzylmercapto-1,3,4-thiadiazole (3).
In a
(
1c) or presence of both simple benzyl and aliphatic
three-necked round bottom flask, 2-amino-5-mercapto-
1,3,4-thiadiazole (2) (25 g, 187 mmol) was taken in
ethanol (100 mL) at 20–30°C. The aqueous KOH
solution (13.6 g of KOH dissolved in 20 mL water) was
added slowly at 20–30°C. The reaction mass was stirred
at the same temperature for 10 min. Subsequently,
benzyl chloride (25.0 g, 197 mmol) was added dropwise
at 20–30°C. The reaction mass was stirred for 2–3 h at
25–30°C. After completion of the reaction as per thin-
layer chromatography (TLC), water (100 mL) was added
to the reaction mass and stirred for 30 min at the same
temperature. The reaction mass was filtered, washed with
groups of urea-based/thiourea-based 1,3,4-thiadiazole
derivatives (1e, 1g, 1j, and 1c) exhibited low antibacterial
and antifungal activities. The compounds having fluoro
(
–F) substituent (1b and 1i) showed excellent activity as
shown in Tables 5 and 6.
CONCLUSION
We have synthesized
a
new series of 1-(5-
(
benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-(3H)-ylidene)-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. R. Mannam, S. S., P. Kumar, and R. S. P. K
Vol 000
water (25 mL), and sucked dried for 30 min. The obtained
wet compound (3) was dried in a hot air oven at 50°C for
–6 h. The compound 3 was obtained as light yellow
solid, 41.0 g, yield: 98.0%; mp: 157–159°C; FT-IR
KBr) υmax: 3292, 3103 (–NH), 1616 (–C═N), 1516,
492 (–C═C–), 1336, 1240, 1060 (C–N ), 712 (C–S);
N-(5-(benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
ylidene)acetamide (6).
A mixture of 5-acetylimino-4-
methyl-2-benzylmercapto-1,3,4-thiadiazole
5
(15 g,
4
5
1 mmol) in a mixture of water–acetic acid (1:5 ratio,
(
90 mL) was taken in a three-necked RB flask at
20–30°C. The reaction mass was cooled to 5–15°C and
chlorine gas (12 g) [Note: The required quantity of
chlorine gas was generated in situ by slow addition of
1
str
1
H NMR (400 MHz, DMSO-d , δ ppm): 4.23 (s, 2H,
6
1
3
–
CH –), 7.25–7.36 (m, 5H, Ar–H); C NMR (100 MHz,
2
δ ppm): 38.46, 127.45, 128.48, 128.97, 137.10, 149.47,
conc. HCl (60 mL) to KMnO (35.0 g)]. The whole
4
+
1
69.87; ESI–MS: m/z 224.03 [M + H] .
-Acetylamino-5-benzylmercapto-1,3,4-thiadiazole (4). In
three-necked round bottom flask, 2-amino-5-
reaction mass was stirred for 2–3 h at the same
temperature. After completion of the reaction as per TLC,
water (150 mL) was added at 5–15°C and stirred for
30 min at the same temperature. The reaction mass was
filtered and washed with water (30 mL) and the wet solid
was dried in a hot air oven for 6–8 h at 50°C. The
compound 6 was obtained as off-white solid, 13.0 g,
2
a
benzylmercapto-1,3,4-thiadiazole (3) (20 g, 89.5 mmol) in
acetic acid (80 mL) was taken at 20–30°C. The acetic
anhydride (10.0 g, 98.0 mmol) was added slowly to the
reaction mass at 20–30°C. The reaction mass was stirred
for 2–3 h at 25–30°C. After completion of the reaction as
per TLC, water (150 mL) was added and stirred at the
same temperature for 30 min. The reaction mass was
filtered, washed with water (40 mL), and sucked dried and
the wet solid was dried in a hot air oven at 55°C for 6–8 h.
The compound 4 was obtained as an off-white solid,
Yield: 82.0%; mp: 126.4–129.5°C; FT-IR (KBr) υmax
:
1618 (C═O), 1491 (C═C), 1371, 1292, 1074 (C–N),
1
1057 (S═O); H NMR (400 MHz, DMSO-d , δ ppm):
6
2.25 (s, 3H, –COCH ), 3.83 (s, 3H, N–CH ), 4.53 (d, 1H,
3
3
–SCH –,
J = 12.8 Hz), 4.61 (d, 1H, –SCH –,
2
2
J = 12.8 Hz), 7.25–7.28 (m, 2H, Ar–H), 7.33–7.35 (m,
13
2
3
1
3.4 g. Yield: 98.5%; mp: 163–165°C; FT-IR (KBr) υmax
:
3H, Ar–H); C NMR (100 MHz, δ ppm): 26.48, 38.14,
161 (–NH), 1695 (C═O), 1560 (C═N), 1497 (C═C),
6082, 128.49, 128.57, 128.91, 130.64, 162.21, 164.38,
1
+
303, 1248 (C–N), 698 (C–S); H NMR (400 MHz,
179.54; ESI–MS: m/z 296.05 [M + H] .
DMSO-d δ ppm): 2.17 (s, 3H, –COCH ), 4.48 (s, 2H, –
5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-imine
6,
3
hydrochloride (7). A mixture of N-(5-(benzylsulfinyl)-3-
methyl-1,3,4-thiadiazol-2(3H)-ylidene)acetamide 6 (12 g,
CH ), 7.26–7.35 (m, 3H, Ar–H), 7.39 (d, 2H, Ar–H,
2
1
3
J = 7.2 Hz), 12.59 (s, 1H, NH); C NMR (100 MHz, δ
4
0.6 mmol) in ethanol (50 mL) was taken in a three-
ppm): 22.28, 37.57, 127.57, 128.54, 128.99, 136.71,
+
necked RB flask at 20–30°C. The conc. HCl (5 mL) was
added slowly to the reaction mass. The reaction mass was
stirred at 50–60°C for 2–3 h. After completion of the
reaction as per TLC, the reaction mass was cooled to
1
57.83, 158.93, 168.70; ESI–MS: m/z 266.12 [M + H] .
5
-Acetylimino-4-methyl-2-benzylmercapto-1,3,4-thiadiazole
(5).
A mixture of 2-acetylamino-5-benzylmercapto-
1,3,4-thiadiazole 4 (20 g, 75.3 mmol), DMC (7.76 g,
79.14 mmol), and TMEDA (1.31 g, 11.3 mmol) in DMF
2
0–30°C, stirred for 30 min, filtered, and washed with
(
2
80 mL) was taken in a three-necked RB flask at
0–30°C. The reaction mass was heated to 90–100°C
The reaction mass was stirred at the same temperature for
–6 h. After completion of the reaction as per TLC, the
reaction mass was cooled to 25–30°C and water
200 mL) was added to the reaction mass at 25–30°C and
ethanol (12 mL). The wet solid was dried in a hot air
oven for 6–8 h at 50°C. The compound 7 was obtained
as off-white solid, 10.6 g. Yield: 90.0%; mp: 174.5–
5
1
76.2°C; FT-IR (KBr) υmax: 1558 (C═N), 1454, 1055
1
(C–N), 1026 (S═O) 698 (C–S); H NMR (400 MHz,
(
DMSO-d , δ ppm): 3.85 (s, 3H, N–CH ), 4.54 (d, 1H,
6
3
stirred for 30 min at the same temperature. The reaction
mass was filtered and washed with water (40 mL) and the
wet solid was dried in a hot air oven at 55°C for 6–8 h.
The compound 5 was obtained as a light yellow solid,
recrystallized from ethanol, dry weight 17.05 g. Yield:
–
SCH –, J = 12.8 Hz), 4.68 (d, 1H, –SCH2–,
2
J = 12.8 Hz), 7.31–7.34 (m, 2H, Ar–H), 7.37–7.39 (m,
13
3
(
1
H, Ar–H), 10.8 (brs, 2H, NH and HCl); C NMR
100 MHz, δ ppm): 38.55, 61.00, 128.46, 128.66, 128.74,
30.87, 163.07, 168.39; ESI–MS: m/z 254.0
+
8
1
1.0%; mp: 80–83°C; FT-IR (KBr) υmax: 1614 (C═O),
514 (C═N), 1379, 1287, 1069 (C–N), 700 (C–S); H
[M + H–HCl] .
1
5-(Benzylsulfinyl)-1,3,4-thiadiazol-2-amine
(9).
A
NMR (400 MHz, DMSO-d , δ ppm): 2.19 (s, 3H,
mixture of 2-amino-5-benzylmercapto-1,3,4-thiadiazole 3
(15 g, 67.17 mmol) in a mixture of water–acetic acid (1:5
ratio, 90 mL) was taken in a three-necked RB flask at
20–30°C. The reaction mass was cooled to 5–15°C and
chlorine gas (12 g) [Note: The required quantity of
chlorine gas was generated in situ by slow addition of
conc. HCl (60 mL) to KMnO4 (35.0 g)]. The whole
6
–
7
7
COCH ), 3.83 (s, 3H, N–CH ), 4.46 (s, 2H, –CH ),
3 3 2
.27–7.31 (m, 1H, Ar–H), 7.33–7.36 (m, 2H, Ar–H),
1
3
.41 (d, 2H, Ar–H, J = 7.2 Hz); C NMR (100 MHz δ
ppm): 26.33, 36.66, 37.80, 127.72, 128.60, 129.06,
1
36.23, 153.67, 163.90, 179.05; ESI–MS: m/z 279.05
+
[M + H] .
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
1-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea
Derivatives and Evaluation of Their Antimicrobial Activities
1
reaction mass was stirred for 2–3 h at the same
temperature. After completion of the reaction as per TLC,
water (150 mL) was added at 5–15°C and stirred for
(S═O), 810 (C–S); H NMR (400 MHz, DMSO-d , δ
6
ppm): 3.84 &3.93 (s, 3H, N–CH Tautomers), 4.56 (d,
3
1H, –SCH –, J = 12.8 Hz), 4.60 (d, 1H, –SCH –,
2
2
3
0 min at the same temperature. The reaction mass was
J = 13.2 Hz), 7.18–7.20 (m, 2H, Ar–H), 7.29–7.30
(m, 5H, Ar–H), 7.62–7.74 (m, 2H, Ar–H), 10.88, 11.03
filtered and washed with water (30 mL) and the wet solid
was dried in a hot air oven for 6–8 h at 50–55°C. The
compound 9 was obtained as off-white solid, 13.0 g.
13
(s, 1H, NH); C NMR (100 MHz, δ ppm): 38.38, 60.84,
115.02 (d, J = 22.0 Hz), 124.24 (d, J = 8.0 Hz), 125.08,
128.54, 129.11, 130.66, 135.75, 159.08, 159.87, 164.7,
Yield: 80.5%; mp: 146.2–147.9°C; FT-IR (KBr) υmax
:
+
1633 (C═N), 1500 (C═C), 1049 (C–N), 1039 (S═O),
167.0, 184.66; ESI–MS: m/z 407.11 [M + H] ; HRMS
1
694 (C–S); H NMR (400 MHz, DMSO-d , δ ppm): 4.45
(EI): calcd for C17
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
ylidene)-3-(4-chlorophenyl)-thiourea (1c).
H15FN OS :406.0392, found: 406.0390.
4 3
6
1
(d, 1H, –SCH –, J = 12.8 Hz), 4.53 (d, 1H, –SCH –,
2
2
Off-white
J = 12.8 Hz), 7.23–7.26 (m, 2H, Ar–H), 7.33–7.35
1
3
powder; yield: 78%; mp: 170.7–172.5°C; FT-IR (KBr)
υmax: 1514 (C═N), 1489 (C═S), 1406, 1328, 1290
(m, 3H, Ar–H), 7.80 (s, 2H, –NH2);
C NMR
(100 MHz, δ ppm): 60.91, 128.28 (d), 129.53, 130.53,
1
+
(C–N), 1047 (S═O), 827 (C–S); H NMR (400 MHz,
161.89 171.60; ESI–MS: m/z 240.03 [M + H] .
DMSO-d , δ ppm): 3.88 & 3.93 (s, 3H, N–CH3
6
General experimental procedure for the synthesis of
Tautomers), 4.56 (d, 1H, –SCH –, J = 12.8 Hz), 4.62 (d,
2
compounds 1a–j.
A mixture of 5-(benzylsulfinyl)-3-
methyl-1,3,4-thiadiazol-2(3H)-imine hydrochloride (7)
500 mg, 1.72 mmol), Et N (0.36 mL, 2.58 mmol), and
1
7
H, –SCH –, J = 12.8 Hz), 7.29–7.41 (m, 7H, Ar–H),
.66–7.67 (d, 2H, Ar–H), 10.94 (d, 1H, NH); C NMR
2
13
(
3
(100 MHz, δ ppm): 38.48, 60.83, 123.77, 124.61, 128.31,
compound 8a (1.89 mmol) in THF (10 mL) was taken at
0–30°C. The temperature of the reaction mass was raised
1
1
28.48, 128.60, 129.12, 130.66, 160.16, 164.73, 167.17,
84.01 184.66; ESI–MS: m/z 423.01 [M + H] ; HRMS
2
+
to 60–65°C and stirred at the same temperature for 3–5 h.
After completion of the reaction as per TLC, the reaction
mass was cooled to 20–30°C. The reaction mass was
filtered and washed with THF (2 mL). The filtrate was
collected and concentrated under vacuum at <50°C. The
obtained crude was purified by column chromatography
over silica gel using mixture of n-hexane-ethyl acetate (3:7
ratio). The pure compound 1a–j was obtained as off-white
solid. The obtained results were presented in Table 1.
The same experimental procedure for both experimental
and purification was adopted for the preparation of
all other compounds (1b–j). The newly synthesized
molecules (1a–j) gave satisfactory spectroscopic data in
accordance with their proposed structures.
(
4
EI): calcd for C H ClN OS : 422.0097, found:
17 15 4 3
22.0093.
1
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
ylidene)-3-(4-nitrophenyl)-thiourea (1d). Off-white powder;
yield: 91%; mp: 178.8–179.5°C; FT-IR (KBr) υmax: 1595
(C═N), 1498 (C═S), 1330,1226 (C–N), 1168 (S═O), 848
1
(
3
(
C–S); H NMR (400 MHz, DMSO-d , δ ppm): 3.98 (s,
6
H, N–CH ), 4.57 (1H, d, –SCH –, J = 12.8 Hz), 4.65
3 2
1H, d, –SCH –, J = 12.8 HZ), 7.30–7.36 (m, 5H,
2
Ar–H), 8.04 (br, 2H, Ar–H), 8.25 (d, 2H, Ar–H,
13
J = 8.8 Hz), 11.36 (s, 1H, NH); C NMR (100 MHz, δ
ppm): 60.93, 121.22, 124.61, 128.55, 128.63, 129.05,
130.72, 142.29, 145.37, 160.46, 184.85; ESI–MS: m/z
434.12 [M + H] ; HRMS (EI): calcd for C H N O S :
4
+
17 15 5 3 3
1
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
33.0337, found: 433.0334.
ylidene)-3-phenylthiourea (1a).
Off-white powder; yield:
5%; mp: 144.6–147.7°C; FT-IR (KBr) υmax: 1593
C═N), 1552 (C═S), 1440, 1180 (C–N), 1076 (S═O),
1
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
7
(
ylidene)-3-ethylthiourea (1e).
72%; mp: 178.8–179.5°C; FT-IR (KBr) υmax: 1602
(C═N), 1558 (C═S), 1498, 1286 (C–N), 1045 (S═O),
779 (C–S); H NMR (400 MHz, DMSO-d , δ ppm):
Off-white powder; yield:
1
9
3
–
04, 754 (C–S); H NMR (400 MHz, DMSO-d , δ ppm):
6
1
.86 & 3.95 (s, 3H, N–CH , Tautomers), 4.56 (d, 1H,
3
6
SCH2–,
J
=
12.8 Hz), 4.62 (d, 1H, –SCH –,
1.11–1.16 (m, 3H, –CH ), 3.42–3.53 (m, 2H, –CH ),
2
3
2
J = 13.2 Hz), 7.11–7.12 (m,1H, Ar–H), 7.28–7.36 (m,
H, Ar–H), 7.62–7.64 (m, 1H, Ar–H), 7.76 (s, 1H,
Ar–H), 10.87 (s, 1H, NH); C NMR (100 MHz, δ ppm):
3.81 and 3.85 (s, 3H, N–CH Tautomers), 4.54 (1H, d,
–SCH –, J = 13.2 Hz), 4.58 (1H, d, –SCH –,
2 2
3
7
1
3
J = 13.2 Hz), 7.28–7.36 (m, 5H, Ar–H), 9.04–9.24 (dt,
13
3
1
1
3
3
8.39, 60.82, 122.30, 122.86, 1213.98, 124.90, 128.40,
28.48, 128.60, 129.15, 130.66, 139.25, 139.49, 159.0,
59.96, 164.52, 167.00, 183.95, 185.08; ESI–MS: m/z
1H, NH, J = 5.6 Hz); C NMR (100 MHz, δ ppm):
13.52, 14.46, 37.86, 38.01, 38.01, 38.29, 60.68, 60.78,
128.44, 128.59, 129.23, 129.26, 130.59, 130.62, 157.91,
159.27, 163.67, 165.79, 184.57, 186.22; ESI–MS: m/z
+
89.14 [M + H] ; HRMS (EI): calcd for C H N OS :
1
7
16
4
3
+
88.0486, found: 388.0483.
379.11 [M + H + K] ; HRMS (EI): calcd for
1
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
C H N OS : 340.0486, found: 340.0483.
13
16
4
3
ylidene)-3-(4-fluorophenyl)-thiourea (1b).
Off-white
1
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
powder; yield: 92%; mp: 166.3–168.4°C; FT-IR (KBr)
υmax: 1680 (C═N), 1602 (C═S), 1490, 1213 (C–N), 1083
ylidene)-3-(4-methyl cyclohexyl) urea (1f).
powder; yield: 75%; mp: 114.5–116.2°C; FT-IR (KBr)
Off-white
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. R. Mannam, S. S., P. Kumar, and R. S. P. K
Vol 000
1
υmax: 1546 (C═O), 1510 (C═N), 1219 (C–N), 1058
698 (C–S); H NMR (400 MHz, DMSO-d , δ ppm):
6
1
(
S═O); H NMR (400 MHz, DMSO-d , δ ppm): 0.86 (d,
3.84 (s, 3H, N–CH ), 4.55 (d, 1H, –SCH –, J = 12.8 Hz),
6
3
2
3
1
1
H, CH3, J = 6.4 Hz), 0.096–1.01 (m, 2H, CH ), 1.19–
4.60 (d, 1H, –SCH –, J = 12.8 Hz), 7.03–7.05 (dd, 1H,
2
2
.29 (m, 3H, CH , CH), 1.66 (d, 2H, CH J = 11.6 H ),
Ar–H), 7.28–7.38 (m, 6H, Ar–H), 7.55–7.57 (d, 1H,
2
2,
Z
13
.76 (d, 2H, CH2, J = 10.8 H ), 3.37–3.44 (m, 1H,
Ar–H), 7.84 (s, 1H, Ar–H), 10.13 (s, 1H, NH);
C
Z
N–CH), 3.71 & 3.76 (s, 3H, N–CH Tautomers), 4.52 (s,
NMR (100 MHz, δ ppm): 37.71, 60.73, 116.85, 121.94,
3
2
3
H, CH ), 7.28 (t, 2H, Ar–H, J = 3.6 Hz), 7.34–7.36 (m,
H, Ar–H), 7.49 (s, 1H, NH); C NMR (100 MHz, δ
128.47, 129.0, 130.30, 130.60, 133.06, 141.46,
2
1
3
+
159.51, 161.04, 164.03; ESI–MS: m/z 407.09 [M + H] ;
ppm): 22.25, 31.48, 32.41, 32.44, 37.30, 49.09, 60.60,
28.43, 128.57, 129.14, 130.56, 159.67, 160.30, 162.32;
ESI–MS: m/z 393.26 [M + H] ; HRMS (EI): calcd for
HRMS (EI): calcd for C H ClN O S :406.0325,
found: 406.0322.
17
15
4 2 2
1
+
C H N O S : 392.1341, found: 392.1338.
1
8 24 4 2 2
1
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
Acknowledgments. The authors are thankful to the management
of Micro Labs Ltd., API Division Centre, ML-27, Bangalore. We
also wish to thank Dr Mohan Reddy Bodireddy and Dr Murugan
Kaliyappan for their valuable support. Our sincere thanks to Dr R.
V. Jayanth Kasyap, Department of English, Yogi Vemana
University, Kadapa.
ylidene)-3-phenethylurea (1g).
Off-white powder; yield:
8%; mp: 135.3–136.5°C; FT-IR (KBr) υmax: 1629
C═O), 1562 (C═N), 1492, 1211 (C–N), 1139 (S═O),
7
(
7
2
1
77(C–S); H NMR (400 MHz, DMSO-d , δ ppm):
.75–2.79 (m, 2H, CH ) 3.32–3.37 (m, 2H, CH ), 3.72
6
2
2
(
s, 3H, N–CH ), 4.52 (1H, d, –SCH –, J = 12.8 Hz), 4.58
3 2
(
1H, d, –SCH –, J = 12.8 Hz), 7.18–7.23 (m, 3H, Ar–H),
2
7
7
3
1
.28–7.31 (m, 4H, Ar–H), 7.35–7.36 (m, 3H, Ar–H),
.67–7.70 (m, 1H, Ar–H); C NMR (100 MHz, δ ppm):
5.31, 37.30, 41.59, 60.60, 126.02, 128.30, 128.42,
CONFLICT OF INTEREST
1
3
The author declared no conflict of interest.
28.57, 129.13, 130.54, 139.46, 159.79, 161.18, 162.5;
+
ESI–MS: m/z 401.23 [M + H] ; HRMS (EI): calcd for
C H N O S : 400.1028, found: 400.1026.
1
1
9
20
4
2
2
REFERENCES AND NOTES
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
ylidene)-3-(4-chloro-3-(trifluoro methyl)phenyl)urea (1h).
Off-white powder; yield: 85%; mp: 215.2–216.6°C, FT-
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1
2
[2] Pfeltz, R. F.; Wilkinson, B. J. Drug Targets Infect Disord
IR (KBr) υmax: 1645 (C═O), 1517 (C═N), 1421,1298
004, 4, 273.
1
(
C–N), 1126 (S═O), 769 (C–S); H NMR (400 MHz,
[3] Roberts, M. C. Curr Drug Targets Infect Disord 2004, 4, 207.
DMSO-d , δ ppm): 3.85 (s, 3H, N–CH ), 4.56 (d, 1H,
[4] Dessen, A.; Mouz, N.; Hopkins, J.; Dideberg, O. J Biol Chem
001, 48, 45106.
6
3
2
–
SCH –,
J
=
12.8 Hz), 4.61 (d, 1H, –SCH –,
2
2
[5] Izumida, M.; Nagai, M.; Ohta, A.; Hashimoto, S.; Kawado,
J = 12.8 Hz), 7.28–7.31 (m, 5H, Ar–H), 7.35–7.37 (m,
H, Ar–H), 7.63–7.89 (m, 1H, Ar–H), 8.28 (s, 1H,
M.; Murakami, Y.; Tada, Y.; Shigematsu, M.; Yasui, Y.; Taniguchi, K.
J Epidemiol 2007, 17, S42.
1
1
3
Ar–H), 10.38 (s,1H, –NH); C NMR (100 MHz, δ ppm):
[
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3
1
7.79, 60.72, 122.79, 123.07, 128.51, 128.61, 129.0,
8
30.63, 132.03, 139.55, 159.66; ESI–MS: m/z 475.15
+
[M + H] ; HRMS (EI): calcd for C H ClF N O S :
1
8
14
3 4 2 2
[
4
74.0199, found: 474.0197.
1
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
[
ylidene)-3-(4-fluorophenyl)urea (1i).
Off-white powder,
yield: 88%; mp: 207.2–208.8°C, FT-IR (KBr) υmax: 1639
C═O), 1502 (C═N), 1406, 1207 (C–N), 1035 (S═O),
[
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(
8
[
12] Almajan, G. L.; Barbuceanu, S. F.; Bancescu, G.; Saramet, I.;
1
35 (C–S); H NMR (400 MHz, DMSO-d , δ ppm): 3.83
6
Saramet, G.; Draghici, C. Eur J Med Chem 2010, 45, 6139.
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1073.
(
s, 3H, N–CH ), 4.55 (d, 1H, –SCH –, J = 12.8 Hz), 4.60
3 2
(
d, 1H, –SCH –, J = 12.8 Hz), 7.10–7.15 (t, 2H, Ar–H),
2
[
7
9
6
1
.28–7.39 (m, 5H, Ar–H), 7.66–7.69 (m, 2H, Ar–H),
.98 (s, 1H, NH); C NMR (100 MHz, δ ppm): 37.63,
0.73, 115.33 (d, J = 22.0 Hz), 119.98 (d, J = 7.0 Hz),
1
3
28.7, 129.04, 130.60, 136.25, 156.42, 158.79, 160.76;
[
+
ESI–MS: m/z 391.09 [M + H] ; HRMS (EI): calcd for
[
[
[
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1
7
15
4 2 2
1
-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-
ylidene)-3-(4-chlorophenyl) urea (1j).
yield: 76%; mp: 202.0–203.8°C; FT-IR (KBr) υmax: 1645
C═O), 1597 (C═N), 1483, 1307 (C–N), 1033 (S═O),
Off-white powder;
2
006, 14, 3069.
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(
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
1-(5-(Benzylsulfinyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-thiourea/urea
Derivatives and Evaluation of Their Antimicrobial Activities
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SUPPORTING INFORMATION
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Additional supporting information may be found online
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Journal of Heterocyclic Chemistry
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