Synthesis, characterization and antibacterial evaluation of some novel benzimidazole derivatives containing 1,3,4-thiadiazole moiety

Article abstract of DOI:10.13005/ojc/330656

A series of novel 5-amino-1,3,4-thiadiazole-2-thiol and 1,3,4-thiadiazole-2,5-dithiol derivatives of benzimidazole were synthesized through nucleophilic substitution reaction of 5-substituted-2-(chloromethyl)-1H-benzimidazole, structures of the synthesized compounds were proved by spectral methods of analysis (FT-IR, ¹H and ¹³C NMR). All the target compounds were screened for their antibacterial activity toward gram-negative (E.coli, P. aeruginosa) and Gram-positive (B. subtilis, S. aureus) bacteria, most of the synthesized derivatives exhibited good to moderate activity toward both Gram-positive (B. subtilis, S. aureus) and Gram-negative (E.coli, P. aeruginosa) bacteria.

Full text of DOI:10.13005/ojc/330656

ISSN: 0970-020 X
CODEN: OJCHEG
017, Vol. 33, No.(6):
Pg. 3138-3143
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
2
www.orientjchem.org
Synthesis, Characterization and Antibacterial Evaluation of
some Novel Benzimidazole Derivatives Containing
1
,3,4-thiadiazole moiety.
1
2
2
MUAYED AHMED REDAYAN *,WASSAN BAQIR ALI and AHMED MUDHAFAR MOHAMMED
1
Department of Chemistry, College of Education for Pure Sciences, Diyala University, Iraq.
2
Department of Chemistry, College of Sciences, Diyala University, Iraq.
*
Corresponding author E-mail: mredayan@gmail.com
http://dx.doi.org/10.13005/ojc/330656
(Received: August 04, 2017; Accepted: September 25, 2017)
ABSTRACT
A series of novel 5-amino-1,3,4-thiadiazole-2-thiol and 1,3,4-thiadiazole-2,5-dithiol
derivatives of benzimidazole were synthesized through nucleophilic substitution reaction of
5
-substituted-2-(chloromethyl)-1H-benzimidazole, structures of the synthesized compounds were
1
13
proved by spectral methods of analysis ( FT-IR, H and C NMR ). All the target compounds were
screened for their antibacterial activity toward gram-negative (E.coli, P. aeruginosa) and
Gram-positive (B. subtilis, S. aureus) bacteria, most of the synthesized derivatives exhibited good
to moderate activity toward both Gram-positive (B. subtilis, S. aureus) and Gram-negative (E.coli,
P. aeruginosa) bacteria.
Keywords: Benzimidazole, Bis benzimidazole, 1,3,4-thiadiazole, Antibacterial activity.
INTRODUCTION
Despite of many attempts to develop and
discover new structural type in the search for great
and more effective antimicrobials, benzimidazoles
still consider as one of the most versatile and
The benzimidazole nucleus consider one
of the most significant and important N-containing
fused organic compounds in a large number of
synthetic pharmaceutical materials and natural
products. Benzimidazole ring count a significant
heterocyclic pharmacophore in the drug discovery,
these compounds which carrying diverse
substituents in the structure of benzimidazole are
associated with a wide range of biological activities
22, 23
significant type of compounds against microbes.
1
,2
The benzimidazole containing compounds
as a structural motif have been widely used in
medicinal chemistry and drugs development.
Amongst the benzimidazole derivatives 2-chloro-
methyl benzimidazole show a considerable importance
in biological chemistry, they are important
intermediates in the synthesis of many biologically
3
,4,5
6,7,8
including: antifungal,
anticancer,
anti-bacterial,
anti-
9
,10
11,12,13
14,15,16,17
inflammatory, antioxidant,
1
8,19
20
anti-viral,
anticoagulant, and anti-hypertensive
2
1
24
properties.
active compounds.

REDAYAN et al., Orient. J. Chem., Vol. 33(6), 3138-3143 (2017)
3139
Designing new compounds in order to
deal with resistant bacteria has become one of the
most significant and great areas of antibacterial
research today. Because the resistance of
pathogenic bacteria toward common and available
antimicrobial drugs is quickly becoming a major
worldwide problem. So the discovery of new and
C-Hstr ( 3040), aliphatic C-Hstr (2966, 2806), C=Ostr
1681), C=N (1614), aromatic C=C (1425-1573),
(
str
str
C-Cl (675), yield: 88%.
st
2-(chloromethyl)-5-nitro-1H-benzimidazole (1d):
Dark yellow crystals, m.p:168-170 °C, IR
-
1
(KBr, cm ): N-H (3259), aromtic C-Hstr (3028),
str
potent antibacterial agent is more hallenging in
current years.
aliphatic C- H (2980, 2800), C=N (1624), C=C (1446,
1471), NO2 str (1334, 1508), C-Cl (690), yield: 85%.
str
str
str
str
25
28
MATERIALS AND METHODS
Synthesis of 5-amino-1,3,4-thiadiazole-2-thiol (2)
A mixture of (4 g, 0.04 mole) of
thiosemicarbazide and (4.66g, 0.04 mole) of
anhydrous sodium carbonate were dissolved in 50
ml of absolute ethanol. (6.4 g, 0.08 mole) of carbon
disulfide was then added to this solution. The
resulting mixture was then refluxed for 11 h,
subsequently the reaction mixture was allowed to
cool down at room temperature. Most of solvent
was distilled off under reduced pressure and the
residue was dissolved in 40 mL of distilled water
and then carefully acidified with cold conc.
Hydrochloric acid to give pale yellow precipitate.
The product was then filtered and washed with cold
water, then recrystallized from hot water, T.L.C
Melting points were determined using
stuart smp3 apparatus and are uncorrected, FT-IR
spectra were recorded on shimadzu FT-IR
spectrophotometer, H and C –NMR spectra were
recorded on brucker 300 MHz spectrophotometer
using (DMSO) as a solvent and TMS as internal
reference. The compounds were checked for their
purity on silica gel TLC plates and the visualization
of spots performed by using UV light.
1
13
General method for the Synthesis of 5
substituted-2-(chloromethyl)-1H-benzimidazole
1
5, 26, 27
1(a-d)
(
mobile phase: ethyl acetate: hexane 2:1 ). m.p: 232-
-
1
A mixture of 4-(un)substituted-o pheny-
lenediamine (0.05 mole) and chloroacetic acid
0.05 mole) was dissolved in ( 25 ml) 4N HCl and
234°C, IR (KBr, cm ): N-H (3399, 3279), S-Hstr
str
(2529), C=Nstr (1601), C=Sstr (1363), C-Sstr (670),
yield 83%.
(
refluxed for 4hrs. The completion of the reaction
was checked by using T.L.C (mobile phase:ethyl
acetate: hexane 2:1). The reaction mixture was
allowed to cool down and neutralized with
ammonium hydroxide solution, the precipitate
appeared was dried and recrystallized from
General method for the Synthesis of compounds
3(a-d)
29
5-amino-1,3,4-thiadiazole-2-thiol (2) (5
mmole) and fused sodium acetate (5 mmole) were
added To the solution of compound (3) (5 mmole)
in absolute ethanol (35 ml), the mixture was
refluxed for 12 h, the reaction completion was
checked by usingT.L.C (mobile phase:ethyl acetate:
hexane 2:1), then the reaction mixture was cooled
and the precipitate was collected by filtration and
dried.
(
methanol/water).
2-(chloromethyl)-1H-benzimidazole (1a):
yellow crystals, m.p: 147-150°C, IR (KBr,
-
1
cm ): N-H (3133), aromtic C-H ( 3050), aliphatic
str
str
C-Hstr (2900, 2846), C=Nstr (1625), aromatic C=Cstr
1520, 1446), C-Clstr (640), Yield: 93%.
(
5
-[(1H-benzimidazol-2-yl-methyl)sulfanyl]-1,3,4-
thiadiazol-2-amine (3a):
Yellow-brown crystals, m.p: 196-198°C, IR
2
-(chloromethyl)-5-methyl-1H-benzimidazole (1b):
Dark brown crystals, m.p:130-134°C, IR
-
1
-1
(
KBr, cm ): N-H (3147), aromtic C-Hstr (3045),
(KBr, cm ): NH
(3252), aromtic C-Hstr (3085),
str
2
str
aliphatic C-H (2919, 2850), C=N (1622), aromatic
aliphatic C-H (2954, 2918), C=N (1622), aromatic
str
str
str str
C=Cstr (1522, 1447), C-Cl (646), yield: 90%.
C=C (1526, 1434), C-S (671), yield 53%.
str str
str
2
-(chloromethyl)-1H- benzimidazole-5carboxylic
acid (1c):
Brown crystals, m.p: 290-293°C, IR (KBr,
cm ): N-H (3379), OHstr (2600-3350), aromtic
5-{[(5-methyl-1H-benzimidazol-2-yl) methyl]
sulfanyl}-1,3,4-thiadiazol-2-amine (3b):
-
Brown crystals, m.p: >350°C, IR (KBr, cm
): NH2 str (3342, 3264), N-H (3133), aromtic C-H
-
1
1
str
str
str

3
140
REDAYAN et al., Orient. J. Chem., Vol. 33(6), 3138-3143 (2017)
(
3080), aliphatic C- H (2972, 2918), C=N (1610), from ethanol. T.L.C (mobile phase: ethyl acetate:
str
str
hexane 2:1). Yellow crystals, m.p:163-166°C, IR
aromatic C=C (1556, 1449), C-S (621), yield 47%.
str
str
-1
(
KBr, cm ):N-H (3055), S-H (2732), C=N (1622),
str str str
C=S (1266), C-S (677), yield 85%.
2
1
-{[(5-amino-1,3,4-thiadiazol-2-yl) sulfanyl] methyl}-
H-benzimidazole-5-carboxylic acid (3c):
Brown crystals, m.p: 240 dec. °C, IR (KBr,
cm ): OH (2800-3550), NH (3442, 3265), N-Hstr
str
str
General methods for the synthesis of compounds
2
9
5
(a-d)
-
1
str
2 str
To the solution of compounds (1)
0.02mole ) in absolute ethanol(60 ml) the 1,3,4-
(3147), aromtic C-H (3051), aliphatic C-H (2941,
s
t
r
s
t
r
(
2
864), C=Ostr (1697), C=N (1616), aromatic C=C
str
str
thiadiazole-2,5-dithiol (4) (0.01 mole) and fused
sodium acetate (0.02 mole) were added and the
mixture was refluxed for 12 hrs, after completion of
the reaction which was checked by T.L.C (mobile
phase: ethyl acetate: hexane 2:1 ) the mixture was
allowed to cool down and cooled in ice bath, the
product was collected by filtration and dried.
1
(
1571, 1512, 1421), C-Sstr (671). HNMR (DMSO-
d6) δ ppm: 3.9 ( s, 2H, CH ), 4.4 ( s, 1H, N-H), 4.58 (s,
2
2
H, NH ), 7.6 – 8.1 (m, 3H, Ar-H), 12.9 (s, 1H, OH),
2
yield 45%.
-{[(5-nitro-1H-benzimidazol-2-yl) methyl]
5
sulfanyl}-1,3,4-thiadiazol-2-amine (3d):
Light brown crystals, m.p: 214°C, IR (KBr,
2
,2'-[1,3,4-thiadiazole-2,5-diylbis (sulfanediy
-
1
cm ): NH (3406, 3284), N-H (3107), aromtic C-
2
str
str
lmethanediyl)]bis(1H-benzimidazole) (5a):
Hstr (3057), aliphatic C-Hstr (2968, 2800), C=Nstr
Yellow-brown crystals, m.p: 218-220
(
1
(
8
1627), aromatic C=C (1537, 1469), N02str (1338,
str
-1
dec.°C, IR (KBr, cm ): N- H (3420), aromtic C-H
1
str
str
514), C-S (640), HNMR (DMSO-d6) δ ppm: 3.37
str
(3100), aliphatic C-Hstr (2978, 2930), C=N (1622),
str
1
s, 1H, N-H), 4.3 (s, 2H, CH ), 7 ( s, 2H, NH ), 7.6-
2
2
aromatic C=Cstr (1526, 1437), C-Sstr (746), HNMR
.1 (m, 3H, Ar-H), yield 90%.
(DMSO-d6) δ ppm: 3.4 (s, 2H, CH ), 4.8 (s, 1H, N-H),
2
7.1-7.7 (m, 8H, Ar-H) yield 47%.
30
Synthesis of 1,3,4-thiadiazole-2,5-dithiol (4)
A mixture of carbon disulfide (0.04 mole,
0 mL) and hydrazine hydrate 80% (0.04 mole,
0 mL) with pyridine (100 mL) was heated under
reflux for 5 hours. Then excess solvent was distilled
off and the solid obtained was separated by adding (50
mL) of water and (10 mL) of hydrochloric acid. The
precipitate was then filtered, dried and recrystallized
2
,2'-[1,3,4-thiadiazole-2,5-diylbis (sulfanediy-
3
1
lmethanediyl)] bis(5-methyl-1H-benzimidazole) (5b):
Light brown crystals, m.p:>300 °C, IR (KBr,
-
1
cm ): N- H (3417), aromtic C-H (3072), aliphatic
str
str
C-Hstr (2976), C=N (1637), aromatic C=C (1618,
str
str
1562), C-Sstr (619), yield 44%.
R
NH
2
O
R
H
N
4
N HCl
Cl
OH
Cl
ref . 4 hrs
NH
2
N
(a-d)
1
R : H,CH
3
,COOH,NO
2
E
rs
tO
h
H
2
1
S
f
.
,
s
Pyridine
Na
2
CO
3
/
EtOH
N N
e
o
N N
r
d
i
CS
2
2 2 2
NH NH .H O
H
2
N
+
CS
2
/
u
N
H
NH
2
te
ta
m
HS
SH
ref . 5 hrs
ref . 11 hrs
HS
S
NH
2
S
e
c
a
a
c
e
2
t
a
4
m
iu
d
te
so
/
,
r
e
H
f.
tO
12
E
h
r
s
H
N
N
N
R
H
N
N
N
H
N
R
R
S
S
NH
2
S
S
S
N
N
N
5(a-d)
3(a-d)
(
route I)
(routeII)
comp no.
a,3a,5a
R
H
1
1
b,3b,5b
CH3
1
c,3c,5c
COOH
1
d,3d,5d
NO
2
scheme1: synthesis of benzimidazzolederivatives

REDAYAN et al., Orient. J. Chem., Vol. 33(6), 3138-3143 (2017)
3141
2
,2'-[1,3,4-thiadiazole-2,5-diylbis (sulfanediylmeth-
anediyl)]bis(1H-benzimidazole-5-carboxylic acid)
5c):
starting material 5-substituted-2-(chloromethyl)-1H-
benzimidazole 1(a-d) was synthesized according
to a reported procedure through the reaction
(
-1
Light green.M.p:284-285°C, IR (KBr, cm ): N-
H (3431), OH (2500-3600), aromtic C-H (3074),
of 4-(un)substituted-o-phenylenediamine with
str
str
str
15,26,27
chloroacetic acid.
Structure of compounds 1(a-
aliphatic C-Hstr (2974, 2889, 2804), C=Ostr (1699),
d) was confirmed by comparison of its physical and
C=Nstr (1631), aromatic C=Cstr (1616, 1564), C-Sstr
26,27,31
spectral data with the reported ones,
nucleophilic
1
(
769), HNMR (DMSO-d6) δ ppm: 5.09 (s, 2H, CH ),
2
substitution reaction of compound +1(a-d) with
-amino-1,3,4-thiadiazole-2-thiol (2) yielded 5-{[(5-
substituted-1H-benzimidazol-2-yl)methyl]sulfanyl}-
,3,4-thiadiazol-2-amine 3(a-d) ( route I), the structure
13
5.3 (s, 1H, N-H), and 7.69-8.3 (m, 6H, Ar-H). CNMR
5
(DMSO-d6) δ ppm: 29.5 (CH ), 114.3, 116.2, 124.5,
2
1
26.7, 134.1, 137.1(Ar-C), 152.1(C=N of
1
benzimidazole ), 164.3(C=N of thiadiazole ,
1
1
of compounds 3(a-d) was confirmed by its IR, H-
67.2(C=O), yield 73%.
NMR, the IR spectra of the compound (3c) exhibited
-
1
2
,2'-[1,3,4-thiadiazole-2,5-diylbis (sulfanediy-
a broad band at (2800-3550 cm for carboxylic OH
-1
-1
lmethanediyl)]bis(5-nitro-1H-benzimidazole)(5d):
), (3442,3265 cm for NH ), (3147 cm for benzimidazole
2
Light brown crystals, m.p: 165°C. IR (KBr,
-1
-1
N-H), (1697 cm for C=O) and band at (671 cm
-
1
cm ): N- H (3419), aromtic C-H (3099), aliphatic
1
str
str
for C-S ). HNMR spectra showed the following
C-Hstr (2974, 2918), C=Nstr (1627), aromatic C=Cstr
chemical shifts at: δ 3.9 (s, 2H, CH ), δ 4.4 (s, 1H, N-
2
(
1597, 1471 ), NO2str (1346, 1519), C-Sstr (738),
H ), δ 4.58 (s, 2H, NH ), δ 7.6 δ 8.1(m, 3H, Ar-H), and
2
1
HNMR (DMSO-d6) δ ppm: δ 3.6 (s, 1H, N-H), ä 5.0
weak signal at δ 12.9 for carboxylic OH, and the IR
spectra of the compound (3d) exhibited the following
13
(s, 2H, CH ), and ä 7.6-8.4 ( m, 6H, Ar-H ). CNMR
2
(
DMSO-d6) δ ppm: 31.0(CH ), 104.7, 108, 116.1, 117.9,
2
-1
-1
bands: (3406, 3284 cm ) for NH , (3107 cm ) for
2
118.2, 129.4(Ar-C), 142.6(C=Nof benzimidazole), 164.5
benzimidazole N-H, and two peaks at (1338, 1323
(
C=N of thiadiazole). Yield 78%.
-
1
cm ) corresponding for NO group, whereas the
2
1
HNMR spectra for this compound revealed the
RESULT AND DISCUSSION
following peaks: δ 3.37 (s, 1H, N-H), δ 4.3 (s, 2H,
CH ), δ 7 ( s, 2H, NH ), and multiplet signals at δ
(7.6-8.1) corresponding for aromatic protons.
The reaction sequence for various title
compounds is summerized in (scheme 1). The
2
2
Table. 1: Physical properties of the compounds
o
Compound
no.
R
m.p ( C)
M.wt(g/mole)
Mol.Formula
C H ClN
Color
Yield %
1
1
1
1
2
3
3
3
3
4
5
5
5
a
b
c
d
H
CH3
COOH
NO2
147-150
130-134
290-293
168-170
232-234
196-198
>350
240 dec.
214
163-166
218-220
>300
166.61
180.64
210.62
211.61
133.19
263.34
277.36
307.35
308.33
150.23
410.53
438.59
498.55
yellow
dark brown
brown
dark yellow
pale yellow
yellow-brown
brown
brown
light brown
yellow
93%
90%
88%
85%
83%
53%
47%
45%
90%
85%
47%
44%
73%
8
7
2
2
C H ClN
9 9
C H ClN O
9 7 2
2
2
C H ClN O
8
6
3
C H N S
2
3
3
2
a
b
c
d
H
CH3
COOH
NO2
C H N S
10 9 5 2
C H N S
11 11 5 2
C H N S
1
1
9
5
2
C H N O S
10
8
6
2
2
C H N S
2 2 2 3
a
b
c
H
CH3
COOH
C H N S
yellow-brown
light brown
light green
1
8
14
6
3
3
C H N S
20 18 6
284-285
C H N O S
20 14 6 4
3
3
5
d
NO2
165
500.53
C H N O S
light brown
78 %
18
12
8
4
dec. : decomposed

3
142
REDAYAN et al., Orient. J. Chem., Vol. 33(6), 3138-3143 (2017)
1
The ( route II ) also included nucleophilic group. The HNMR spectra showed the chemical
substitution reaction of compound 1(a-d) with 1,3,4- shifts: δ 3.6 (s, 1H, N-H), δ 5.0 (s, 2H, CH ), and
2
13
thiadiazole-2,5-dithiol (4) yielded 2,2'-[1,3,4- peaks at δ 7.6-8.4 ( m, 6H, Ar-H ). CNMR spectra
thiadiazole-2,5-diylbis (sulfanediyl methanediyl)] result for this compound found in full agreement
bis(5-subsituted-1H-benzimidazole) 5(a-d), The with its assigned structures. Beginning with signal
structure of compounds 5(a-d) was confirmed by appeared at about δ 31.0 corresponding for the
1
13
its IR, H-NMR and C-NMR, The IR spectra of the methylene group (-CH -), signals of benzene ring
2
compound (5c) showed a broad band at 2500-3600 appeared at about δ (104.7, 108, 116.1, 117.9, 118.2,
-
1
-1
cm for carboxylic OH group, 3431 cm for 129.4) where as the chemical shifts at about 142.6
-
1
benzimidazole N-H, 1699 cm
631 cm for C=N group, and band at 769 cm for (-C=N ) group respectively. The purity of the
C-S group. Whereas the HNMR spectra exhibited synthesized compounds was monitored by TLC.
for C=O group, and 164.5 related to benzimidazole and thiadiazole
-
1
-1
1
1
Physical properties of the synthesized compounds
are shown in Table 1.
the following chemical shifts: δ 5.09 (s, 2H, CH ), δ
2
5
.3 (s, 1H, N-H), and δ 7.69-8.3 (m, 6H, Ar-H). The
13
signals in CNMR was appeared at around: δ 29.5
Antibacterial evaluation
accounted for the methylene group (-CH -), signals
2
Some of the newly synthesized compounds
at (114.3, 116.2, 124.5, 126.7, 134.1, 137.1) could
were tested for their in-vitro antibacterial activities
against Gram-negative including (Pseudomonas
aeruginosa, Esherichia coli) and gram-positive
including (Staphylococcus aureus, Bacillus subtilis)
bacteria by disc diffusion method, the concentration
of the compounds used were (10 mg/mL and 100
mg/ml ). Inhibition zones were measured in
millimeters and compared with (Ampicillin and
ciprofloxacin) as a standard antibiotics references.
The results are illustrated in ( Table 2) which
13
be for benzene ring, also CNMR spectra showed
signal about 152.1 and 164.3 for (-C=N) of
benzimidazole and thiadiazole ring respectively,
whereas signal at 167.2 accounted for (-C=O) group.
The IR spectra for the compound (5d)
-
1
found have the following bands: 3419 cm for N-H
-
1
group , 1627 cm for C=N group, and two bands
-
1
observed at (1346, 1315 cm ) accounted for NO
2
Table. 2 : Antibacterial activity of the synthesized compounds
Compound
no.
Concentration
(mg / ml)
Zone of inhibition ( in mm)
Gram-positive Gram-negative
S. aureus
B. subtilis
P. aeruginosa
E. coli
3
3
3
3
5
5
5
5
a
b
c
d
a
b
c
d
10
12
14
-
11
-
22
12
12
-
-
-
12
11
30
-
18
17
-
12
-
23
19
18
15
-
14
15
13
30
11
-
12
-
-
24
25
-
1
00
10
1
00
-
-
10
12
18
11
-
-
-
-
-
12
15
-
12
19
22
20
12
-
-
-
14
22
15
-
1
00
10
1
00
10
1
00
10
1
00
10
1
00
10
1
00
-
-
Ampicillin
ciprofloxacin
DMSO solvent
22
19
0
23
23
0
-
29
0
10
-
0

REDAYAN et al., Orient. J. Chem., Vol. 33(6), 3138-3143 (2017)
3143
demonstrates that most of compounds tested for
their antibacterial activity exhibited good to
moderate activities. Amongst all compounds tested
cological study was performed to determine the
effects of substituent on the antibacterial activity,
most of the derivatives showed good to moderate
activity toward Gram-negative (E.coli, P.aeruginosa) and
Gram-positive (B. subtilis, S. aureus) bacteria.
(3a, 3c, 3d, 5c) showed good to moderate activity
against all types of bacteria used.
CONCLUSION
ACKNOWLEDGMENT
Bnzimidazole derivatives containing
-amino-1,3,4-thiadiazole-2-thiol and 1,3,4-
thiadiazole-2,5-dithiol were synthesized by
nucleophilic substitution reaction of 5-substituted-
Authors are thankful to Chemistry department,
college of education for pure sciences, Diyala
University and also Chemistry department,
Sciences college, Diyala University for their help
and support.
5
2
-(chloromethyl)-1H-benzimidazole. The pharma-
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