Design, synthesis and biological evaluation of benzimidazolyl and benzothiazolyl picolinamide derivatives as antimicrobial agents

Article abstract of DOI:10.14233/ajchem.2015.19235

A series of benzothiazolyl amides and benzimidazolyl amides (6a-f) has been synthesized from the coupling reaction of substituted picolinic acid with benzothiazole and benzimidazoles, respectively. The newly synthesized compounds were evaluated for their efficacy as antimicrobial agents against various Gram-positive and Gram-negative strains of bacteria and fungal strains. Amongst these compounds 6f was found to be the most potent against Bacillus subtilis and Candida albicans. Moreover, other compounds also found to be potential antibacterial agents in comparison to the standard drugs.

Full text of DOI:10.14233/ajchem.2015.19235

Asian Journal of Chemistry; Vol. 27, No. 12 (2015), 4575-4578
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.19235
Design, Synthesis and Biological Evaluation of Benzimidazolyl and
Benzothiazolyl Picolinamide Derivatives as Antimicrobial Agents
1
1,*
2
VASU NAMANI , B. BHARATH KUMAR GOUD , Y. BHARATHI KUMARI ,
3
4
4
RAMESH KUMBHAM , KANNOJU BALAKRISHNA and BHUKYA BHIMA
1
2
3
4
Suven Life Sciences Ltd, Jeedimetla, Hyderabad-500 055, India
Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 072, India
Rational Laboratories Private Ltd, Mallapur, Hyderabad-500 007, India
Department of Microbiology, University College of Science, Osmania University, Hyderabad-500 007, India
*Corresponding author: E-mail: bkgoud2014@gmail.com
Received: 8 April 2015; Accepted: 16 May 2015;
Published online: 29 August 2015;
AJC-17510
A series of benzothiazolyl amides and benzimidazolyl amides (6a-f) has been synthesized from the coupling reaction of substituted
picolinic acid with benzothiazole and benzimidazoles, respectively. The newly synthesized compounds were evaluated for their efficacy
as antimicrobial agents against various Gram-positive and Gram-negative strains of bacteria and fungal strains.Amongst these compounds
6f was found to be the most potent against Bacillus subtilis and Candida albicans. Moreover, other compounds also found to be potential
antibacterial agents in comparison to the standard drugs.
Keywords: Benzothiazoles, Benzimidazoles, Antimicrobial activities.
biological activities of benzimidzoles with remarkable pharma-
cological potentialities. In last few years it was reported that
benzothiazole, its bioisosters and derivatives had antimicrobial
activities against Gram-negative and Gram-positive bacteria
INTRODUCTION
The demand for developing novel and potent antibacterial
agents remains an attractive field in the medicinal chemistry.
For last few decades, continuous efforts have been carried out
on the structural modifications on the existing scaffolds for
the identification of novels antibacterial agents. However, the
rapid emergence of resistance to the organisms limited the
clinical use of current antibacterial drugs and development of
antibacterials is increasingly becoming global health problem.
For this reason, there is a strong need to develop more effective
antibacterial agents to treat infections caused by antibiotic
resistant bacterial pathogens.
(
e.g., Enterobacter, Pseudomonas aeruginosa, E. coli and
Staphylococcus epidermidis etc.) and the yeast (e.g., Candida
12,13
albicans) . Furthermore, sulfur and nitrogen atoms constitute
the core structure of thiazole and many pharmacologically and
biologically active compounds. Therefore, various benzothia-
zole compounds are of considerable interest for their diverse
pharmaceutical uses and play a vital role in the synthesis of
fused heterocyclic systems.
The goal of outset of this research is to find and develop
new effective antimicrobial agents possessing benzothiazole
and benzimidazole nuclei in their structures. In continuation
of our research, herein we have prescribed the synthesis and
antibacterial studies of two series, benzothiazole and benzimi-
dazole derivatives coupled with other heteroaryl ring system.
Almost all compounds showed promising antibacterial activity
against Gram-positive and Gram-negative bacterial strains.
Benzothiazoles belong to an important class of heterocyclic
compounds which display a variety of biological properties
1
-3
4,5
including antibacterial and antifungal , anti-HIV , hyper-
6
7
8
9
tension , anti-inflammatory , anticancer , anticonvulsant ,
10
11,12
antiinflammation and antidepressant activities . In the past
few years, benzothiazole ring system has attracted much
interest for the development of potent antibacterial agents either
by the structural modification of this scaffold or by developing
hybrid compounds. On the other hand, benzimidazoles are
found to exhibit diverse biological activities such as antibac-
terial, antifungal and anticancer etc. During past few years
there have been considerable interesting developments in the
EXPERIMENTAL
All reagents and solvents were used as purchased without
further purification. Crude products were purified by column
chromatography on silica gel of 60-120 mesh. NMR spectra

4
576 Namani et al.
Asian J. Chem.
1
were recorded on aVarian 400 MHz spectrometer for H NMR.
Melting points were determined on a Fisher-Johns melting
point apparatus and are uncorrected. The chemical shifts were
reported as ppm down field using TMS as an internal standard.
A mass spectrum was recorded on a VG-Micro mass 7070H
spectrometer operating at 70 eV.
O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium
hexafluorophosphate (HATU) (570 mg, 0.0015 mol), N,N-
diisopropylethylamine (DIPEA) (0.358 mL, 0.0020 mol) and
the mixture was stirred for 16 h at ambient temperature. Water
was added and extracted with ethyl acetate, dried and purified
by column chromatography using a gradient of hexane-EtOAc
(8:2-5:5) to give compound 4.
Synthesis of 2-amino benzothiazole (2a-d): To a mixture
of aniline (1) (2.0 g, 0.021 mol) and ammonium thiocyanate
6.5 g, 0.086 mol), bromine (2.2 mL, 0.043 mol) in dichloro-
N-(Benzo[d]thiazol-2-yl)-5-bromo-6-methoxypicolina-
1
(
mide (4a): Off-white solid; yield: 66 %, m.p.: 190-192 °C; H
methane (20 mL) and stirred for 16 h at ambient temperature.
Later than water was added to the reaction mixture and the
product was extracted in dichloromethane (3 × 30 mL). The
solvent was evaporated under vacuum to afford the as crude,
which was further purified by column chromatography using
EtOAc:Hexane (4:6) to give compounds 2a-d.
NMR (400 MHz, CDCl
3
) δ: 4.20 (s, 3H, OCH ), 7.37-7.39
3
(m, 1H, Ar-H), 7.42-7.44 (m, 1H, Ar-H), 7.80-7.84 (m, 3H,
Ar-H), 8.06-8.08 (m, 1H, Ar-H), 10.76-10.78 (s, 1H, NH);
+
2
MS: m/z (%) 365.65 [M ], UPLC purity (98.61 %).
5-Bromo-N-(4-fluorobenzo[d]thiazol-2-yl)-6-methoxy-
picolinamide (4b): Pale yellow solid; yield: 61 %, m.p.: 190-
1
2
-Amino-benzothiazole (2a): Off-white solid; yield: 70
192 °C; H NMR (400 MHz, CDCl
3
) δ: 4.02 (s, 3H, OCH ),
3
1
%
7
1
, m.p.: 126-128 °C; H NMR (400 MHz, DMSO-d
.00 (m, 1H, Ar-H), 7.18-7.20 (m, 1H, Ar-H), 7.32-7.34 (m,
H, Ar-H), 7.40-7.42 (s, 2H, NH ), 8.02-8.21 (m, 1H, Ar-H);
6
) δ: 6.98-
7.20-7.22 (m, 1H, Ar-H), 7.58-7.60 (m, 1H, Ar-H), 7.76-
7.78(m, 2H, Ar-H), 8.07-8.09 (m, 1H, Ar-H), 10.70-10.72 (s,
1H, NH); MS: m/z (%) 383.8 [M ], UPLC purity (98.01 %).
+2
2
+
MS: m/z (%) 150.8 [M ], UPLC purity (99.89 %).
-Amino-4-fluoro-benzothiazole (2b): Yellow solid;
5-Bromo-N-(6-fluorobenzo[d]thiazol-2-yl)-6-methoxy-
2
picolinamide (4c): Pale yellow solid; yield: 63 %, m.p.: 186-
1
1
yield: 76 %, m.p.: 140-142 °C; H NMR (400 MHz, DMSO-
188 °C; H NMR (400 MHz, CDCl
3
) δ: 4.18 (s, 3H, OCH ),
3
d
6
) δ: 7.00-7.04 (m, 1H,Ar-H), 7.22-7.24 (m, 1H,Ar-H), 7.40-
7.18-7.20 (m, 1H, Ar-H), 7.56-7.58 (m, 1H, Ar-H), 7.78-7.82
(m, 2H, Ar-H), 8.06-8.08 (m, 1H, Ar-H), 10.70(s, 1H, NH);
7.42 (s, 2H, NH ), 7.50-7.52 (m, 1H,Ar-H); MS: m/z (%) 168.8
2
+
+2
[
M ], UPLC purity (99.03 %).
-Amino-6-fluoro-benzothiazole (2c): Yellow solid;
MS: m/z (%) 383.8 [M ], UPLC purity (95.10 %).
2
5-Bromo-N-(6-methoxybenzo[d]thiazol-2-yl)-6-methoxy-
1
yield: 78 %, m.p.: 145-147 °C; H NMR (400 MHz, DMSO-
picolinamide (4d): White solid; Yield: 65 %, m.p.: 182-
1
d
6
) δ: 6.98-7.02 (m, 1H,Ar-H), 7.25-7.28 (m, 1H,Ar-H), 7.38-
184 °C; H NMR (400 MHz, CDCl
3
) δ: 4.12 (s, 3H, OCH
), 7.20-7.22 (m, 1H, Ar-H), 7.43-7.55 (m,
1H, Ar-H), 7.51-7.62 (m, 2H, Ar-H), 7.90-8.00 (m, 1H, Ar-
3
),
7.42 (s, 2H, NH ), 7.53-7.56 (m, 1H,Ar-H); MS: m/z (%) 168.8
2
3.88 (s, 3H, OCH
3
+
[
M ], UPLC purity (99.23 %).
-Amino-6-methoxy-benzothiazole (2d): White solid;
+2
2
H), 10.62 (s, 1H, NH); MS: m/z (%) 395.9 (M ), UPLC purity
(97.10 %).
1
yield: 72 %, m.p.: 160-162 °C; H NMR (400 MHz, DMSO-
) δ: 3.82 (s, 3H, OCH ), 6.85-6.98 (m, 1H, Ar-H), 7.22-7.35
m, 1H, Ar-H), 7.46-7.57 (s, 2H, NH ), 8.11-8.24 (m, 1H, Ar-
d
(
6
3
N-(1H-Benzo[d]imidazol-2-yl)-5-bromo-6-methoxy-
2
picolinamide (4e): Off-white solid; yield: 66 %, m.p.: 210-
+
1
H); MS: m/z (%) 179.8 [M ], UPLC purity (99.89 %).
Synthesis of 2-amino benzimidazole (2e, f): To a stirred
solution of 2-amino aniline 1 (2.85 g, 0.026 mol) in acetonitrile
212°C H NMR (400 MHz, DMSO-d
6
) δ: 4.15 (s, 3H, OCH ),
3
7.25 (m, 2H, Ar-H), 7.45 (m, 1H, Ar-H), 7.62 (m, 1H, Ar-H),
7.80 (d, 1H, Ar-H), 8.05 (d, 1H, Ar-H) 10.42 (broad s, 1H,
NH), 11.02 (broad s, 1H, NH); MS: m/z (%) 348.7 [M ], UPLC
purity (98.9 %).
+2
(20 mL) and water (4 mL) at 0 °C, was added cyanogen bromide
5
M in ACN (6.45 mL, 0.032 mol), the reaction mixture was
stirred for 16 h at ambient temperature. Later than reaction
was quenched with saturated aqueous sodium hydrogen
carbonate (100 mL) and shaken the resulting solid was filtered
off, was washed with water and dried under reduced pressure
to afford compounds 2e, f.
5-Bromo-N-(5-fluoro-1H-benzo[d]imidazol-2-yl)-6-
methoxypicolinamide (4f): Pale yellow solid; yield: 63 %,
1
m.p.: 218-220 °C; H NMR (400 MHz, DMSO-d
6
) δ: 4.16 (s,
3H, OCH ), 7.26-7.18 (m, 1H, Ar-H), 7.46-7.52 (m, 1H, Ar-
3
H), 7.64-7.71 (m, 1H, Ar-H), 7.84 (d, 1H, Ar-H, J = 7.98 Hz),
2
-Amino-benzimidazole (2e): Off-white solid; yield: 70
8.08 (d, 1H, Ar-H), 10.44 (broad s, 1H, NH), 11.05 (broad s,
1H, NH); MS: m/z (%) 366.7 [M ], UPLC purity (98.2 %).
1
+2
%
6
2
, m.p.: 229- 231°C; H NMR (400 MHz, DMSO- d
.08 (s, 2H, NH ), 6.82-6.86 (m, 2H, Ar-H), 7.08-7.10 (m,
H,Ar-H), 10.60-10.65 (broad s, 1H, NH); MS: m/z (%) 133.85
6
) δ: 6.06-
2
Synthesis of N-(R-benzo[d]thiazol-2-yl)-6-methoxy-5-
(4-methyl-1H-imidazol-1-yl)picolinamide and N-(R-benzo-
[d]imidazol-2-yl)-6-methoxy5-(4-methyl-1H-imidazol-1-
yl)picolinamide (6): Compound 4 (50 mg, 0.00013 mol),
compound 5 (16.9 mg, 0.0002 mol), CuI (13 mg, 0.000068
+
(
M ], HPLC purity (99.83 %).
-Amino-5-fluoro-benzimidazole (2f): Yellow solid;
2
1
yield: 78 %, m.p.: 232-234 °C; H NMR (400 MHz, DMSO-
d
6
) δ: 6.10-6.12 (s, 2H, NH
2
), 6.94-6.98 (m, 2H, Ar-H), 7.08-
mol), K
3
PO (58.2 mg, 0.00027mol), trans-1,2-diaminocyclo-
4
7.10 (s, 1H, Ar-H), 10.64-10.68 (broad s, 1H, NH);MS: m/z
hexane (7.82 mg, 0.000068 mol) in dioxane (1.0 mL), were
heated at 120 °C for 16 h. The solvent was evaporated in vacuo
and the residue on purification by column chromatography
+
(
%) 151.84 [M ], UPLC purity (99.05 %).
Synthesis of N-(benzo[d]thiazol-2-yl)-5-bromo-6-
methoxypicolinamide and N-(1H-benzo[d]imidazol-2-yl)-
-bromo-6-methoxypicolinamide (4): To a solution of
using CH
2
Cl -MeOH (9.8:0.2-9.5:0.5) gave the title compound 6.
2
5
N-(Benzo[d]thiazol-2-yl)-6-methoxy 5-(4-methyl-1H-
compound 2 (150 mg, 0.001 mol) in dichloromethane (4 mL),
cooled to 0 °C, was added compound 3 (255 mg, 0.0011 mol),
imidazol-1-yl)picolinamide (6a): Off-white solid; yield:
1
68 %, m.p.: 166-170 °C; H NMR (400 MHz, CDCl
3
) δ: 2.32

Vol. 27, No. 12 (2015)
Synthesis and Biological Evaluation of Benzimidazolyl and Benzothiazolyl Picolinamide Derivatives 4577
(
1
7
s, 3H), 4.22 (s, 3H, OCH
3
), 7.05 (s, 1H, Ar-H), 7.35-7.40 (m,
H, Ar-H), 7.49-7.51(m, 1H, Ar-H), 7.80 (d, 1H, Ar-H, J =
.87 Hz), 7.85-7.88 (m, 2H, Ar-H), 7.91 (s, 1H, Ar-H), 8.09
(s, 1H, Ar-H), 7.44 (m, 2H, Ar-H), 7.62 (m, 1H, Ar-H), 7.78
(m, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 8.04 (m, 1H, Ar-H), MS:
m/z (%) 348.9 [M ], UPLC purity (95.02 %). Anal. calcd. For
+
1
(
d, 1H, Ar-H, J = 8.22 Hz), 10.75 (s, 1H, NH); H NMR (400
MHz, D O exchange) δ: 2.32 (s, 3H), 4.22 (s, 3H, OCH ),
.05 (s, 1H, Ar-H), 7.35-7.40 (m, 1H, Ar-H), 7.49-7.51 (m,
H, Ar-H), 7.80 (d, 1H, Ar-H, J = 7.78 Hz), 7.85-7.88 (m, 2H,
C
18
H
16
N
6
O
2
: C, 62.06; H, 4.63; N, 24.12. Found C, 61.99; H,
4.65; N, 24.10.
N-(5-Fluoro-1H-benzo[d]imidazol-2-yl)-6-methoxy-5-
2
3
7
1
(4-methyl-1H-imidazol-1-yl)picolinamide (6f): Pale yellow
1
Ar-H), 7.91 (s, 1H, Ar-H), 8.08 (d, 1H, Ar-H, J = 8.31 Hz),
MS: m/z (%) 365.9 [M ], UPLC purity (96.02 %).Anal. calcd.
for C18
H, 4.12; N, 19.22.
solid; yield: 64 %, m.p.: 224-226 °C; H NMR (400 MHz,
+
CDCl
3
) δ:2.34 (s, 3H), 4.20 (s, 3H, OCH ), 7.02 (s, 1H,Ar-H),
3
H
15
5 2
N O S: C, 59.16; H, 4.14; N, 19.17. Found C, 59.20;
7.32 (m, 1H, Ar-H), 7.40 (m, 1H, Ar-H), 7.58 (m, 1H, Ar-H),
7.78 (m, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 8.04 (m, 1H, Ar-H),
1
N-(4-Fluoro-benzo[d]thiazol-2-yl)-6-methoxy-5-(4-
10.36 (bs, 1H, NH), 10.98 (bs, 1H, NH); H NMR (400 MHz,
methyl-1H-imidazol-1-yl)picolinamide (6b): Pale yellow
D
2
O exchange). 2.34 (s, 3H), 4.20 (s, 3H, OCH ), 7.02 (s, 1H,
3
1
solid; yield: 65 %, m.p.: >220 °C; H NMR (400 MHz, CDCl
3
)
Ar-H), 7.32 (m, 1H, Ar-H), 7.40 (m, 1H, Ar-H), 7.58 (m, 1H,
Ar-H), 7.78 (m, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 8.04 (m, 1H,
Ar-H): MS: m/z (%) 366.9 [M ], UPLC purity (96.4 %). Anal.
calcd. For C18
Found: C, 59.15; H, 4.12; N, 22.89.
δ: 2.33 (s, 3H), 4.24 (s, 3H, OCH ), 7.06 (s, 1H, Ar-H), 7.20-
3
+
7
7
6
.22 (m, 1H, Ar-H), 7.56 (d, 1H, Ar-H, J = 7.98 Hz), 7.80-
.82 (m, 2H, Ar-H), 7.95 (s, 1H, Ar-H), 8.11 (d, 1H, Ar-H, J =
H15FN
6
O : C, 59.01; H, 4.13; F, 5.19; N, 22.94.
2
1
.85 Hz), 10.74 (s, 1H, NH); H NMR (400 MHz, D
2
O exchange)
δ: 2.33(s, 3H), 4.24 (s, 3H, OMe), 7.06 (s, 1H, Ar-H), 7.20-
Antibacterial assay: The minimum inhibitory concen-
tration (MIC) of the test compound was obtained against a
panel of bacteria using a conventional method. The Muller
Hinton agar medium was used as test media. Tests were
performed in 96-well round bottom sterile culture plates. All
the compounds previously solubilized in DMSO were serially
diluted to two folds in the liquid medium and gave a range of
concentrations from 10 to 500 µg/mL. The final bacterial
7
7
6
.22 (m, 1H, Ar-H), 7.56 (d, 1H, Ar-H, J = 7.95 Hz), 7.80-
.82 (m, 2H, Ar-H), 7.95 (s, 1H, Ar-H), 8.12 (d, 1H, Ar-H, J =
.88 Hz), MS: m/z (%) 383.9 [M ], UPLC purity (98.01 %).
+
Anal. calcd. for C18
H14FN
5
O S: C, 56.39; H, 3.68; N, 18.27.
2
Found C, 56.44; H, 3.66; N, 18.21.
N-(6-Fluoro-benzo[d]thiazol-2-yl)-6-methoxy5-(4-
methyl-1H-imidazol-1-yl)picolinamide (6c): Pale yellow
1
5
solid; yield: 64 %, m.p.: >220 °C; H NMR (400 MHz, CDCl
3
)
inoculum contained approximately 5-10 CFU/mL was run
δ: 2.32 (s, 3H), 4.21 (s, 3H, OCH
3
), 7.05 (s, 1H, Ar-H), 7.19-
.21 (m, 1H, Ar-H), 7.55 (d, 1H, Ar-H, J = 7.22 Hz), 7.78-
on microtiter plates. The volume in each well was 100 µL and
the plates were inoculated at 35 °C for 18 h. The standard
antibiotic ampicillin was used as positive control, whereas,
the equivalent amount of solvent (DMSO) did not exhibit any
7
7
8
.80 (m, 2H, Ar-H), 7.92 (s, 1H, Ar-H), 8.08 (d, 1H, Ar-H, J =
.20 Hz), 10.71(s, 1H, NH); H NMR (400 MHz, D
1
2
O
14
exchange) δ: 2.32 (s, 3H), 4.21 (s, 3H, OCH
Ar-H), 7.19-7.21 (m, 1H, Ar-H), 7.55 (d, 1H, Ar-H, J = 7.22
Hz), 7.78-7.80 (m, 2H,Ar-H), 7.92 (s, 1H, Ar-H), 8.08 (d, 1H,
Ar-H, J = 8.21 Hz), MS: m/z (%) 383.9 [M ], UPLC purity
3
), 7.05 (s, 1H,
activity in the assay .
Antifungal assay: The method followed for antifungal
bioassay is similar to that followed for antibacterial assay,
where the medium is PDA 39 g/L. All the test compounds
were studied for their antifungal activity at concentration 100-
150 mg/mL using DMSO as a solvent. The solvent did not
exhibit any activity at the concentrations used. The treated
and the controls were kept in an incubator at 28 °C for 48 h
and inhibition zones were measured to the nearest millimeter.
Three replicates were maintained for each treatment.
Amphotericin-B (50 mg/mL) was used as positive control.
+
(
98.01 %). Anal. calcd. For C18
H14FN
5
2
O S: C, 56.39; H, 3.68;
N, 18.27. Found C, 56.42; H, 3.66; N, 18.22.
N-(6-Methoxy-benzo[d]thiazol-2-yl)-6-methoxy5-(4-
methyl-1H-imidazol-1-yl)picolinamide (6d): Pale yellow
1
solid; yield: 76 %, m.p.: 172-174 °C; H NMR (400 MHz,
CDCl
.14 (s, 1H, Ar-H), 7.22-7.29 (m, 1H, Ar-H), 7.51 (d, 1H, Ar-
H, J = 6.87 Hz), 7.61-7.74 (m, 2H, Ar-H), 7.85 (s, 1H, Ar-H),
3
) δ: 2.29 (s, 3H), 4.23 (s, 3H, OCH
3
), 3.95 (s, 3H, OCH
3
),
7
1
RESULTS AND DISCUSSION
8
(
3
.28 (d, 1H, Ar-H, J = 8.12 Hz), 10.81(s, 1H, NH); H NMR
400 MHz, D O exchange) δ: 2.29 (s, 3H), 4.23 (s, 3H, OCH ),
.95 (s, 3H, OCH ), 7.14 (s, 1H, Ar-H), 7.22-7.29 (m, 1H, Ar-
2
3
The synthesis of 2-amino benzothiazoles was carried out
by the action of ammonium thiocyanate and bromine on
substituted anilines (1) to afford substituted 2-aminobenzo-
3
H), 7.51 (d, 1H, Ar-H, J = 6.87 Hz), 7.61-7.74 (m, 2H, Ar-H),
.85 (s, 1H, Ar-H), 8.28 (d, 1H, Ar-H, J = 8.12 Hz), MS: m/z
7
15
thiazoles (2a-d) as reported in the literature (Scheme-I).
+
(
%) 395.9 [M ], UPLC purity (98.01 %). Anal. calcd. for
S: C, 57.71; H, 4.33; N, 17.71. Found C, 57.77; H,
Similarly, 2-amino benzimidazoles (2e-f) were synthesized by
the reaction of substituted anilines (1) with cyanogens bromide.
Compounds 2a-f were coupled with 3 using HATU and DIPEA
to afford 4a-f Finally, compounds 4a-f were reacted with
methylimidazole (5) in the presence of CuI, trans-1,2-diamino
C
19
H
17
N O
5 3
4.30; N, 17.73.
N-(1H-Benzo[d]imidazol-2-yl)-6-methoxy-5-(4-methyl-
1
6
H-imidazol-1-yl)picolinamide (6e): Off-white solid; yield:
8 %, m.p.: 212-214 °C; H NMR (400 MHz, CDCl
1
3
) δ: 2.32
cyclohexane and K
3
PO furnished the final targets 6a-f.
4
(s, 3H), 4.20 (s, 3H, OCH
3
), 7.04 (s, 1H, Ar-H), 7.25 (s, 1H,
Conclusion
Ar-H), 7.44 (m, 2H, Ar-H), 7.62 (m, 1H, Ar-H), 7.78 (m, 1H,
Ar-H), 7.92 (s, 1H, Ar-H), 8.04 (m, 1H, Ar-H), 10.42 (m, 1H,
In summary, the synthesis and screening of antibacterial
and antifungal activities for a novel series of benzothiazole
and benzimidazole conjugates have been investigated. All the
1
2
NH), 11.02 (m, 1H, NH); H NMR (400 MHz, D O exchange)
δ: 2.32 (s, 3H), 4.20 (s, 3H, OCH
3
), 7.04 (s, 1H, Ar-H), 7.25

4
578 Namani et al.
Asian J. Chem.
O
NH2
N
X
HOOC
NH2
R1
N
X
(
i)
NH
(ii)
+
N
N
R
Br
R
Br
R
1
OMe
3
OMe
2
a-f
4a-f
HN
2
2
a: X=S, R=H
R1=H, R=H,
R1=H, R=2F,
R1=H, R=4F,
R1=H, R=4-OMe,
R1=NH , R=H,
b: X=S, R=4-F
(iii)
N
2c: X=S, R=6-F
2d: X=S, R=6-OMe
: X=NH, R=H
: X=NH, R=5-F
5
2
2
e
O
2
f
N
X
6
R1=NH , R=4F
2
NH
N
R
N
a-f
OMe
N
6
6
6
6
6
a
b
: X=S, R=H
: X=S, R=4-F
c: X=S, R=6-F
d
: X=S, R=6-OMe
e
: X=NH, R=H
6
f: X=NH, R=5-F
Reaction and condition: (i) Ammonium thiocyanate, Br2, DCM, RT, 16 h (for 2a-d) and cyanogen bromide, acetonitrile/water,
°C-RT (for 2e-f); (ii) HATU, DIPEA, RT, 16 h, (iii) K PO , CuI, trans-1,2-diamino cyclohexane, dioxane, 16 h, 120 °C
0
3
4
Scheme-I
TABLE-1
ANTIBACTERIAL ACTIVITY (MIC IN µg/mL) AND ANTIFUNGAL ACTIVITY (ZONE OF INHIBITION IN mm AT 100 µg/mL) OF 6a-f
Antibacterial strains
Antifungal strains
Compd.
a
a
a
b
c
c
B. subtilis
180
125
210
120
150
90
S. aureus
M. luteus
E. coli
C. albicans
A. fumigatus
d
d
d
d
6
6
a
b
–
–
10
–
–
–
d
d
d
180
270
150
180
150
120
–
240
–
180
–
150
150
–
–
–
d
d
6
c
120
240
180
15
-
–
6
d
5
d
d
d
6
e
–
–
d
6
f
–
10
–
–
5
–
–
Ampicillin
Amphotericin-B
60
–
120
–
a
b
Gram-positive bacteria: Bacillus subtilis MTCC 2415, Staphylococcus aureus MTCC 9886 and Micrococcus luteus MTCC 1538; Gram-negative
bacteria: Escherichia coli MTCC 448. Yeasts: Candida albicans ATCC 1369 and Aspergillus fumigates MTCC 9657.
c
4
5
.
.
C.G. Mortimer, G. Wells, J.-P. Crochard, E.L. Stone, T.D. Bradshaw,
M.F.G. Stevens and A.D. Westwell, J. Med. Chem., 49, 179 (2006).
B. Soni, M.S. Ranawat, R. Sharma, A. Bhandari and S. Sharma, Eur. J.
Med. Chem., 45, 2938 (2010).
compounds have shown mild to potent inhibitory activity
against B. subtilis and exhibited mild to moderate antibacterial
activities against the other tested organisms (Table-1). Comp-
ounds 6b, 6c and 6f were found to be the most active against
most of the tested organisms. Some of the compounds have
shown significant antibacterial activity in comparison to the
controls. This novel class of new benzothiazole/benzimidazole
pyridine imidazole derivatives reported to have a great probability
to emerge as a valuable lead series to be used as antibacterial
agent and as promising candidates for further evaluation.
Further studies on the structural modification of bioactive
scaffold to get more efficient antibacterial agents are underway
in our program.
6. B. Soni, M.S. Ranawat, R. Sharma, A. Bhandari and S. Sharma, Eur. J.
Med. Chem., 45, 2938 (2010).
7
.
F.W. Bell, A.S. Cantrell, M. Hoegberg, S.R. Jaskunas, N.G. Johansson,
C.L. Jordan, M.D. Kinnick, P. Lind and J.M. Morin, J. Med. Chem.,
3
8, 4929 (1995).
8. R.L. Mital and S.K. Jain, J. Chem. Soc. C, 2148 (1969).
9
.
W.C. Patt, H.W. Hamilton, M.D. Taylor, M.J. Ryan, D.G. Taylor, C.J.C.
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1
1
1
1
0. M.T. Migawa, J.-L. Girardet, J.A. Walker, G.W. Koszalka, S.D. Cham-
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