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